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1
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Salem FM, Martin WR, Zhao X, Adbus Sayeed SK, Ighneim S, Greene M, Mohamed E, Orahoske CM, Zhang W, Li B, Su B. Synthesis and biological evaluation of orally active anti-Trypanosoma agents. Bioorg Med Chem 2024; 107:117751. [PMID: 38762979 DOI: 10.1016/j.bmc.2024.117751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/01/2024] [Accepted: 05/06/2024] [Indexed: 05/21/2024]
Abstract
In previous studies, we developed anti-trypanosome tubulin inhibitors with promising in vitro selectivity and activity against Human African Trypanosomiasis (HAT). However, for such agents, oral activity is crucial. This study focused on further optimizing these compounds to enhance their ligand efficiency, aiming to reduce bulkiness and hydrophobicity, which should improve solubility and, consequently, oral bioavailability. Using Trypanosoma brucei brucei cells as the parasite model and human normal kidney cells and mouse macrophage cells as the host model, we evaluated 30 new analogs synthesized through combinatorial chemistry. These analogs have fewer aromatic moieties and lower molecular weights than their predecessors. Several new analogs demonstrated IC50s in the low micromolar range, effectively inhibiting trypanosome cell growth without harming mammalian cells at the same concentration. We conducted a detailed structure-activity relationship (SAR) analysis and a docking study to assess the compounds' binding affinity to trypanosome tubulin homolog. The results revealed a correlation between binding energy and anti-Trypanosoma activity. Importantly, compound 7 displayed significant oral activity, effectively inhibiting trypanosome cell proliferation in mice.
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Affiliation(s)
- Fatma M Salem
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - William R Martin
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA; Genomic Medicine Institute, Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Xiaotong Zhao
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - S K Adbus Sayeed
- Department of Biology, Geo. & Env. Sciences, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Sabreena Ighneim
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - McKenna Greene
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Eman Mohamed
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Cody M Orahoske
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Wenjing Zhang
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Bibo Li
- Department of Biology, Geo. & Env. Sciences, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
| | - Bin Su
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Arts and Sciences, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
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2
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González-Matos M, Aguado ME, Izquierdo M, Monzote L, González-Bacerio J. Compounds with potentialities as novel chemotherapeutic agents in leishmaniasis at preclinical level. Exp Parasitol 2024; 260:108747. [PMID: 38518969 DOI: 10.1016/j.exppara.2024.108747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/27/2024] [Accepted: 03/19/2024] [Indexed: 03/24/2024]
Abstract
Leishmaniasis are neglected infectious diseases caused by kinetoplastid protozoan parasites from the genus Leishmania. These sicknesses are present mainly in tropical regions and almost 1 million new cases are reported each year. The absence of vaccines, as well as the high cost, toxicity or resistance to the current drugs determines the necessity of new treatments against these pathologies. In this review, several compounds with potentialities as new antileishmanial drugs are presented. The discussion is restricted to the preclinical level and molecules are organized according to their chemical nature, source and molecular targets. In this manner, we present antimicrobial peptides, flavonoids, withanolides, 8-aminoquinolines, compounds from Leish-Box, pyrazolopyrimidines, and inhibitors of tubulin polymerization/depolymerization, topoisomerase IB, proteases, pteridine reductase, N-myristoyltransferase, as well as enzymes involved in polyamine metabolism, response against oxidative stress, signaling pathways, and sterol biosynthesis. This work is a contribution to the general knowledge of these compounds as antileishmanial agents.
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Affiliation(s)
- Maikel González-Matos
- Center for Protein Studies, Faculty of Biology, University of Havana, Calle 25 #455 Entre I y J, Vedado, La Habana, Cuba
| | - Mirtha Elisa Aguado
- Center for Protein Studies, Faculty of Biology, University of Havana, Calle 25 #455 Entre I y J, Vedado, La Habana, Cuba
| | - Maikel Izquierdo
- Center for Protein Studies, Faculty of Biology, University of Havana, Calle 25 #455 Entre I y J, Vedado, La Habana, Cuba
| | - Lianet Monzote
- Department of Parasitology, Center for Research, Diagnosis and Reference, Tropical Medicine Institute "Pedro Kourí", Autopista Novia Del Mediodía Km 6½, La Lisa, La Habana, Cuba.
| | - Jorge González-Bacerio
- Center for Protein Studies, Faculty of Biology, University of Havana, Calle 25 #455 Entre I y J, Vedado, La Habana, Cuba; Department of Biochemistry, Faculty of Biology, University of Havana, Calle 25 #455 Entre I y J, Vedado, La Habana, Cuba.
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3
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Monti L, Liu LJ, Varricchio C, Lucero B, Alle T, Yang W, Bem-Shalom I, Gilson M, Brunden KR, Brancale A, Caffrey CR, Ballatore C. Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5-a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis. ChemMedChem 2023; 18:e202300193. [PMID: 37429821 PMCID: PMC10615688 DOI: 10.1002/cmdc.202300193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 07/08/2023] [Accepted: 07/10/2023] [Indexed: 07/12/2023]
Abstract
Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT-active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for in vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T. brucei-infected mice with tolerable doses of TPDs significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses at 10 mg/kg of a candidate TPD significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.
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Affiliation(s)
- Ludovica Monti
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA
- Present affiliation: Chemistry Department, Molecular Sciences Research Hub, Imperial College London, 82 Wood Lane, W12 0BZ, London, UK
| | - Lawrence J Liu
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA
| | - Carmine Varricchio
- Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF103NB, Cardiff, UK
| | - Bobby Lucero
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA
- Department of Chemistry & Biochemistry, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA
| | - Thibault Alle
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA
| | - Wenqian Yang
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA
| | - Ido Bem-Shalom
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA
| | - Michael Gilson
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA
| | - Kurt R Brunden
- Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, 19104-6323, Philadelphia, PA, USA
| | - Andrea Brancale
- Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF103NB, Cardiff, UK
- Present affiliation: Vysoká škola chemicko-technologická v Praze, Department of Organic Chemistry, Technická 5, 16628, Prague 6, Czech Republic
| | - Conor R Caffrey
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA
| | - Carlo Ballatore
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA
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Ríos-Valencia DG, Ambrosio J, Tirado-Mendoza R, Carrero JC, Laclette JP. What about the Cytoskeletal and Related Proteins of Tapeworms in the Host's Immune Response? An Integrative Overview. Pathogens 2023; 12:840. [PMID: 37375530 DOI: 10.3390/pathogens12060840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/09/2023] [Accepted: 06/11/2023] [Indexed: 06/29/2023] Open
Abstract
Recent advances have increased our understanding of the molecular machinery in the cytoskeleton of mammalian cells, in contrast to the case of tapeworm parasites, where cytoskeleton remains poorly characterized. The pertinence of a better knowledge of the tapeworm cytoskeleton is linked to the medical importance of these parasitic diseases in humans and animal stock. Moreover, its study could offer new possibilities for the development of more effective anti-parasitic drugs, as well as better strategies for their surveillance, prevention, and control. In the present review, we compile the results of recent experiments on the cytoskeleton of these parasites and analyze how these novel findings might trigger the development of new drugs or the redesign of those currently used in addition to supporting their use as biomarkers in cutting-edge diagnostic tests.
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Affiliation(s)
- Diana G Ríos-Valencia
- Department of Microbiology and Parasitology, School of Medicine, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México 04510, Mexico
| | - Javier Ambrosio
- Department of Microbiology and Parasitology, School of Medicine, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México 04510, Mexico
| | - Rocío Tirado-Mendoza
- Department of Microbiology and Parasitology, School of Medicine, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México 04510, Mexico
| | - Julio César Carrero
- Department of Immunology, Biomedical Research Institute, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México 04510, Mexico
| | - Juan Pedro Laclette
- Department of Immunology, Biomedical Research Institute, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México 04510, Mexico
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5
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Monti L, Liu LJ, Varricchio C, Lucero B, Alle T, Yang W, Bem-Shalom I, Gilson M, Brunden KR, Brancale A, Caffrey CR, Ballatore C. Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5- a ]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.11.532093. [PMID: 36945407 PMCID: PMC10028969 DOI: 10.1101/2023.03.11.532093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT- active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for in vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T. brucei -infected mice with tolerable doses of TPDs 3 and 4 significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses of 4 at 10 mg/kg significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.
