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Borrallo-Lopez L, Guzman L, Romero NG, Sampietro A, Mallo-Abreu A, Guardia-Escote L, Teixidó E, Flick B, Fernàndez-Busquets X, Muñoz-Torrero D, Barenys M. Combining the zebrafish embryo developmental toxicity assay (ZEDTA) with hemoglobin staining to accelerate the research of novel antimalarial drugs for pregnant women. Int J Parasitol Drugs Drug Resist 2025; 27:100582. [PMID: 39889312 PMCID: PMC11833639 DOI: 10.1016/j.ijpddr.2025.100582] [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: 09/07/2024] [Revised: 12/20/2024] [Accepted: 01/14/2025] [Indexed: 02/02/2025]
Abstract
BACKGROUND Malaria during pregnancy implies a high risk for the mother and the developing child. However, the therapeutic options for pregnant women have historically been very limited, especially during the first trimester of pregnancy due to potential adverse effects on embryo-fetal development. Recently, there has been great controversy regarding these potential embryo-fetal adverse effects because the results of rodent studies were not in accordance with the clinical data available, and finally the WHO has changed the recommendations for pregnant women with uncomplicated P. falciparum malaria to treatment with artemether-lumefantrine during the first trimester. The discrepancy between pre-clinical and clinical studies has been attributed to species-differences in the duration of the window of susceptibility of circulating primitive erythroblasts. METHODS Here we provide a tool based on an alternative method to animal experimentation that accelerates the research of novel drugs for pregnant women. We have adapted the zebrafish embryo developmental toxicity assay to include hemoglobin staining in the embryos and two time-points of lethality and dysmorphogenesis evaluation. These two time-points were selected to include one when the development is independent of and one when the development is dependent of erythrocytes function. The method was used to test four marketed antimalarial drugs and three new antimalarial drug candidates. RESULTS Our combination of tests can correctly predict the teratogenic and non-teratogenic effects of several antimalarial marketed drugs (artemisinin, quinine, chloroquine, and dihydroartemisinin + desbutyl-lumefantrine). Furthermore, we have tested three new drug candidates (GS-GUAN, DONE3TCl, and YAT2150) with novel mechanisms of action, and different from those of the marketed antimalarial drugs. CONCLUSIONS We propose a decision tree combining the results of the two time-points of evaluation together with the information on significant erythrocyte depletion. The aim of this decision tree is to identify compounds with no or lower hazard on teratogenicity or erythrocyte depletion at an early phase of the drug development process.
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Affiliation(s)
- Lucia Borrallo-Lopez
- GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - Laura Guzman
- GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Neurociències, Universitat de Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Instituto de Carlos III, Madrid, Spain
| | - Noelia G Romero
- GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Nutrició i Seguretat Alimentària (INSA), Universitat de Barcelona, Barcelona, Spain; Universidad Nacional de Itapua (UNI), Paraguay
| | - Anna Sampietro
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain
| | - Ana Mallo-Abreu
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain
| | - Laia Guardia-Escote
- GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - Elisabet Teixidó
- GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Nutrició i Seguretat Alimentària (INSA), Universitat de Barcelona, Barcelona, Spain
| | - Burkhard Flick
- Department of Toxicology, NUVISAN ICB GmbH, Berlin, Germany
| | - Xavier Fernàndez-Busquets
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-Universitat de Barcelona), Barcelona, Spain; Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institut de Nanociència i Nanotecnologia (IN2UB), Universitat de Barcelona, Barcelona, Spain
| | - Diego Muñoz-Torrero
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain
| | - Marta Barenys
- GRET and Toxicology Unit, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Institut de Nutrició i Seguretat Alimentària (INSA), Universitat de Barcelona, Barcelona, Spain; German Centre for the Protection of Laboratory Animals (Bf3R), German Federal Institute for Risk Assessmen (BfR), Berlin, Germany.
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Oyeneyin OE, Moodley R, Mashaba C, Garnie LF, Omoboyowa DA, Rakodi GH, Maphoru MV, Balogun MO, Hoppe HC, Egan TJ, Tukulula M. In vitro antiplasmodium and antitrypanosomal activities, β-haematin formation inhibition, molecular docking and DFT computational studies of quinoline-urea-benzothiazole hybrids. Heliyon 2024; 10:e38434. [PMID: 39397937 PMCID: PMC11471183 DOI: 10.1016/j.heliyon.2024.e38434] [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] [Received: 06/06/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/15/2024] Open
Abstract
Quinoline-urea-benzothiazole hybrids exhibited low to sub-micromolar in vitro activities against the Plasmodium falciparum (P. falciparum) 3D7 chloroquine (CQ)-sensitive strain, with compounds 5a, 5b and 5f showing activities ranging from 0.33 to 0.97 μM. Against the formation of β-haematin, the majority of the tested compounds were comparable to the reference drug, chloroquine (CQ), with compounds 5c (IC50 = 9.55 ± 0.62 μM) and 5h (IC50 = 9.73 ± 1.38 μM), exhibiting slightly better in vitro efficacy than CQ. The hybrids also exhibited low micromolar to submicromolar activities against Trypanosoma brucei brucei, with 5j-5k being comparable to the reference drug, pentamidine. Compound 5b displayed higher in silico binding energy than CQ when docked against P. falciparum dihydroorotate dehydrogenase enzyme. Compounds 5j and 5k showed higher binding energies than pentamidine within the trypanothione reductase enzyme binding pocket. The root means square deviations of the hit compounds 5b, 5j and 5k were stable throughout the 100 ns simulation period. Post-molecular dynamics MMGBSA binding free energies showed that the selected hybrids bind spontaneously to the respective enzymes. The DFT investigation revealed that the compounds have regions that can bind to the electropositive and electronegative sites of the proteins.
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Affiliation(s)
- Oluwatoba E. Oyeneyin
- School of Chemistry and Physics, University of KwaZulu Natal, Westville Campus, Durban, 4000, South Africa
- Department of Chemical Sciences, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria
| | - Rashmika Moodley
- School of Chemistry and Physics, University of KwaZulu Natal, Westville Campus, Durban, 4000, South Africa
| | - Chakes Mashaba
- School of Chemistry and Physics, University of KwaZulu Natal, Westville Campus, Durban, 4000, South Africa
| | - Larnelle F. Garnie
- Department of Chemistry, Faculty of Science, University of Cape Town, Rondebosch, Cape Town, 7700, South Africa
| | - Damilola A. Omoboyowa
- Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Ondo State, Nigeria
| | - Goitsemodimo H. Rakodi
- Department of Chemistry, Faculty of Science, Tshwane University of Technology, Pretoria, 001, South Africa
| | - Mabuatsela V. Maphoru
- Department of Chemistry, Faculty of Science, Tshwane University of Technology, Pretoria, 001, South Africa
| | - Mohamed O. Balogun
- Bio-Polymer Modification and Therapeutics Laboratory, Council for Scientific and Industrial Research (CSIR), Pretoria, 0001, South Africa
| | - Heinrich C. Hoppe
- Centre for Chemico- and Biomedical Research, Rhodes University, Makhanda, 6140, South Africa
- Department of Biochemistry and Microbiology, Faculty of Science, Rhodes University, Makhanda, 6140, South Africa
| | - Timothy J. Egan
- Department of Chemistry, Faculty of Science, University of Cape Town, Rondebosch, Cape Town, 7700, South Africa
- Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Rondebosch, 7701, South Africa
| | - Matshawandile Tukulula
- School of Chemistry and Physics, University of KwaZulu Natal, Westville Campus, Durban, 4000, South Africa
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Camarero-Hoyos C, Bouzón-Arnáiz I, Avalos-Padilla Y, Fallica AN, Román-Álamo L, Ramírez M, Portabella E, Cuspinera O, Currea-Ayala D, Orozco-Quer M, Ribera M, Siden-Kiamos I, Spanos L, Iglesias V, Crespo B, Viera S, Andreu D, Sulleiro E, Zarzuela F, Urtasun N, Pérez-Torras S, Pastor-Anglada M, Arce EM, Muñoz-Torrero D, Fernàndez-Busquets X. Leveraging the Aggregated Protein Dye YAT2150 for Malaria Chemotherapy. Pharmaceutics 2024; 16:1290. [PMID: 39458619 PMCID: PMC11514582 DOI: 10.3390/pharmaceutics16101290] [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: 07/01/2024] [Revised: 09/09/2024] [Accepted: 09/28/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: YAT2150 is a first-in-class antiplasmodial compound that has been recently proposed as a new interesting drug for malaria therapy. Methods/Results: The fluorescence of YAT2150 rapidly increases upon its entry into Plasmodium, a property that can be of use for the design of highly sensitive diagnostic approaches. YAT2150 blocks the in vitro development of the ookinete stage of Plasmodium and, when added to an infected blood meal, inhibits oocyst formation in the mosquito. Thus, the compound could possibly contribute to future transmission-blocking antimalarial strategies. Cell influx/efflux studies in Caco-2 cells suggest that YAT2150 is internalized by endocytosis and also through the OATP2B1 transporter, whereas its main export route would be via OSTα. YAT2150 has an overall favorable drug metabolism and pharmacokinetics profile, and its moderate cytotoxicity can be significantly reduced upon encapsulation in immunoliposomes, which leads to a dramatic increase in the drug selectivity index to values close to 1000. Although YAT2150 binds amyloid-forming peptides, its in vitro fluorescence emission is stronger upon association with peptides that form amorphous aggregates, suggesting that regions enriched in unstructured proteins are the preferential binding sites of the drug inside Plasmodium cells. The reduction of protein aggregation in the parasite after YAT2150 treatment, which has been suggested to be directly related to the drug's mode of action, is also observed following treatment with quinoline antimalarials like chloroquine and primaquine. Conclusions: Altogether, the data presented here indicate that YAT2150 can represent the spearhead of a new family of compounds for malaria diagnosis and therapy due to its presumed novel mode of action based on the interaction with functional protein aggregates in the pathogen.
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Affiliation(s)
- Claudia Camarero-Hoyos
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
- Doctoral School of Biotechnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, 08028 Barcelona, Spain
| | - Inés Bouzón-Arnáiz
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
| | - Yunuen Avalos-Padilla
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
| | - Antonino Nicolò Fallica
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
| | - Lucía Román-Álamo
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
| | - Miriam Ramírez
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
| | - Emma Portabella
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
| | - Ona Cuspinera
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
| | - Daniela Currea-Ayala
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
| | - Marc Orozco-Quer
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
| | - Maria Ribera
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
| | - Inga Siden-Kiamos
- Institute of Molecular Biology and Biotechnology, FORTH, N. Plastira 100, 700 13 Heraklion, Greece; (I.S.-K.); (L.S.)
| | - Lefteris Spanos
- Institute of Molecular Biology and Biotechnology, FORTH, N. Plastira 100, 700 13 Heraklion, Greece; (I.S.-K.); (L.S.)
| | - Valentín Iglesias
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
- Institut de Biotecnologia i de Biomedicina (IBB) and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
- Clinical Research Centre, Medical University of Białystok, Kilińskiego 1, 15-369 Białystok, Poland
| | - Benigno Crespo
- Global Health Medicines R&D, GlaxoSmithKline (GSK), 28760 Tres Cantos, Spain; (B.C.); (S.V.)
| | - Sara Viera
- Global Health Medicines R&D, GlaxoSmithKline (GSK), 28760 Tres Cantos, Spain; (B.C.); (S.V.)
| | - David Andreu
- Department of Medicine and Life Sciences, Barcelona Biomedical Research Park, Pompeu Fabra University, Dr. Aiguader 88, 08003 Barcelona, Spain;
| | - Elena Sulleiro
- Microbiology Department, Vall d’Hebron University Hospital (VHUH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (E.S.); (F.Z.)
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Carlos III Health Institute, 28029 Madrid, Spain
| | - Francesc Zarzuela
- Microbiology Department, Vall d’Hebron University Hospital (VHUH), Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (E.S.); (F.Z.)
| | - Nerea Urtasun
- Molecular Pharmacology and Experimental Therapeutics (MPET), Department of Biochemistry and Molecular Biology, University of Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain; (N.U.); (S.P.-T.); (M.P.-A.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III Health Institute, 28029 Madrid, Spain
- Institut de Recerca Hospital Sant Joan de Déu de Barcelona (IRSJD), Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain
- Institute of Biomedicine (IBUB), University of Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain;
| | - Sandra Pérez-Torras
- Molecular Pharmacology and Experimental Therapeutics (MPET), Department of Biochemistry and Molecular Biology, University of Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain; (N.U.); (S.P.-T.); (M.P.-A.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III Health Institute, 28029 Madrid, Spain
- Institut de Recerca Hospital Sant Joan de Déu de Barcelona (IRSJD), Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain
- Institute of Biomedicine (IBUB), University of Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain;
| | - Marçal Pastor-Anglada
- Molecular Pharmacology and Experimental Therapeutics (MPET), Department of Biochemistry and Molecular Biology, University of Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain; (N.U.); (S.P.-T.); (M.P.-A.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Carlos III Health Institute, 28029 Madrid, Spain
- Institut de Recerca Hospital Sant Joan de Déu de Barcelona (IRSJD), Santa Rosa 39-57, 08950 Esplugues de Llobregat, Spain
- Institute of Biomedicine (IBUB), University of Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain;
| | - Elsa M. Arce
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, 08028 Barcelona, Spain;
| | - Diego Muñoz-Torrero
- Institute of Biomedicine (IBUB), University of Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain;
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, 08028 Barcelona, Spain;
| | - Xavier Fernàndez-Busquets
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Rosselló 149-153, 08036 Barcelona, Spain; (C.C.-H.); (I.B.-A.); (Y.A.-P.); (A.N.F.); (L.R.-Á.); (M.R.); (E.P.); (O.C.); (D.C.-A.); (M.O.-Q.); (M.R.); (V.I.)
- Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain
- Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain
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Román-Álamo L, Avalos-Padilla Y, Bouzón-Arnáiz I, Iglesias V, Fernández-Lajo J, Monteiro JM, Rivas L, Fisa R, Riera C, Andreu D, Pintado-Grima C, Ventura S, Arce EM, Muñoz-Torrero D, Fernàndez-Busquets X. Effect of the aggregated protein dye YAT2150 on Leishmania parasite viability. Antimicrob Agents Chemother 2024; 68:e0112723. [PMID: 38349159 PMCID: PMC10916400 DOI: 10.1128/aac.01127-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/15/2024] [Indexed: 03/07/2024] Open
Abstract
The problems associated with the drugs currently used to treat leishmaniasis, including resistance, toxicity, and the high cost of some formulations, call for the urgent identification of new therapeutic agents with novel modes of action. The aggregated protein dye YAT2150 has been found to be a potent antileishmanial compound, with a half-maximal inhibitory concentration (IC50) of approximately 0.5 µM against promastigote and amastigote stages of Leishmania infantum. The encapsulation in liposomes of YAT2150 significantly improved its in vitro IC50 to 0.37 and 0.19 µM in promastigotes and amastigotes, respectively, and increased the half-maximal cytotoxic concentration in human umbilical vein endothelial cells to >50 µM. YAT2150 became strongly fluorescent when binding intracellular protein deposits in Leishmania cells. This fluorescence pattern aligns with the proposed mode of action of this drug in the malaria parasite Plasmodium falciparum, the inhibition of protein aggregation. In Leishmania major, YAT2150 rapidly reduced ATP levels, suggesting an alternative antileishmanial mechanism. To the best of our knowledge, this first-in-class compound is the only one described so far having significant activity against both Plasmodium and Leishmania, thus being a potential drug for the treatment of co-infections of both parasites.
