Antimalarial Pyrido[1,2‑a]benzimidazole Derivatives with Mannich Base Side Chains: Synthesis, Pharmacological Evaluation, and Reactive Metabolite Trapping Studies

• Published in: ACS infectious diseases 2019-03, Vol.5 (3), p.372-384
• Main Authors: Okombo, John, Brunschwig, Christel, Singh, Kawaljit, Dziwornu, Godwin Akpeko, Barnard, Linley, Njoroge, Mathew, Wittlin, Sergio, Chibale, Kelly
• Format: Article
• Language: English
• Subjects: Animals; Antimalarials - administration & dosage; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacokinetics; Benzimidazoles - administration & dosage; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacokinetics; Drug Evaluation, Preclinical; Humans; Malaria - drug therapy; Malaria - parasitology; Male; Mannich Bases - chemistry; Mice; Mice, Inbred BALB C; Plasmodium berghei; Plasmodium falciparum - drug effects; Plasmodium falciparum - physiology; Structure-Activity Relationship
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.8b00279

A novel series of pyrido­[1,2-a]­benzimidazoles bearing Mannich base side chains and their metabolites were synthesized and evaluated for in vitro antiplasmodium activity, microsomal metabolic stability, reactive metabolite (RM) formation, and in vivo antimalarial efficacy in a mouse model. Oral administration of one of the derivatives at 4 × 50 mg/kg reduced parasitemia by 95% in Plasmodium berghei-infected mice, with a mean survival period of 16 days post-treatment. The in vivo efficacy of these derivatives is likely a consequence of their active metabolites, two of which showed potent in vitro antiplasmodium activity against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum (P. falciparum) strains. Rapid metabolism was observed for all the analogues with