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6
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Carvalho LL, Bittencourt Pena R, Correia Romeiro N, Nepomuceno‐Silva JL. A Concise Synthesis of Triazole Analogues of Lavendustin A via Click Chemistry Approach and Preliminary Evaluation of Their Antiparasitic Activity Against
Trypanosoma cruzi. ChemistrySelect 2022. [DOI: 10.1002/slct.202200128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Leandro Lara Carvalho
- Laboratory of Catalysis and Synthesis of Bioactive Substances (LACASB) Federal University of Rio de Janeiro (UFRJ) – Campus Macaé Imburo Road, No Number, Ajuda de Baixo 27979-000 Macaé RJ Brazil
| | - Raynná Bittencourt Pena
- Laboratory of Catalysis and Synthesis of Bioactive Substances (LACASB) Federal University of Rio de Janeiro (UFRJ) – Campus Macaé Imburo Road, No Number, Ajuda de Baixo 27979-000 Macaé RJ Brazil
- Integrated Laboratory of Scientific Computing (LICC) Federal University of Rio de Janeiro (UFRJ) – Campus Macaé Aluizio da Silva Gomes Avenue, 50, Granja dos Cavaleiros 27930-560 Macaé RJ Brazil
| | - Nelilma Correia Romeiro
- Integrated Laboratory of Scientific Computing (LICC) Federal University of Rio de Janeiro (UFRJ) – Campus Macaé Aluizio da Silva Gomes Avenue, 50, Granja dos Cavaleiros 27930-560 Macaé RJ Brazil
| | - José Luciano Nepomuceno‐Silva
- Hatisaburo Masuda Integrated Laboratory of Biochemistry (LIBHM) Institute of Biodiversity and Sustainability (NUPEM) Federal University of Rio de Janeiro (UFRJ) São José do Barreto Avenue, 764, Barreto 27965-550 Macaé RJ Brazil
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Monti L, Cornec AS, Oukoloff K, Kovalevich J, Prijs K, Alle T, Brunden KR, Smith AB, El-Sakkary N, Liu LJ, Syed A, Skinner DE, Ballatore C, Caffrey CR. Congeners Derived from Microtubule-Active Phenylpyrimidines Produce a Potent and Long-Lasting Paralysis of Schistosoma mansoni In Vitro. ACS Infect Dis 2021; 7:1089-1103. [PMID: 33135408 DOI: 10.1021/acsinfecdis.0c00508] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Schistosomiasis is a parasitic disease that affects approximately 200 million people in developing countries. Current treatment relies on just one partially effective drug, and new drugs are needed. Tubulin and microtubules (MTs) are essential constituents of the cytoskeleton in all eukaryotic cells and considered potential drug targets to treat parasitic infections. The α- and β-tubulin of Schistosoma mansoni have ∼96% and ∼91% sequence identity to their respective human tubulins, suggesting that compounds which bind mammalian tubulin may interfere with MT-mediated functions in the parasite. To explore the potential of different classes of tubulin-binding molecules as antischistosomal leads, we completed a series of in vitro whole-organism screens of a target-based compound library against S. mansoni adults and somules (postinfective larvae), and identified multiple biologically active compounds, among which phenylpyrimidines were the most promising. Further structure-activity relationship studies of these hits identified a series of thiophen-2-yl-pyrimidine congeners, which induce a potent and long-lasting paralysis of the parasite. Moreover, compared to the originating compounds, which showed cytotoxicity values in the low nanomolar range, these new derivatives were 1-4 orders of magnitude less cytotoxic and exhibited weak or undetectable activity against mammalian MTs in a cell-based assay of MT stabilization. Given their selective antischistosomal activity and relatively simple drug-like structures, these molecules hold promise as candidates for the development of new treatments for schistosomiasis.
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Affiliation(s)
- Ludovica Monti
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Anne-Sophie Cornec
- Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, Pennsylvania 19104-6323, United States
| | - Killian Oukoloff
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Jane Kovalevich
- Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104-6323, United States
| | - Kristen Prijs
- Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104-6323, United States
| | - Thibault Alle
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Kurt R. Brunden
- Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, Pennsylvania 19104-6323, United States
| | - Amos B. Smith
- Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, Pennsylvania 19104-6323, United States
| | - Nelly El-Sakkary
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Lawrence J. Liu
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Ali Syed
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Danielle E. Skinner
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Carlo Ballatore
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
| | - Conor R. Caffrey
- Center for Discovery and Innovation in Parasitic Diseases (CDIPD), Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States
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Ullah I, Gahalawat S, Booshehri LM, Niederstrasser H, Majumdar S, Leija C, Bradford JM, Hu B, Ready JM, Wetzel DM. An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box Promotes Leishmania Tubulin Polymerization. ACS Infect Dis 2020; 6:2057-2072. [PMID: 32686409 PMCID: PMC8059355 DOI: 10.1021/acsinfecdis.0c00122] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The few frontline antileishmanial drugs are poorly effective and toxic. To search for new drugs for this neglected tropical disease, we tested the activity of compounds in the Medicines for Malaria Venture (MMV) "Pathogen Box" against Leishmania amazonensis axenic amastigotes. Screening yielded six discovery antileishmanial compounds with EC50 values from 50 to 480 nM. Concentration-response assays demonstrated that the best hit, MMV676477, had mid-nanomolar cytocidal potency against intracellular Leishmania amastigotes, Trypanosoma brucei, and Plasmodium falciparum, suggesting broad antiparasitic activity. We explored structure-activity relationships (SAR) within a small group of MMV676477 analogs and observed a wide potency range (20-5000 nM) against axenic Leishmania amastigotes. Compared to MMV676477, our most potent analog, SW41, had ∼5-fold improved antileishmanial potency. Multiple lines of evidence suggest that MMV676477 selectively disrupts Leishmania tubulin dynamics. Morphological studies indicated that MMV676477 and analogs affected L. amazonensis during cell division. Differential centrifugation showed that MMV676477 promoted partitioning of cellular tubulin toward the polymeric form in parasites. Turbidity assays with purified Leishmania and porcine tubulin demonstrated that MMV676477 promoted leishmanial tubulin polymerization in a concentration-dependent manner. Analogs' antiparasitic activity correlated with their ability to facilitate purified Leishmania tubulin polymerization. Chemical cross-linking demonstrated binding of the MMV676477 scaffold to purified Leishmania tubulin, and competition studies established a correlation between binding and antileishmanial activity. Our studies demonstrate that MMV676477 is a potent antiparasitic compound that preferentially promotes Leishmania microtubule polymerization. Due to its selectivity for and broad-spectrum activity against multiple parasites, this scaffold shows promise for antiparasitic drug development.
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Affiliation(s)
- Imran Ullah
- Department of Pediatrics and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Suraksha Gahalawat
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Laela M. Booshehri
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Hanspeter Niederstrasser
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Shreoshi Majumdar
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Christopher Leija
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - James M. Bradford
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Bin Hu
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Joseph M. Ready
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Dawn M. Wetzel
- Department of Pediatrics and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
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Pinheiro S, Pinheiro EMC, Muri EMF, Pessôa JC, Cadorini MA, Greco SJ. Biological activities of [1,2,4]triazolo[1,5-a]pyrimidines and analogs. Med Chem Res 2020. [DOI: 10.1007/s00044-020-02609-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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10
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Zhao A, Li Y, Orahoske CM, Schnur B, Sabbagh A, Zhang W, Li B, Su B. Lead optimization of selective tubulin inhibitors as anti-trypanosomal agents. Bioorg Med Chem 2019; 27:1517-1528. [PMID: 30833159 DOI: 10.1016/j.bmc.2019.02.049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 02/15/2019] [Accepted: 02/22/2019] [Indexed: 12/16/2022]
Abstract
Previously synthesized tubulin inhibitors showed promising in vitro selectivity and activity against Human African Trypanosomiasis. Current aim is to improve the ligand efficiency and reduce overall hydrophobicity of the compounds, by lead optimization. Via combinatorial chemistry, 60 new analogs were synthesized. For biological assay Trypanosoma brucei brucei Lister 427 cell line were used as the parasite model and for the host model human embryonic kidney cell line HEK-293 and mouse macrophage cell line RAW 264.7 were used to test efficacy. Of the newly synthesized compounds 5, 39, 40, and 57 exhibited IC50s below 5 µM inhibiting the growth of trypanosome cells and not harming the mammalian cells at equipotent concentration. Comparably, the newly synthesized compounds have a reduced amount of aromatic moieties resulting in a decrease in molecular weight. Due to importance of tubulin polymerization during protozoan life cycle its activity was assessed by western blot analyses. Our results indicated that compound 5 had a profound effect on tubulin function. A detailed structure activity relationship (SAR) was summarized that will be used to guide future lead optimization.
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Affiliation(s)
- Anran Zhao
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Yaxin Li
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Cody M Orahoske
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Brittny Schnur
- Department of Biology, Geo. & Env. Sciences, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Abboud Sabbagh
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Wenjing Zhang
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Bibo Li
- Department of Biology, Geo. & Env. Sciences, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
| | - Bin Su
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
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11
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Ramirez-Barrios R, Reyna-Bello A, Parra O, Valeris R, Tavares-Marques L, Brizard JP, Demettre E, Seveno M, Martinez-Moreno A, Holzmuller P. Trypanosoma vivax infection in sheep: Different patterns of virulence and pathogenicity associated with differentially expressed proteomes. Vet Parasitol 2019; 276S:100014. [PMID: 32904712 PMCID: PMC7458391 DOI: 10.1016/j.vpoa.2019.100014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 05/22/2019] [Accepted: 05/27/2019] [Indexed: 11/18/2022]
Abstract
Trypanosoma vivax strains exhibit different virulence and pathogenicity patterns. TvMT1 strain showed low virulence and high pathogenicity. TvLIEM176 strain showed high virulence and moderate pathogenicity. Protein expression varies in high virulence/moderate pathogenicity strain vs low virulence/high pathogenicity strain. Cattle trypanosomosis caused by Trypanosoma vivax is a widely distributed disease in Africa and Latin America. It causes significant losses in the livestock industry and is characterized by fluctuating parasitemia, anemia, fever, lethargy, and weight loss. In this study we evaluated the virulence (capacity to multiply inside the host and to modulate the host response) and pathogenicity (ability to produce disease and/or mortality) patterns of two T. vivax strains (TvMT1 and TvLIEM176) in experimentally-infected sheep and determined the proteins differentially expressed in the proteomes of these two strains. Hematological and clinical parameters were monitored in experimentally-infected versus non-infected sheep for 60 days. All the infected animals developed discernable parasitemia at 3 days post-infection (dpi), and the first parasitemia peak was observed at 6 dpi. The maximum average value of parasitemia was 1.3 × 107 (95% CI, 7.9 × 105–2 × 108) parasites/ml in TvLIEM176-infected animals, and 2.5 × 106 (95% CI, 1.6 × 105–4 × 107) parasites/ml in TvMT1-infected ones. Anemia and clinical manifestations were more severe in the animals infected by TvMT1 strain than in those infected by TvLIEM176. In the proteomic analysis, a total of 29 proteins were identified, of which 14 exhibited significant differences in their expression levels between strains. Proteins with higher expression in TvLIEM176 were: alpha tubulin, beta tubulin, arginine kinase, glucose-regulated protein 78, paraflagellar protein 3, and T-complex protein 1 subunit theta. Proteins with higher expression in TvMT1 were: chaperonin HSP60, T-complex protein 1 subunit alpha, heat shock protein 70, pyruvate kinase, glycerol kinase, inosine-5'-monophosphate dehydrogenase, 73 kDa paraflagellar rod protein, and vacuolar ATP synthase. There was a difference in the virulence and pathogenicity between the T. vivax strains: TvLIEM176 showed high virulence and moderate pathogenicity, whereas TvMT1 showed low virulence and high pathogenicity. The proteins identified in this study are discussed for their potential involvement in strains’ virulence and pathogenicity, to be further defined as biomarkers of severity in T. vivax infections.
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12
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Liu C, Yao J, Yin J, Xue J, Zhang H. Recombinant α- and β-tubulin from Echinococcus granulosus: expression, purification and polymerization. ACTA ACUST UNITED AC 2018; 25:62. [PMID: 30516131 PMCID: PMC6280675 DOI: 10.1051/parasite/2018063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 11/19/2018] [Indexed: 12/29/2022]
Abstract
Echinococcosis, which causes a high disease burden and is of great public health significance, is caused by the larval stage of Echinococcus species. It has been suggested that tubulin is the target of benzimidazoles, the only drugs for the treatment of echinococcosis. This study evaluated the characteristics of tubulins from Echinococcus granulosus. The full-length cDNAs of E. granulosus α- and β-tubulin isoforms were cloned by reverse transcription PCR from protoscolex RNA. Then, these two tubulin isoforms (α9 and β4) were recombinantly expressed as insoluble inclusion bodies in Escherichia coli. Nickel affinity chromatography was used to purify and refold the contents of these inclusion bodies as active proteins. The polymerization of tubulins was monitored by UV spectrophotometry (A350) and confirmed by confocal microscopy and transmission electron microscopy (TEM). Nucleotide sequence analysis revealed that E. granulosus 1356 bp α9-tubulin and 1332 bp β4-tubulin encode corresponding proteins of 451 and 443 amino acids. The average yields of α9- and β4-tubulin were 2.0–3.0 mg/L and 3.5–5.0 mg/L of culture, respectively. Moreover, recombinant α9- and β4-tubulin were capable of polymerizing into microtubule-like structures under appropriate conditions in vitro. These recombinant tubulins could be helpful for screening anti-Echinococcus compounds targeting the tubulins of E. granulosus.
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Affiliation(s)
- Congshan Liu
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Laboratory of Parasite and Vector Biology, MOH, National Center for International Research on Tropical Diseases, WHO Collaborating Centre for Tropical Diseases, Shanghai 200025, People's Republic of China
| | - Jiaqing Yao
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Laboratory of Parasite and Vector Biology, MOH, National Center for International Research on Tropical Diseases, WHO Collaborating Centre for Tropical Diseases, Shanghai 200025, People's Republic of China
| | - Jianhai Yin
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Laboratory of Parasite and Vector Biology, MOH, National Center for International Research on Tropical Diseases, WHO Collaborating Centre for Tropical Diseases, Shanghai 200025, People's Republic of China
| | - Jian Xue
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Laboratory of Parasite and Vector Biology, MOH, National Center for International Research on Tropical Diseases, WHO Collaborating Centre for Tropical Diseases, Shanghai 200025, People's Republic of China
| | - Haobing Zhang
- National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Laboratory of Parasite and Vector Biology, MOH, National Center for International Research on Tropical Diseases, WHO Collaborating Centre for Tropical Diseases, Shanghai 200025, People's Republic of China
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13
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Vicente-Blázquez A, González M, Álvarez R, Del Mazo S, Medarde M, Peláez R. Antitubulin sulfonamides: The successful combination of an established drug class and a multifaceted target. Med Res Rev 2018; 39:775-830. [PMID: 30362234 DOI: 10.1002/med.21541] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 09/02/2018] [Accepted: 09/06/2018] [Indexed: 12/13/2022]
Abstract
Tubulin, the microtubules and their dynamic behavior are amongst the most successful antitumor, antifungal, antiparasitic, and herbicidal drug targets. Sulfonamides are exemplary drugs with applications in the clinic, in veterinary and in the agrochemical industry. This review summarizes the actual state and recent progress of both fields looking from the double point of view of the target and its drugs, with special focus onto the structural aspects. The article starts with a brief description of tubulin structure and its dynamic assembly and disassembly into microtubules and other polymers. Posttranslational modifications and the many cellular means of regulating and modulating tubulin's biology are briefly presented in the tubulin code. Next, the structurally characterized drug binding sites, their occupying drugs and the effects they induce are described, emphasizing on the structural requirements for high potency, selectivity, and low toxicity. The second part starts with a summary of the favorable and highly tunable combination of physical-chemical and biological properties that render sulfonamides a prototypical example of privileged scaffolds with representatives in many therapeutic areas. A complete description of tubulin-binding sulfonamides is provided, covering the different species and drug sites. Some of the antimitotic sulfonamides have met with very successful applications and others less so, thus illustrating the advances, limitations, and future perspectives of the field. All of them combine in a mechanism of action and a clinical outcome that conform efficient drugs.