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Affiliation(s)
- Lucía Román-Álamo
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Doctoral School of Biotechnology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - Yunuen Avalos-Padilla
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Inés Bouzón-Arnáiz
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Valentín Iglesias
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Institut de Biotecnologia i de Biomedicina (IBB) and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Jorge Fernández-Lajo
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Juan M. Monteiro
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Luis Rivas
- Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
| | - Roser Fisa
- Section of Parasitology Department of Biology, Health and Environment, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - Cristina Riera
- Section of Parasitology Department of Biology, Health and Environment, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - David Andreu
- Department of Medicine and Life Sciences, Barcelona Biomedical Research Park, Pompeu Fabra University, Barcelona, Spain
| | - Carlos Pintado-Grima
- Institut de Biotecnologia i de Biomedicina (IBB) and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Salvador Ventura
- Institut de Biotecnologia i de Biomedicina (IBB) and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Elsa M. Arce
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
| | - Diego Muñoz-Torrero
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain
| | - Xavier Fernàndez-Busquets
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-Universitat de Barcelona, Barcelona, Spain
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Barcelona, Spain
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Bao LQ, Baecker D, Mai Dung DT, Phuong Nhung N, Thi Thuan N, Nguyen PL, Phuong Dung PT, Huong TTL, Rasulev B, Casanola-Martin GM, Nam NH, Pham-The H. Development of Activity Rules and Chemical Fragment Design for In Silico Discovery of AChE and BACE1 Dual Inhibitors against Alzheimer's Disease. Molecules 2023; 28:molecules28083588. [PMID: 37110831 PMCID: PMC10142303 DOI: 10.3390/molecules28083588] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer's disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of novel dual-target acetylcholinesterase (AChE) and β-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds with AChE and BACE1 measurements were curated from the ChEMBL database. The best global accuracies of training/external validation for AChE and BACE1 were 0.85/0.80 and 0.83/0.81, respectively. The rules were then applied to screen dual inhibitors from the original databases. Based on the best rules obtained from each classification tree, a set of potential AChE and BACE1 inhibitors were identified, and active fragments were extracted using Murcko-type decomposition analysis. More than 250 novel inhibitors were designed in silico based on active fragments and predicted AChE and BACE1 inhibitory activity using consensus QSAR models and docking validations. The rule-based and ML approach applied in this study may be useful for the in silico design and screening of new AChE and BACE1 dual inhibitors against AzD.
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Affiliation(s)
- Le-Quang Bao
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi 10000, Vietnam
| | - Daniel Baecker
- Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany
| | - Do Thi Mai Dung
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi 10000, Vietnam
| | - Nguyen Phuong Nhung
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi 10000, Vietnam
| | - Nguyen Thi Thuan
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi 10000, Vietnam
| | - Phuong Linh Nguyen
- College of Computing & Informatics, Drexel University, 3141 Chestnut St., Philadelphia, PA 19104, USA
| | - Phan Thi Phuong Dung
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi 10000, Vietnam
| | - Tran Thi Lan Huong
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi 10000, Vietnam
| | - Bakhtiyor Rasulev
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA
| | | | - Nguyen-Hai Nam
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi 10000, Vietnam
| | - Hai Pham-The
- Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan Kiem, Hanoi 10000, Vietnam
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6
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Bouzón-Arnáiz I, Avalos-Padilla Y, Biosca A, Caño-Prades O, Román-Álamo L, Valle J, Andreu D, Moita D, Prudêncio M, Arce EM, Muñoz-Torrero D, Fernàndez-Busquets X. The protein aggregation inhibitor YAT2150 has potent antimalarial activity in Plasmodium falciparum in vitro cultures. BMC Biol 2022; 20:197. [PMID: 36271358 PMCID: PMC9587658 DOI: 10.1186/s12915-022-01374-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 07/12/2022] [Indexed: 11/25/2022] Open
Abstract
Background By 2016, signs of emergence of Plasmodium falciparum resistance to artemisinin and partner drugs were detected in the Greater Mekong Subregion. Recently, the independent evolution of artemisinin resistance has also been reported in Africa and South America. This alarming scenario calls for the urgent development of new antimalarials with novel modes of action. We investigated the interference with protein aggregation, which is potentially toxic for the cell and occurs abundantly in all Plasmodium stages, as a hitherto unexplored drug target in the pathogen. Results Attempts to exacerbate the P. falciparum proteome’s propensity to aggregation by delivering endogenous aggregative peptides to in vitro cultures of this parasite did not significantly affect their growth. In contrast, protein aggregation inhibitors clearly reduced the pathogen’s viability. One such compound, the bis(styrylpyridinium) salt YAT2150, exhibited potent antiplasmodial activity with an in vitro IC50 of 90 nM for chloroquine- and artemisinin-resistant lines, arresting asexual blood parasites at the trophozoite stage, as well as interfering with the development of both sexual and hepatic forms of Plasmodium. At its IC50, this compound is a powerful inhibitor of the aggregation of the model amyloid β peptide fragment 1-40, and it reduces the amount of aggregated proteins in P. falciparum cultures, suggesting that the underlying antimalarial mechanism consists in a generalized impairment of proteostasis in the pathogen. YAT2150 has an easy, rapid, and inexpensive synthesis, and because it fluoresces when it accumulates in its main localization in the Plasmodium cytosol, it is a theranostic agent. Conclusions Inhibiting protein aggregation in Plasmodium significantly reduces the parasite’s viability in vitro. Since YAT2150 belongs to a novel structural class of antiplasmodials with a mode of action that potentially targets multiple gene products, rapid evolution of resistance to this drug is unlikely to occur, making it a promising compound for the post-artemisinin era. Supplementary Information The online version contains supplementary material available at 10.1186/s12915-022-01374-4.
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Affiliation(s)
- Inés Bouzón-Arnáiz
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-University of Barcelona), Rosselló 149-153, 08036, Barcelona, Spain.,Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028, Barcelona, Spain.,Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain
| | - Yunuen Avalos-Padilla
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-University of Barcelona), Rosselló 149-153, 08036, Barcelona, Spain.,Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028, Barcelona, Spain.,Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain
| | - Arnau Biosca
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-University of Barcelona), Rosselló 149-153, 08036, Barcelona, Spain.,Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028, Barcelona, Spain.,Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain
| | - Omar Caño-Prades
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-University of Barcelona), Rosselló 149-153, 08036, Barcelona, Spain.,Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028, Barcelona, Spain.,Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain
| | - Lucía Román-Álamo
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-University of Barcelona), Rosselló 149-153, 08036, Barcelona, Spain.,Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028, Barcelona, Spain.,Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain
| | - Javier Valle
- Department of Medicine and Life Sciences, Barcelona Biomedical Research Park, Pompeu Fabra University, Dr. Aiguader 88, 08003, Barcelona, Spain
| | - David Andreu
- Department of Medicine and Life Sciences, Barcelona Biomedical Research Park, Pompeu Fabra University, Dr. Aiguader 88, 08003, Barcelona, Spain
| | - Diana Moita
- Instituto de Medicina Molecular, Fac. Medicina Univ. Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal
| | - Miguel Prudêncio
- Instituto de Medicina Molecular, Fac. Medicina Univ. Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal
| | - Elsa M Arce
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain
| | - Diego Muñoz-Torrero
- Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain
| | - Xavier Fernàndez-Busquets
- Barcelona Institute for Global Health (ISGlobal, Hospital Clínic-University of Barcelona), Rosselló 149-153, 08036, Barcelona, Spain. .,Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028, Barcelona, Spain. .,Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain.
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7
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Mezeiova E, Soukup O, Korabecny J. Huprines — an insight into the synthesis and biological properties. RUSSIAN CHEMICAL REVIEWS 2020. [DOI: 10.1070/rcr4938] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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8
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Feng LS, Xu Z, Chang L, Li C, Yan XF, Gao C, Ding C, Zhao F, Shi F, Wu X. Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug-resistant Plasmodium falciparum. Med Res Rev 2019; 40:931-971. [PMID: 31692025 DOI: 10.1002/med.21643] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 09/16/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022]
Abstract
Malaria is a tropical disease, leading to around half a million deaths annually. Antimalarials such as quinolines are crucial to fight against malaria, but malaria control is extremely challenged by the limited pipeline of effective pharmaceuticals against drug-resistant strains of Plasmodium falciparum which are resistant toward almost all currently accessible antimalarials. To tackle the growing resistance, new antimalarial drugs are needed urgently. Hybrid molecules which contain two or more pharmacophores have the potential to overcome the drug resistance, and hybridization of quinoline privileged antimalarial building block with other antimalarial pharmacophores may provide novel molecules with enhanced in vitro and in vivo activity against drug-resistant (including multidrug-resistant) P falciparum. In recent years, numerous of quinoline hybrids were developed, and their activities against a panel of drug-resistant P falciparum strains were screened. Some of quinoline hybrids were found to possess promising in vitro and in vivo potency. This review emphasized quinoline hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug-resistant P falciparum, covering articles published between 2010 and 2019.
