Incorporation of Trifluoromethyltriazoline in the Side Chain of 4-Aminoquinolines: Synthesis and Evaluation as Antiplasmodial Agents.

Reported herein is the identification of a novel class of 4-aminoquinoline-trifluormethyltriazoline compounds as possible antiplasmodial agents. The compounds have been accessed through an Ag-catalyzed three-component reaction of trifluorodiazoethane with in situ generated Schiff base from corresponding quinolinylamine and aldehydes. Besides, while attempting to incorporate a sulfonyl moiety, the triazoline formed underwent spontaneous oxidative aromatization to afford triazole derivatives. All synthesized compounds were tested for their antimalarial potential in vitro and in vivo. Out of the 32 compounds, 6e, 6i, 6o & 6s have shown the most promising antimalarial activity with IC50 of 4, 9, 18 & 20 nM against Pf3D7 (CQ sensitive) and 120, 100, 150, 450 nM against PfK1 (CQ resistant) strain respectively. Compound 6e was also found effective in animal studies; it showed a 99.9% reduction in parasitic load on day 7 post-infection along with a 40% cure rate and longest host life span.