Synthesis and bioevaluation of novel 4-aminoquinoline-tetrazole derivatives as potent antimalarial agents

•A series of 4-aminoquinoline-tetrazoles were synthesized via Ugi multicomponent reaction.•Most of the compounds exhibited potent antimalarial activity against K1-strain.•Compounds 20 and 23 found to be orally active against CQ-resistant strain of Plasmodium yoelii.•In vivo oral pharmacokinetic study of compound 20 and 23 were also performed.•Compound 20 and 23 could be worthy candidates for developing new antimalarials.

A series of novel tetrazole derivatives of 4-aminoquinoline were synthesized and screened for their antimalarial activities against both chloroquine-senstive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum as well as for cytotoxicity against VERO cell lines. Most of the synthesized compounds exhibited potent antimalarial activity as compared to chloroquine against K1-strain. Compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii following both intraperitoneal (ip) and oral administration, wherein compounds 20 and 23 each showed in vivo suppression of 99.99% parasitaemia on day 4.

Graphical abstractSeries of novel 4-aminoquinoline-tetrazole derivatives were synthesized. Most of the compounds exhibited potent activity against resistant strain (K1). Compounds 20 and 23 also showed in vivo suppression of 99.99% parasitaemia on day 4.Figure optionsDownload full-size imageDownload as PowerPoint slide