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Affiliation(s)
| | - Zhi Xu
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Le Chang
- WuXi AppTec Co, Ltd, Wuhan, China
| | - Chuan Li
- WuXi AppTec Co, Ltd, Wuhan, China
| | | | | | | | | | - Feng Shi
- WuXi AppTec Co, Ltd, Wuhan, China
| | - Xiang Wu
- WuXi AppTec Co, Ltd, Wuhan, China
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9
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Narula AK, Azad CS, Nainwal LM. New dimensions in the field of antimalarial research against malaria resurgence. Eur J Med Chem 2019; 181:111353. [DOI: 10.1016/j.ejmech.2019.05.043] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 04/16/2019] [Accepted: 05/15/2019] [Indexed: 12/20/2022]
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10
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Schmidt I, Göllner S, Fuß A, Stich A, Kucharski A, Schirmeister T, Katzowitsch E, Bruhn H, Miliu A, Krauth-Siegel RL, Holzgrabe U. Bistacrines as potential antitrypanosomal agents. Bioorg Med Chem 2017; 25:4526-4531. [PMID: 28698054 DOI: 10.1016/j.bmc.2017.06.051] [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: 02/15/2017] [Revised: 06/28/2017] [Accepted: 06/30/2017] [Indexed: 02/05/2023]
Abstract
Human African Trypanosomiasis (HAT) is caused by two subspecies of the genus Trypanosoma, namely Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. In preliminary studies, dimeric tacrine derivatives were found to inhibit parasite growth with IC50-values in the nanomolar concentration range. This prompted the synthesis of a small, but smart library of monomeric and dimeric tacrine-type compounds and their evaluation of antiprotozoal activity. Rhodesain, a lysosomal cathepsin-L like cysteine protease of T. brucei rhodesiense is essential for parasite survival and likely target of the tacrine derivatives. In addition, the inhibition of trypanothione reductase by bistacrines was found. This flavoprotein oxidoreductase is the main defense against oxidative stress in the thiol redox system unique for protozoa.
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Affiliation(s)
- Ines Schmidt
- Institute for Pharmacy and Food Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany
| | - Sarah Göllner
- Biochemistry Center (BZH), Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany
| | - Antje Fuß
- Medical Mission Institute, Hermann-Schell-Strasse 7, 97074 Würzburg, Germany
| | - August Stich
- Medical Mission Institute, Hermann-Schell-Strasse 7, 97074 Würzburg, Germany
| | - Anna Kucharski
- Institute for Pharmacy and Food Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany
| | - Tanja Schirmeister
- Institute for Pharmacy and Biochemistry, Johannes-Gutenberg-University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany
| | - Elena Katzowitsch
- Institute for Molecular Infection Biology, Julius-Maximilians-University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany
| | - Heike Bruhn
- Institute for Molecular Infection Biology, Julius-Maximilians-University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany
| | - Alexandra Miliu
- Biochemistry Center (BZH), Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany
| | - R Luise Krauth-Siegel
- Biochemistry Center (BZH), Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany
| | - Ulrike Holzgrabe
- Institute for Pharmacy and Food Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
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11
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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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12
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Sola I, Artigas A, Taylor MC, Pérez-Areales FJ, Viayna E, Clos MV, Pérez B, Wright CW, Kelly JM, Muñoz-Torrero D. Synthesis and biological evaluation of N-cyanoalkyl-, N-aminoalkyl-, and N-guanidinoalkyl-substituted 4-aminoquinoline derivatives as potent, selective, brain permeable antitrypanosomal agents. Bioorg Med Chem 2016; 24:5162-5171. [PMID: 27591008 PMCID: PMC5080452 DOI: 10.1016/j.bmc.2016.08.036] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 08/19/2016] [Accepted: 08/20/2016] [Indexed: 11/30/2022]
Abstract
Current drugs against human African trypanosomiasis (HAT) suffer from several serious drawbacks. The search for novel, effective, brain permeable, safe, and inexpensive antitrypanosomal compounds is therefore an urgent need. We have recently reported that the 4-aminoquinoline derivative huprine Y, developed in our group as an anticholinesterasic agent, exhibits a submicromolar potency against Trypanosoma brucei and that its homo- and hetero-dimerization can result in to up to three-fold increased potency and selectivity. As an alternative strategy towards more potent smaller molecule anti-HAT agents, we have explored the introduction of ω-cyanoalkyl, ω-aminoalkyl, or ω-guanidinoalkyl chains at the primary amino group of huprine or the simplified 4-aminoquinoline analogue tacrine. Here, we describe the evaluation of a small in-house library and a second generation of newly synthesized derivatives, which has led to the identification of 13 side chain modified 4-aminoquinoline derivatives with submicromolar potencies against T. brucei. Among these compounds, the guanidinononyltacrine analogue 15e exhibits a 5-fold increased antitrypanosomal potency, 10-fold increased selectivity, and 100-fold decreased anticholinesterasic activity relative to the parent huprine Y. Its biological profile, lower molecular weight relative to dimeric compounds, reduced lipophilicity, and ease of synthesis, make it an interesting anti-HAT lead, amenable to further optimization to eliminate its remaining anticholinesterasic activity.