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Affiliation(s)
- Alba Vicente-Blázquez
- Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Laboratory of Cell Death and Cancer Therapy, Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Myriam González
- Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain
| | - Raquel Álvarez
- Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain
| | - Sara Del Mazo
- Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain
| | - Manuel Medarde
- Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain
| | - Rafael Peláez
- Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.,Facultad de Farmacia, Centro de Investigación de Enfermedades Tropicales de la Universidad de Salamanca (CIETUS), Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain
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14
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Monti L, Wang SC, Oukoloff K, Smith AB, Brunden KR, Caffrey CR, Ballatore C. Brain-Penetrant Triazolopyrimidine and Phenylpyrimidine Microtubule Stabilizers as Potential Leads to Treat Human African Trypanosomiasis. ChemMedChem 2018; 13:1751-1754. [PMID: 29969537 DOI: 10.1002/cmdc.201800404] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Indexed: 11/07/2022]
Abstract
In vitro whole-organism screens of Trypanosoma brucei with representative examples of brain-penetrant microtubule (MT)-stabilizing agents identified lethal triazolopyrimidines and phenylpyrimidines with sub-micromolar potency. In mammalian cells, these antiproliferative compounds disrupt MT integrity and decrease total tubulin levels. Their parasiticidal potency, combined with their generally favorable pharmacokinetic properties, which include oral bioavailability and brain penetration, suggest that these compounds are potential leads against human African trypanosomiasis.
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Affiliation(s)
- Ludovica Monti
- Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Steven C Wang
- Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Killian Oukoloff
- Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Amos B Smith
- Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA, 19104-6323, USA
| | - Kurt R Brunden
- Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA, 19104-6323, USA
| | - Conor R Caffrey
- Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Carlo Ballatore
- Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
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15
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Casino AD, Lukinović V, Bhatt R, Randle LE, Dascombe MJ, Fennell DBJ, Drew MGB, Bell A, Fielding AJ, Ismail FMD. Synthesis, Structural Determination, and Pharmacology of Putative Dinitroaniline Antimalarials. ChemistrySelect 2018. [DOI: 10.1002/slct.201801723] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Alessio del Casino
- School of Pharmacy and Biomolecular SciencesLiverpool John Moores University Byrom Street, Liverpool L3 3AF United Kingdom
| | - Valentina Lukinović
- School of Chemistry and the Photon Science InstituteThe University of Manchester, Manchester M13 9PL United Kingdom
| | - Rakesh Bhatt
- Henkel Loctite Adhesives LtdKelsey House, Wood Lane End Hemel Hempstead, Herts HP2 4RQ United Kingdom
| | - Laura E. Randle
- School of Pharmacy and Biomolecular SciencesLiverpool John Moores University Byrom Street, Liverpool L3 3AF United Kingdom
| | - Michael J. Dascombe
- Faculty of BiologyMedicine and HealthStopford Building The University of Manchester Oxford Road, Manchester M13 9PT United Kingdom
| | - Dr Brian J. Fennell
- School of Genetics and MicrobiologyMoyne InstituteTrinity College, Dublin 2 Ireland
| | - Michael G. B. Drew
- Department of ChemistryUniversity of Reading, Reading, Berks, RG6 6AD United Kingdom
| | - Angus Bell
- School of Genetics and MicrobiologyMoyne InstituteTrinity College, Dublin 2 Ireland
| | - Alistair J. Fielding
- School of Pharmacy and Biomolecular SciencesLiverpool John Moores University Byrom Street, Liverpool L3 3AF United Kingdom
| | - Fyaz M. D. Ismail
- School of Pharmacy and Biomolecular SciencesLiverpool John Moores University Byrom Street, Liverpool L3 3AF United Kingdom
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16
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Choudhary S, Singh PK, Verma H, Singh H, Silakari O. Success stories of natural product-based hybrid molecules for multi-factorial diseases. Eur J Med Chem 2018; 151:62-97. [PMID: 29605809 DOI: 10.1016/j.ejmech.2018.03.057] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 03/19/2018] [Accepted: 03/20/2018] [Indexed: 12/18/2022]
Abstract
Complex diseases comprises of highly complicated etiology resulting in limited applicability of conventional targeted therapies. Consequently, conventional medicinal compounds suffer major failure when used for such disease conditions. Additionally, development of multidrug resistance (MDR), adverse drug reactions and clinical specificity of single targeted drug therapy has increased thrust for novel drug therapy. In this rapidly evolving era, natural product-based discovery of hybrid molecules or multi-targeted drug therapies have shown promising results and are trending now a days. Historically, nature has blessed human with different sources viz. plant, animal, microbial, marine and ethnopharmaceutical sources which has given a wide variety of medicinally active compounds. These compounds from natural origin are always choice of interest of medicinal chemists because of their minimum side effects. Hybrid molecules synthesized by fusing or conjugating different active molecules obtained from these sources are reported to synergistically block different pathways which contribute in the pathogenesis of complex diseases. This review strives to encompass all natural product-derived hybrid molecules which act as multi-targeting agents striking various targets involved in different pathways of complex diseased conditions reported in literature.
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Affiliation(s)
- Shalki Choudhary
- Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug research, Punjabi University, Patiala, Punjab, 147002, India
| | - Pankaj Kumar Singh
- Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug research, Punjabi University, Patiala, Punjab, 147002, India
| | - Himanshu Verma
- Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug research, Punjabi University, Patiala, Punjab, 147002, India
| | | | - Om Silakari
- Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug research, Punjabi University, Patiala, Punjab, 147002, India.
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17
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G Silva M, Knowles DP, Antunes S, Domingos A, Esteves MA, Suarez CE. Inhibition of the in vitro growth of Babesia bigemina, Babesia caballi and Theileria equi parasites by trifluralin analogues. Ticks Tick Borne Dis 2017; 8:593-597. [PMID: 28416183 DOI: 10.1016/j.ttbdis.2017.04.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 03/31/2017] [Accepted: 04/04/2017] [Indexed: 10/19/2022]
Abstract
Bovine and equine babesiosis caused by Babesia bovis, Babesia bigemina and Babesia caballi, along with equine theileriosis caused by Theileria equi are global tick-borne hemoprotozoan diseases characterized by fever, anemia, weight losses and abortions. A common feature of these diseases are transition from acute to chronic phases, in which parasites may persist in the hosts for life. Antiprotozoal drugs are important for managing infection and disease. Previous research demonstrated that trifluralin analogues, designated (TFLAs) 1-15, which specifically bind to regions of alpha-tubulin protein in plants and protozoan parasites, have the ability to inhibit the in vitro growth of B. bovis. The inhibitory activity of TFLAs 1-15 minus TFLA 5 was tested in vitro against cultured B. bigemina, B. caballi and T. equi. The four TFLAs with greatest inhibitory activity were then analyzed for hemolytic activity and toxicity against erythrocytes. All TFLAs tested in the study showed inhibitory effects against the three parasite species. TFLA 2, TFLA 11, TFLA 13 and TFLA 14 were the most effective inhibitors for the three species tested, with estimated IC50 between 5.1 and 10.1μM at 72h. The drug's solvent (DMSO/ethanol) did not statistically affect the growth of the parasites nor cause hemolysis. Also, TFLA 2, 13 and 14 did not cause statistically significant hemolytic activity on bovine and equine erythrocytes at 15μM, and TFLA 2, 11 and 13 had no detectable toxic effects on bovine and equine erythrocytes at 15μM, suggesting that these drugs do not compromise erythrocyte viability. The demonstrated ability of the trifluralin analogues to inhibit in vitro growth of Babesia spp. and Theileria equi, and their lack of toxic effects on erythrocytes supports further in vivo testing and eventually their development as novel alternatives for the treatment of babesiosis and theileriosis.
