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Antimalarial benzimidazole derivatives incorporating phenolic mannich base side chains inhibit microtubule and hemozoin formation: structure-activity relationship and in vivo oral efficacy studies

Dziwornu, G. A. and Coertzen, D. and Leshabane, M. and Korkor, C. M. and Cloete, C. K. and Njoroge, M. and Gibhard, L. and Lawrence, N. and Reader, J. and van der Watt, M. and Wittlin, S. and Birkholtz, L. M. and Chibale, K.. (2021) Antimalarial benzimidazole derivatives incorporating phenolic mannich base side chains inhibit microtubule and hemozoin formation: structure-activity relationship and in vivo oral efficacy studies. Journal of medicinal chemistry, 64 (8). pp. 5198-5215.

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Official URL: https://edoc.unibas.ch/89033/

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Abstract

A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 x 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:0022-2623
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:20 Dec 2022 09:12
Deposited On:20 Dec 2022 09:12

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