Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy

Abstract

A novel 4-aminoquinoline derivative [(<i>S</i>)-7-chloro-<i>N</i>-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against <i>in vitro</i> and <i>in vivo</i> experimental malaria models. The <i>in vitro</i> absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.