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Affiliation(s)
- Marta G Silva
- Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164-7040, USA.
| | - Donald P Knowles
- Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164-7040, USA; Animal Disease Research Unit, USDA-ARS, 3003 ADBF, WSU, Pullman, WA, 99163-6630, USA.
| | - Sandra Antunes
- Global Health and Tropical Medicine, Instituto de Higiene e Medicina Tropical, Rua da Junqueira 100, 1349-008 Lisboa, Portugal.
| | - Ana Domingos
- Global Health and Tropical Medicine, Instituto de Higiene e Medicina Tropical, Rua da Junqueira 100, 1349-008 Lisboa, Portugal.
| | - Maria A Esteves
- Laboratório Nacional de Energia e Geologia, LNEG, Paço do Lumiar, 22, 1649-038 Lisboa, Portugal.
| | - Carlos E Suarez
- Animal Disease Research Unit, USDA-ARS, 3003 ADBF, WSU, Pullman, WA, 99163-6630, USA.
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18
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Bobba V, Nanavaty V, Idippily ND, Zhao A, Li B, Su B. Synthesis and biological evaluation of selective tubulin inhibitors as anti-trypanosomal agents. Bioorg Med Chem 2017; 25:3215-3222. [PMID: 28428042 DOI: 10.1016/j.bmc.2017.04.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 03/30/2017] [Accepted: 04/05/2017] [Indexed: 11/28/2022]
Abstract
African trypanosomiasis is still a threat to human health due to the severe side-effects of current drugs. We identified selective tubulin inhibitors that showed the promise to the treatment of this disease, which was based on the tubulin protein structural difference between mammalian and trypanosome cells. Further lead optimization was performed in the current study to improve the efficiency of the drug candidates. We used Trypanosoma brucei brucei cells as the parasite model, and human normal kidney cells and mouse macrophage cells as the host model to evaluate the compounds. One new analog showed great potency with an IC50 of 70nM to inhibit the growth of trypanosome cells and did not affect the viability of mammalian cells. Western blot analyses reveal that the compound decreased tubulin polymerization in T. brucei cells. A detailed structure activity relationship (SAR) was summarized that will be used to guide future lead optimization.
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Affiliation(s)
- Viharika Bobba
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Vishal Nanavaty
- Department of Biology, Geo. & Env. Sciences, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Nethrie D Idippily
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Anran Zhao
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Bibo Li
- Department of Biology, Geo. & Env. Sciences, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
| | - Bin Su
- Department of Chemistry, Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
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19
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Sueth-Santiago V, Decote-Ricardo D, Morrot A, Freire-de-Lima CG, Lima MEF. Challenges in the chemotherapy of Chagas disease: Looking for possibilities related to the differences and similarities between the parasite and host. World J Biol Chem 2017; 8:57-80. [PMID: 28289519 PMCID: PMC5329715 DOI: 10.4331/wjbc.v8.i1.57] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 12/30/2016] [Accepted: 01/14/2017] [Indexed: 02/05/2023] Open
Abstract
Almost 110 years after the first studies by Dr. Carlos Chagas describing an infectious disease that was named for him, Chagas disease remains a neglected illness and a death sentence for infected people in poor countries. This short review highlights the enormous need for new studies aimed at the development of novel and more specific drugs to treat chagasic patients. The primary tool for facing this challenge is deep knowledge about the similarities and differences between the parasite and its human host.
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20
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Voggu RR, Zhou X, Su B, Guo B. A Simple and Rapid LC-MS/MS Method for the Determination of BMCL26 a Novel Anti-Parasitic Agent in Rat Plasma. ACTA ACUST UNITED AC 2016; 6. [PMID: 26823991 PMCID: PMC4727756 DOI: 10.4172/2155-9872.1000266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BMCL26 is a potential drug derived from nimesulide, which has exhibited the substantial anti-parasitic activity in various cell lines. To conduct various pharmacological and toxicological properties of this drug, we developed and validated a rapid LC-MS/MS method for its quantification in accordance with the FDA guidelines. Protein precipitation with 0.1% formic acid in acetonitrile was used to extract the analytes along with the internal standard (JCC76) from rat plasma. It was found that the calibration curve of the method had an excellent linearity (r2 ≥ 0.9993) for the analyte concentration ranging from 0.5 to 100 ng/mL with acceptable inter- and intra-assay, precision, accuracy and stability. The matrix effect and extraction recovery were in the range of 101.30-110.10% and 90.16- 105.00%, respectively. This LC-MS/MS method is simple and rapid and can be used in the future pharmaceutical studies of BMCL26.
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Affiliation(s)
| | - Xiang Zhou
- Department of Chemistry, Cleveland State University, USA
| | - Bin Su
- Department of Chemistry, Cleveland State University, USA
| | - Baochuan Guo
- Department of Chemistry, Cleveland State University, USA
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21
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Nanavaty V, Lama R, Sandhu R, Zhong B, Kulman D, Bobba V, Zhao A, Li B, Su B. Orally Active and Selective Tubulin Inhibitors as Anti-Trypanosome Agents. PLoS One 2016; 11:e0146289. [PMID: 26771307 PMCID: PMC4714897 DOI: 10.1371/journal.pone.0146289] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 12/15/2015] [Indexed: 11/21/2022] Open
Abstract
Objectives There is an urgent need to develop a safe, effective, orally active, and inexpensive therapy for African trypanosomiasis due to the drawbacks of current drugs. Selective tubulin inhibitors have the potential to be promising drug candidates for the treatment of this disease, which is based on the tubulin protein structural difference between mammalian and trypanosome cells. We propose to identify novel tubulin inhibitors from a compound library developed based on the lead compounds that selectively target trypanosomiasis. Methods We used Trypanosoma brucei brucei as the parasite model, and human normal kidney cells and mouse microphage cells as the host model. Growth rates of both trypanosomes and mammalian cells were determined as a means to screen compounds that selectively inhibit the proliferation of parasites. Furthermore, we examined the cell cycle profile of the parasite and compared tubulin polymerization dynamics before and after the treatment using identified compounds. Last, in vivo anti-parasite activities of these compounds were determined in T. brucei-infected mice. Results Three compounds were selected that are 100 fold more effective against the growth of T. brucei cells than mammalian cells. These compounds caused cell cycle progression defects in T. brucei cells. Western analyses indicated that these compounds decreased tubulin polymerization in T. brucei cells. The in vivo investigation revealed that these compounds, when admitted orally, inhibited T. brucei cell proliferation in mouse blood. However, they were not potent enough to clear up the infection completely. Conclusions These compounds are promising lead compounds as orally active agents for drug development of anti-trypanosome agents. A more detail structure activity relationship (SAR) was summarized that will be used to guide future lead optimization to improve the selectivity and potency of the current compounds.
