Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 8, Pages 5198-5215Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00354
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Funding
- University of Cape Town [64767, 84627]
- South African Medical Research Council [64767, 84627]
- South African Research Chairs Initiative of the Department of Science and Innovation [64767, 84627]
- NRF Community of Practice on Evaluating Malaria Control Interventions [110666]
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A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position possess high activities against both asexual blood and sexual stages. 1-benzylbenzimidazole analogues demonstrate microtubule inhibitory activity and low cytotoxicity to mammalian cells.
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 H-1-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 H-1-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.
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