Synthesis and Antimalarial Activity of 4-Methylaminoquinoline Compounds against Drug-Resistant Parasite.

A series of novel 4-aminoquinoline analogues bearing a methyl group at 4-aminoquinoline moiety were synthesized a new and robust synthetic route comprising -butoxycarbonyl (Boc) deprotection-methylation cascade resulting in the corresponding N-methylated secondary amine using Red-Al and an efficient microwave-assisted strategy for the fusion of N-methylated secondary amine with 4-chloroquinoline nucleus to access the series of novel 4--methylaminoquinoline analogues. The new series of compounds were evaluated for their antimalarial activity in and models. Among 21 tested compounds, - have shown a half-maximal inhibitory concentration (IC) value less than 0.5 μM (., <500 nM) against both chloroquine-sensitive strain 3D7 and chloroquine-resistant strain K1 of with acceptable cytotoxicity. Based on the antimalarial activity, selected compounds were screened for their antimalarial activity against (a multidrug-resistant) parasite in Swiss mice. Most of the compounds have shown significant inhibition on day 4 post infection at the oral dose of 100 mg/kg. Compound has shown 100% parasite inhibition on day 4, and out of five treated mice, two were cured till the end of the experiment. The present study suggests that 4-methylamino substitution is well tolerated for the antiplasmodial activity with reduced toxicity and therefore will be highly useful for the discovery of a new antimalarial agent against drug-resistant malaria.