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Affiliation(s)
- Vishal Nanavaty
- Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Rati Lama
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Ranjodh Sandhu
- Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Bo Zhong
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Daniel Kulman
- Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Viharika Bobba
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Anran Zhao
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Bibo Li
- Department of Biology, Geo. & Env. Sciences, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.,Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
| | - Bin Su
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America.,Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio, 44115, United States of America
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22
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Vandekerckhove S, D'hooghe M. Quinoline-based antimalarial hybrid compounds. Bioorg Med Chem 2014; 23:5098-119. [PMID: 25593097 DOI: 10.1016/j.bmc.2014.12.018] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 12/03/2014] [Accepted: 12/11/2014] [Indexed: 10/24/2022]
Abstract
Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the Plasmodium parasite against these drugs and the lack of licensed malaria vaccines have forced chemists to develop synthetic strategies toward novel biologically active molecules. A strategy that has attracted considerable attention in current medicinal chemistry is based on the conjugation of two biologically active molecules into one hybrid compound. Since quinolines are considered to be privileged antimalarial building blocks, the synthesis of quinoline-containing antimalarial hybrids has been elaborated extensively in recent years. This review provides a literature overview of antimalarial hybrid molecules containing a quinoline core, covering publications between 2009 and 2014.
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Affiliation(s)
- Stéphanie Vandekerckhove
- SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
| | - Matthias D'hooghe
- SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
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23
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Njogu PM, Gut J, Rosenthal PJ, Chibale K. Design, Synthesis, and Antiplasmodial Activity of Hybrid Compounds Based on (2R,3S)-N-Benzoyl-3-phenylisoserine. ACS Med Chem Lett 2013; 4:637-41. [PMID: 24900723 DOI: 10.1021/ml400164t] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 05/22/2013] [Indexed: 11/28/2022] Open
Abstract
A series of hybrid compounds based on (2R,3S)-N-benzoyl-3-phenylisoserine, artemisinin, and quinoline moieties was synthesized and tested for in vitro antiplasmodial activity against erythrocytic stages of K1 and W2 strains of Plasmodium falciparum. Two hybrid compounds incorporating (2R,3S)-N-benzoyl-3-phenylisoserine and artemisinin scaffolds were 3- to 4-fold more active than dihydroartemisinin, with nanomolar IC50 values against Plasmodium falciparum K1 strain.
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Affiliation(s)
- Peter M. Njogu
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
| | - Jiri Gut
- Department of Medicine, San
Francisco General Hospital, University of California, San Francisco, California 94143, United States
| | - Philip J. Rosenthal
- Department of Medicine, San
Francisco General Hospital, University of California, San Francisco, California 94143, United States
| | - Kelly Chibale
- Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
- Institute of Infectious Disease
and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
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24
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Silva MG, Domingos A, Esteves MA, Cruz MEM, Suarez CE. Evaluation of the growth-inhibitory effect of trifluralin analogues on in vitro cultured Babesia bovis parasites. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE 2013; 3:59-68. [PMID: 24533294 DOI: 10.1016/j.ijpddr.2013.01.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Revised: 01/09/2013] [Accepted: 01/12/2013] [Indexed: 10/27/2022]
Abstract
Bovine babesiosis, caused by Babesia bovis, is a global tick borne hemoprotozoan parasite disease characterized by fever, anemia, weight losses and ultimately death. Several babesicidal drugs that have been in use in cattle for years have proven to be only partially effective and the development of alternative chemotherapeutics that are highly specific and have low toxicity against babesiosis is needed. Trifluralin derivatives specifically bind alpha-tubulin in plants and protozoa parasites causing growth inhibition. A set of 12 trifluralin analogues (TFLA) has previously been shown to be inhibitory for the growth of Leishmania species. The conservation of several key amino acids involved in the trifluralin binding site of alpha-tubulin among Leishmania sp. and B. bovis provides rationale for testing these compounds also as babesiacides. The previously tested Leishmania inhibitory, TFLA 1-12 minus TFLA 5, in addition to three novel TFLA (termed TFLA 13-15), were tested against in vitro cultured B. bovis parasites. While all of the TFLA tested in the study showed inhibition of B. bovis growth in vitro TFLA 7, TFLA 10 and TFLA 13, were the most effective inhibitors with estimated IC50 (μM) at 72 h of 8.5 ± 0.3; 9.2 ± 0.2; 8.9 ± 0.7, respectively for the biologically attenuated cloned B. bovis Mo7 strain, and 13.6 ± 1.5; 18.7 ± 1.6; 10.6 ± 1.9, respectively for the virulent B. bovis T3Bo strain. The differences found between the two strains were not statistically significant. Importantly, these drugs displayed low levels of toxicity for the host erythrocytes and bovine renal arterial endothelial cells at the doses tested. The demonstrated ability of trifluralin analogues to inhibit in vitro growth of B. bovis parasites combined with their low toxicity for host cells suggests that these compounds may be further developed as novel alternatives for the treatment of bovine babesiosis.
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Affiliation(s)
- Marta G Silva
- Animal Disease Research Unit, USDA-ARS, 3003 ADBF, WSU, Pullman, WA 99164-6630, USA ; Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164-7040, USA
| | - Ana Domingos
- Centro de Malária e Outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Rua da Junqueira 100, 1349-008 Lisboa, Portugal
| | - M Alexandra Esteves
- Fuel Cells and Hydrogen Unit, National Laboratory for Energy and Geology, Estrada do Paço do Lumiar, 1649-038 Lisboa, Portugal
| | - Maria E M Cruz
- Unit of New Forms of Bioactive Agents, Faculty of Pharmacy of the University of Lisbon, Estrada do Paço do Lumiar, 1649-038 Lisboa, Portugal
| | - Carlos E Suarez
- Animal Disease Research Unit, USDA-ARS, 3003 ADBF, WSU, Pullman, WA 99164-6630, USA
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25
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Müller J, Hemphill A. New approaches for the identification of drug targets in protozoan parasites. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2013; 301:359-401. [PMID: 23317822 DOI: 10.1016/b978-0-12-407704-1.00007-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
Antiparasitic chemotherapy is an important issue for drug development. Traditionally, novel compounds with antiprotozoan activities have been identified by screening of compound libraries in high-throughput systems. More recently developed approaches employ target-based drug design supported by genomics and proteomics of protozoan parasites. In this chapter, the drug targets in protozoan parasites are reviewed. The gene-expression machinery has been among the first targets for antiparasitic drugs and is still under investigation as a target for novel compounds. Other targets include cytoskeletal proteins, proteins involved in intracellular signaling, membranes, and enzymes participating in intermediary metabolism. In apicomplexan parasites, the apicoplast is a suitable target for established and novel drugs. Some drugs act on multiple subcellular targets. Drugs with nitro groups generate free radicals under anaerobic growth conditions, and drugs with peroxide groups generate radicals under aerobic growth conditions, both affecting multiple cellular pathways. Mefloquine and thiazolides are presented as examples for antiprotozoan compounds with multiple (side) effects. The classic approach of drug discovery employing high-throughput physiological screenings followed by identification of drug targets has yielded the mainstream of current antiprotozoal drugs. Target-based drug design supported by genomics and proteomics of protozoan parasites has not produced any antiparasitic drug so far. The reason for this is discussed and a synthesis of both methods is proposed.
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Affiliation(s)
- Joachim Müller
- Institute of Parasitology, University of Berne, Berne, Switzerland.
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26
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Lama R, Sandhu R, Zhong B, Li B, Su B. Identification of selective tubulin inhibitors as potential anti-trypanosomal agents. Bioorg Med Chem Lett 2012; 22:5508-16. [PMID: 22850214 DOI: 10.1016/j.bmcl.2012.07.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2012] [Revised: 07/05/2012] [Accepted: 07/06/2012] [Indexed: 11/16/2022]
Abstract
The potency of a series of sulfonamide tubulin inhibitors against the growth of Trypanosoma brucei (T. brucei), as well as human cancer and primary fibroblast cells were evaluated with the aim of determining whether compounds that selectively inhibit parasite proliferation could be identified. Several compounds showed excellent selectivity against T. brucei growth, and have the potential to be used for the treatment of Human African trypanosomiasis. A T. brucei tubulin protein homology model was built based on the crystal structure of the bovine tubulin. The colchicine-binding domain, which is also the binding site of the tested sulfonamide tubulin inhibitors, showed clear differences between the tubulin structures and presumably explained the selectivity of the compounds.
