Darline Dize, M. Tali, Cyrille Armel Njanpa Ngansop, R. Keumoe, Eugenie Aimée Madiesse Kemgne, Lauve Rachel Tchokouaha Yamthe, Patrick Valere Tsouh Fokou, Boniface Pone Kamdem, Katsura Hata, Fabrice Fekam Boyom
{"title":"Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro","authors":"Darline Dize, M. Tali, Cyrille Armel Njanpa Ngansop, R. Keumoe, Eugenie Aimée Madiesse Kemgne, Lauve Rachel Tchokouaha Yamthe, Patrick Valere Tsouh Fokou, Boniface Pone Kamdem, Katsura Hata, Fabrice Fekam Boyom","doi":"10.3390/futurepharmacol4010013","DOIUrl":null,"url":null,"abstract":"Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute major global health problems, especially in developing countries; however, the development of drug resistance coupled with the toxicity of current treatments has hindered their management. The involvement of certain enzymes (dihydrofolate reductase [DHFR]) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y, and Z) and one K+ channel blocker (E4031) were screened for their inhibitory effects on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. A resazurin assay was used to assess the antitrypanosomal and antileishmanial activities of the test compounds, whereas the antiplasmodial activity was evaluated through the SYBR Green I test. Moreover, the cytotoxicities of the test compounds were evaluated in Vero, Raw 264.7, and HepG-2 cells using a resazurin-based test, while their pharmacokinetic properties were predicted using the online tool, pkCSM. As a result, compound Y exhibited selective (selectivity index range: from 2.69 to >61.4; Vero, Raw 264.7, and HepG-2 cells) and broad-spectrum antiprotozoal activity against L. donovani promastigotes (IC50: 12.4 µM), amastigotes (IC50: 4.28 µM), P. falciparum (IC50: 0.028 µM), and T. brucei brucei (IC50: 0.81 µM). In addition, compound X inhibited the growth of P. falciparum (IC50: 0.0052 µM) and T. brucei brucei (IC50: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug likeness scores, as none of the criteria for Lipinski’s rule were violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support the discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K+ channel blockers and DHFR inhibitors.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"5 2","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Future Pharmacology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3390/futurepharmacol4010013","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute major global health problems, especially in developing countries; however, the development of drug resistance coupled with the toxicity of current treatments has hindered their management. The involvement of certain enzymes (dihydrofolate reductase [DHFR]) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y, and Z) and one K+ channel blocker (E4031) were screened for their inhibitory effects on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. A resazurin assay was used to assess the antitrypanosomal and antileishmanial activities of the test compounds, whereas the antiplasmodial activity was evaluated through the SYBR Green I test. Moreover, the cytotoxicities of the test compounds were evaluated in Vero, Raw 264.7, and HepG-2 cells using a resazurin-based test, while their pharmacokinetic properties were predicted using the online tool, pkCSM. As a result, compound Y exhibited selective (selectivity index range: from 2.69 to >61.4; Vero, Raw 264.7, and HepG-2 cells) and broad-spectrum antiprotozoal activity against L. donovani promastigotes (IC50: 12.4 µM), amastigotes (IC50: 4.28 µM), P. falciparum (IC50: 0.028 µM), and T. brucei brucei (IC50: 0.81 µM). In addition, compound X inhibited the growth of P. falciparum (IC50: 0.0052 µM) and T. brucei brucei (IC50: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug likeness scores, as none of the criteria for Lipinski’s rule were violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support the discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K+ channel blockers and DHFR inhibitors.