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Affiliation(s)
- Irene Sola
- Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain
| | - Albert Artigas
- Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain
| | - Martin C Taylor
- Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
| | - F Javier Pérez-Areales
- Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain
| | - Elisabet Viayna
- Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain
| | - M Victòria Clos
- Department of Pharmacology, Therapeutics and Toxicology, Institute of Neurosciences, Autonomous University of Barcelona, E-08193, Bellaterra, Barcelona, Spain
| | - Belén Pérez
- Department of Pharmacology, Therapeutics and Toxicology, Institute of Neurosciences, Autonomous University of Barcelona, E-08193, Bellaterra, Barcelona, Spain
| | - Colin W Wright
- Bradford School of Pharmacy, University of Bradford, West Yorkshire BD7 1 DP, United Kingdom
| | - John M Kelly
- Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
| | - Diego Muñoz-Torrero
- Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
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13
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Synthetic Advances in the Indane Natural Product Scaffolds as Drug Candidates. ACTA ACUST UNITED AC 2016. [DOI: 10.1016/b978-0-444-63932-5.00008-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
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14
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Di Pietro O, Vicente-García E, Taylor MC, Berenguer D, Viayna E, Lanzoni A, Sola I, Sayago H, Riera C, Fisa R, Clos MV, Pérez B, Kelly JM, Lavilla R, Muñoz-Torrero D. Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity. Eur J Med Chem 2015; 105:120-37. [PMID: 26479031 PMCID: PMC4638191 DOI: 10.1016/j.ejmech.2015.10.007] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Revised: 09/28/2015] [Accepted: 10/06/2015] [Indexed: 11/28/2022]
Abstract
Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[h][1,6]naphthyridines, pyrrolo[3,2-c]quinolines, azepino[3,2-c]quinolines, and pyrano[3,2-c]quinolines through 2–4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei, T. cruzi, and Leishmania infantum, as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC50 values of 1.5 μM, 6.1 μM and 29.2 μM against T. brucei, L. infantum and T. cruzi, respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC50 > 30 μM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells.
Novel classes of tricyclic heterofused quinolines have been synthesized. Their 2–4-step syntheses involve a multicomponent Povarov reaction as the key step. Some compounds exhibit single digit micromolar potencies against 2 trypanosomatids. All compounds with multi-trypanosomatid activity can cross the blood–brain barrier. Most compounds with multi-trypanosomatid activity have drug like properties.
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Affiliation(s)
- Ornella Di Pietro
- Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain
| | | | - Martin C Taylor
- Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
| | - Diana Berenguer
- Laboratori de Parasitologia, Departament de Microbiologia i Parasitologia Sanitàries, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain
| | - Elisabet Viayna
- Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain
| | - Anna Lanzoni
- Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain
| | - Irene Sola
- Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain
| | - Helena Sayago
- Barcelona Science Park, Baldiri Reixac, 10-12, E-08028, Barcelona, Spain
| | - Cristina Riera
- Laboratori de Parasitologia, Departament de Microbiologia i Parasitologia Sanitàries, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain
| | - Roser Fisa
- Laboratori de Parasitologia, Departament de Microbiologia i Parasitologia Sanitàries, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain
| | - M Victòria Clos
- Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193, Bellaterra, Barcelona, Spain
| | - Belén Pérez
- Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193, Bellaterra, Barcelona, Spain
| | - John M Kelly
- Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
| | - Rodolfo Lavilla
- Barcelona Science Park, Baldiri Reixac, 10-12, E-08028, Barcelona, Spain; Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain
| | - Diego Muñoz-Torrero
- Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.
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