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Affiliation(s)
- Rati Lama
- Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA
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27
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Chatterji BP, Jindal B, Srivastava S, Panda D. Microtubules as antifungal and antiparasitic drug targets. Expert Opin Ther Pat 2011; 21:167-86. [PMID: 21204724 DOI: 10.1517/13543776.2011.545349] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Diseases caused by fungi and parasites are major illnesses in humans as well as in animals. Microtubule-targeted drugs are highly effective for the treatment of fungal and parasitic infections; however, several human parasitic infections such as malaria, trypanosomiasis and leishmaniasis do not have effective remedial drugs. In addition, the emergence of drug-resistant fungi and parasites makes the discovery of new drugs imperative. AREAS COVERED This article describes similarities and dissimilarities between parasitic, fungal and mammalian tubulins and focuses on microtubule-targeting agents and therapeutic approaches for the treatment of fungal and parasitic diseases. New microtubule-targeted antileishmanial, antimalarial and antifungal drugs, with structures, biological activities and related patents, are described. The potential of dsRNA against tubulin to inhibit proliferation of protozoan and helminthic parasites is also discussed. Patent documents up to 2010 have been searched on USPTO, Patentscope, and Espacenet resources. EXPERT OPINION The article suggests that vaccination with tubulin may offer novel opportunities for the antiparasitic treatment. Native or recombinant tubulin used as antigen has been shown to elicit immune response and cure infection partially or fully in animals upon challenge by protozoan parasites and helminths, thus indicating the suitability of tubulin as a vaccine against parasitic diseases.
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Affiliation(s)
- Biswa Prasun Chatterji
- Indian Institute of Technology Bombay, Department of Biosciences and Bioengineering, Powai, Mumbai-400076, India
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28
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α-Tubulin mutations alter oryzalin affinity and microtubule assembly properties to confer dinitroaniline resistance. EUKARYOTIC CELL 2010; 9:1825-34. [PMID: 20870876 DOI: 10.1128/ec.00140-10] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Plant and protozoan microtubules are selectively sensitive to dinitroanilines, which do not disrupt vertebrate or fungal microtubules. Tetrahymena thermophila is an abundant source of dinitroaniline-sensitive tubulin, and we have modified the single T. thermophila α-tubulin gene to create strains that solely express mutant α-tubulin in functional dimers. Previous research identified multiple α-tubulin mutations that confer dinitroaniline resistance in the human parasite Toxoplasma gondii, and when two of these mutations (L136F and I252L) were introduced into T. thermophila, they conferred resistance in these free-living ciliates. Purified tubulin heterodimers composed of L136F or I252L α-tubulin display decreased affinity for the dinitroaniline oryzalin relative to wild-type T. thermophila tubulin. Moreover, the L136F substitution dramatically reduces the critical concentration for microtubule assembly relative to the properties of wild-type T. thermophila tubulin. Our data provide additional support for the proposed dinitroaniline binding site on α-tubulin and validate the use of T. thermophila for expression of genetically homogeneous populations of mutant tubulins for biochemical characterization.
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29
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Dinitroaniline activity in Toxoplasma gondii expressing wild-type or mutant alpha-tubulin. Antimicrob Agents Chemother 2010; 54:1453-60. [PMID: 20145086 DOI: 10.1128/aac.01150-09] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The human parasite Toxoplasma gondii is sensitive to dinitroaniline compounds which selectively disrupt microtubules in diverse protozoa but which have no detectable effect on vertebrate host cell microtubules or other functions. Replication of wild-type T. gondii is inhibited by 0.5 to 2.5 microM oryzalin, but mutant parasites harboring amino acid substitutions in the predicted dinitroaniline binding site confer resistance up to 40 microM oryzalin. However, the precise interaction between dinitroanilines and the binding site in alpha-tubulin remains unclear. We have investigated the activity of 12 dinitroanilines and the related compound amiprophos methyl on wild-type and dinitroaniline-resistant parasite lines that contain proposed binding site mutations. These data indicate that dinitramine is the most effective dinitroaniline to inhibit Toxoplasma growth in wild-type parasites and most resistant lines. Dinitramine has an amine group at the meta position not present in any of the other dinitroanilines tested here that is predicted to form hydrogen bonds with residues Arg2 and Gln133 according to docking data. Remarkably, although the binding site mutation Ile235Val confers increased resistance to most dinitroanilines, it confers increased sensitivity to GB-II-5, a compound optimized for activity against kinetoplastid tubulin. Kinetoplastid parasites have a valine at position 235 of alpha-tubulin, whereas apicomplexan parasites have an isoleucine at this site. We suggest that this heterogeneity in binding site environment influences relative dinitroaniline sensitivity in distinct protozoan lineages and hypothesize that a mutation that makes the apicomplexan dinitroaniline binding site more like the kinetoplastid site increases sensitivity to a dinitroaniline optimized for activity in the latter parasites.
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30
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Roberts CW, Henriquez FL. Drug target identification, validation, characterisation and exploitation for treatment of Acanthamoeba (species) infections. Exp Parasitol 2009; 126:91-6. [PMID: 20035751 DOI: 10.1016/j.exppara.2009.11.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2009] [Revised: 11/19/2009] [Accepted: 11/30/2009] [Indexed: 12/15/2022]
Abstract
New more efficacious antimicrobials as required for the treatment of Acanthamoeba infections as those currently available require arduous treatment regimes, are not always effective and are poorly active against the cystic stages. Herein, we review potential drug targets including tubulin, alternative oxidase, amino acid biosynthesis and myosin. In addition, we review the literature for current missing tools and resources for the identification, validation and development of new antimicrobials for this organism. Additional targets should come to light through a concerted genome sequencing effort.
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Affiliation(s)
- Craig W Roberts
- Strathclyde Institute for Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow G4 0NR, UK
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31
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Morgan RE, Werbovetz KA. Selective lead compounds against kinetoplastid tubulin. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2008; 625:33-47. [PMID: 18365657 DOI: 10.1007/978-0-387-77570-8_4] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Kinetoplastid parasites are responsible for the potentially fatal diseases leishmaniasis, African sleeping sickness and Chagas disease. The current treatments for these diseases are far from ideal and new compounds are needed as antiparasitic drug candidates. Tubulin is the accepted target for treatments against cancer and helminths, suggesting that kinetoplastid tubulin is also a suitable target for antiprotozoal compounds. Selective lead compounds against kinetoplastid tubulin have been identified that could represent a starting point for the development of new drug candidates against these parasites.
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Affiliation(s)
- R E Morgan
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA
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32
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Fennell BJ, Naughton JA, Barlow J, Brennan G, Fairweather I, Hoey E, McFerran N, Trudgett A, Bell A. Microtubules as antiparasitic drug targets. Expert Opin Drug Discov 2008; 3:501-18. [DOI: 10.1517/17460441.3.5.501] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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33
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Molecular basis for resistance of acanthamoeba tubulins to all major classes of antitubulin compounds. Antimicrob Agents Chemother 2007; 52:1133-5. [PMID: 18070965 DOI: 10.1128/aac.00355-07] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Tubulin is essential to eukaryotic cells and is targeted by several antineoplastics, herbicides, and antimicrobials. We demonstrate that Acanthamoeba spp. are resistant to five antimicrotubule compounds, unlike any other eukaryote studied so far. Resistance correlates with critical amino acid differences within the inhibitor binding sites of the tubulin heterodimers.
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34
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Abstract
The spread of parasitic resistance has necessitated the development of new drugs and drug targets for the treatment of malaria. Microtubules, which have gained outstanding importance as target molecules for the development of anticancer drugs, are likely to be potent antimalarial targets. The clinical implementation of microtubule inhibitors has given rise to a detailed mechanistic understanding of their interaction with tubulin on the molecular level and their effects on the cellular level. By comparison, our knowledge on Plasmodium falciparum, the causative agent of the most severe form of malaria, is rather poor. This article gives an overview on the microtubule inhibitors that have been explored in the parasite, reviews their effects on parasite growth and assesses their potential as novel antimalarials.
