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 were accessed through a silver‐catalyzed three‐component reaction of trifluorodiazoethane with in situ generated Schiff base from corresponding quinolinylamine and aldehydes. 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 32 compounds, four showed the most promising antimalarial activity with IC50 values ranging from 4 to 20 nM against Pf3D7 (chloroquine‐sensitive) and from 120 to 450 nM against PfK1 (chloroquine‐resistant) strains. One of these compounds was also found to be effective in animal studies; it showed a 99.9 % decrease in parasitic load on day 7 post‐infection along with a 40 % cure rate and longest host life span. We identified a novel class of 4‐aminoquinoline‐trifluormethyltriazolines as potential antiplasmodial agents. The compounds were accessed through a silver‐catalyzed three‐component reaction of trifluorodiazoethane with in situ generated Schiff base from corresponding quinolinylamine and aldehydes. Four of the 32 compounds showed promising antimalarial activity: IC50 values 4–20 nM against Pf3D7 (chloroquine‐sensitive) and 120–450 nM against PfK1 (chloroquine‐resistant) strains. One compound was also effective in animal studies, with a 99.9 % decrease in parasitic load on day 7 post‐infection and a 40 % cure rate and longest host life span.