Data Entry: Please note that the research database will be replaced by UNIverse by the end of October 2023. Please enter your data into the system https://universe-intern.unibas.ch. Thanks
Antimalarial benzimidazole derivatives incorporating phenolic mannich base side chains inhibit microtubule and hemozoin formation: structure-activity relationship and in vivo oral efficacy studies
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID
4646430
Author(s)
Dziwornu, G. A.; Coertzen, D.; Leshabane, M.; Korkor, C. M.; Cloete, C. K.; Njoroge, M.; Gibhard, L.; Lawrence, N.; Reader, J.; van der Watt, M.; Wittlin, S.; Birkholtz, L. M.; Chibale, K.
Antimalarial benzimidazole derivatives incorporating phenolic mannich base side chains inhibit microtubule and hemozoin formation: structure-activity relationship and in vivo oral efficacy studies
Journal
Journal of medicinal chemistry
Volume
64
Number
8
Pages / Article-Number
5198-5215
Mesh terms
Administration, Oral; Animals; Antimalarials, therapeutic use; Benzimidazoles, therapeutic use; Disease Models, Animal; Drug Design; Drug Resistance, drug effects; Drug Stability; Half-Life; Hemeproteins, metabolism; Life Cycle Stages, drug effects; Malaria, parasitology; Male; Mannich Bases, chemistry; Mice; Mice, Inbred BALB C; Microsomes, Liver, metabolism; Microtubules, metabolism; Plasmodium berghei, physiology; Structure-Activity Relationship
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.