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Affiliation(s)
- Barbara Kappes
- Universitätsklinikum Heidelberg, Abteilung für Parasitologie, Im Neuenheimer Feld 324, Heidelberg, Germany.
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35
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Chavan HD, Singh G, Dey CS. Confocal microscopic investigation of tubulin distribution and effect of paclitaxel on posttranslationally modified tubulins in sodium arsenite resistant Leishmania donovani. Exp Parasitol 2007; 116:320-6. [PMID: 17367783 DOI: 10.1016/j.exppara.2007.01.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2006] [Revised: 01/15/2007] [Accepted: 01/21/2007] [Indexed: 11/26/2022]
Abstract
The affinity of arsenic towards the cytoskeleton leading to disturbance of tubulin polymerization is well known. Tubulin undergoes extensive posttranslational modifications which effect stability and dynamics of microtubules but little is known about the effect of antimicrotubule drugs on their distribution and function in kinetoplastid parasites such as Leishmania. The current study was undertaken to investigate the effect of continuous sodium arsenite exposure on the tubulin distribution profile in wild type and sodium arsenite resistant Leishmania donovani together with effect of paclitaxel, a tubulin-polymerizing agent, on that distribution using confocal microscopy. Immunofluorescence studies using specific monoclonal antibodies against alpha-tubulin and posttranslationally modified tubulins (acetylated and tyrosinated) have revealed distinct differences in the organization of microtubule arrays in wild type and sodium arsenite resistant L. donovani that is further affected by paclitaxel treatment. Microtubules are arranged in spiral arrays in wild type as compared to the longitudinal arrays in arsenite resistant L. donovani. The difference in microtubular structure organization may explain the parasite response to continuous drug pressure and illustrate the fundamental impact of arsenite on microtubules in arsenite resistant L. donovani.
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Affiliation(s)
- Hemantkumar D Chavan
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research(1), Sector 67, SAS Nagar, Punjab, India
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36
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Fennell BJ, Naughton JA, Dempsey E, Bell A. Cellular and molecular actions of dinitroaniline and phosphorothioamidate herbicides on Plasmodium falciparum: Tubulin as a specific antimalarial target. Mol Biochem Parasitol 2006; 145:226-38. [PMID: 16406111 DOI: 10.1016/j.molbiopara.2005.08.020] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2005] [Revised: 08/02/2005] [Accepted: 08/30/2005] [Indexed: 11/21/2022]
Abstract
Microtubules play important roles in cell division, motility and structural integrity of malarial parasites. Some microtubule inhibitors disrupt parasite development at very low concentrations, but most of them also kill mammalian cells. However, the dinitroaniline family of herbicides, which bind specifically to plant tubulin, have inhibitory activity on plant cells but are relatively non-toxic to human cells. Certain dinitroanilines are also inhibitory to various protozoal parasites including Plasmodium. Here we demonstrate that the dinitroanilines trifluralin and oryzalin inhibited progression of erythrocytic Plasmodium falciparum through schizogony, blocked mitotic division, and caused accumulation of abnormal microtubular structures. Moreover, radiolabelled trifluralin interacted with purified, recombinant parasite tubulins but to a much lesser extent with bovine tubulins. The phosphorothioamidate herbicide amiprophos-methyl, which has the same herbicidal mechanism as dinitroanilines, also had antimalarial activity and a similar action on schizogony. These data suggest that P. falciparum tubulin contains a dinitroaniline/phosphorothioamidate-binding site that is not conserved in humans and might be a target for new antimalarial drugs.
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Affiliation(s)
- Brian J Fennell
- Department of Microbiology, Moyne Institute of Preventive Medicine, The University of Dublin-Trinity College, Dublin, Ireland
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37
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Jayanarayan KG, Dey CS. Altered tubulin dynamics, localization and post-translational modifications in sodium arsenite resistant Leishmania donovani in response to paclitaxel, trifluralin and a combination of both and induction of apoptosis-like cell death. Parasitology 2005; 131:215-30. [PMID: 16145938 DOI: 10.1017/s0031182005007687] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
In this study the anti-leishmanial activity and anti-microtubule effects of paclitaxel, trifluralin and a combination of paclitaxel and trifluralin have been tested in a wild type and sodium arsenite-resistant strain of Leishmania donovani. Both paclitaxel and trifluralin have been shown to be effective in limiting parasite growth. Specific alterations in morphology, tubulin polymerization dynamics, post-translational modifications and cellular distribution of the tubulins have been confirmed to be a part of the intracellular anti-microtubule-events that occur in arsenite-resistant L. donovani in response to these agents, ultimately leading to death of the parasite. DNA analyses of the drug-treated wild type and arsenite-resistant strains revealed an apoptosis-like death in response to paclitaxel and the combination but not to trifluralin. Data provide valuable information for further development of chemotherapeutic strategies based on anti-microtubule agents against drug resistant Leishmania parasites.
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Affiliation(s)
- K G Jayanarayan
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.4S IVAGAR, Punjab 160062, India
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38
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Van Miert S, Van Dyck S, Schmidt TJ, Brun R, Vlietinck A, Lemière G, Pieters L. Antileishmanial activity, cytotoxicity and QSAR analysis of synthetic dihydrobenzofuran lignans and related benzofurans. Bioorg Med Chem 2005; 13:661-9. [PMID: 15653333 DOI: 10.1016/j.bmc.2004.10.058] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2004] [Accepted: 10/27/2004] [Indexed: 11/16/2022]
Abstract
A series of synthetic dihydrobenzofuran lignans and related benzofurans were evaluated for their cytotoxicity in a screening panel consisting of various human tumour cell lines, and for their antiprotozoal activity against L. donovani (axenic amastigotes), chloroquine resistant Plasmodium falciparum (strain K1), Trypanosoma brucei rhodesiense and T. cruzi, and for cytotoxicity on L6 cells. No promising cytotoxicities against human tumour cell lines were observed for newly synthesised compounds, but the dimerisation product of some lipophylic esters of caffeic acid, such as compound 2g, showed a high activity against chloroquine-resistant P. falciparum (strain K1) (IC50 0.43 microg/mL) and L. donovani (axenic amastigotes) (IC50 0.12 microg/mL), which was confirmed in an infected macrophage assay (IC50 0.19 microg/mL). QSAR models for the cytotoxic and antileishmanial activity were generated using Quasar receptor surface modelling.
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Affiliation(s)
- Sabine Van Miert
- Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
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39
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Borges VM, Lopes UG, De Souza W, Vannier-Santos MA. Cell structure and cytokinesis alterations in multidrug-resistant Leishmania (Leishmania) amazonensis. Parasitol Res 2004; 95:90-6. [PMID: 15592939 DOI: 10.1007/s00436-004-1248-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2004] [Accepted: 09/28/2004] [Indexed: 10/26/2022]
Abstract
Multidrug-resistant Leishmania (Leishmania) amazonensis may be obtained by in vitro selection with vinblastine. In order to determine whether this phenotype is linked to structural alterations, we analyzed the cell architecture by electron microscopy. The vinblastine resistant CL2 clone of L. (L.) amazonensis, but not wild-type parasites, showed a cytokinesis dysfunction. The CL2 promastigotes had multiple nuclei, kinetoplasts and flagella, suggesting that vinblastine resistance may be associated with truncated cell division. The subpellicular microtubule plasma membrane connection was also affected. Wild-type parasites treated with vinblastine displayed similar alterations, presenting lobulated and multinucleated cells. Taken together, these data indicate that antimicrotubule drug-selected parasites may show evidence of the mutation of cytoskeleton proteins, impairing normal cell function.
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Affiliation(s)
- V M Borges
- Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, FIOCRUZ, Salvador, BA, Brazil
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