Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies. Issue 17 (1st September 2015)

• Record Type: Journal Article
• Authors: Ongarora, Dennis S.B.; Strydom, Natasha; Wicht, Kathryn; Njoroge, Mathew; Wiesner, Lubbe; Egan, Timothy J.; Wittlin, Sergio; Jurva, Ulrik; Masimirembwa, Collen M.; Chibale, Kelly
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 17(2015)
• Page Start: 5419
• Page End: 5432
• Publication Date: 2015-09-01
• Subjects: po oral administration -- iv intraveneous administration -- MSD mean survival days -- PK pharmacokinetics -- AUC area under curve -- TLC thin layer chromatography -- ADQ amodiaquine -- ACN acetonitrile -- mp melting point -- equiv equivalent; Amodiaquine -- Benzoxazole -- Antiplasmodial activity -- Antimalarial activity -- Malaria -- Reactive metabolite -- 4-Aminoquinolines -- Bioactivation -- Structure–activity relationship -- β-Haematin -- Quinone imine; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.07.051
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum . Structure–activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50 s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4 × 10 mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively.