1,2,4-Triazole amides: Design, synthesis, characterisation, in vitro and in silico evaluation against blood stage parasites of Plasmodium falciparum.

Malaria, a protozoan parasitic disease caused by Plasmodium species, poses significant health risks in endemic regions and contributes to substantial morbidity and mortality. The intricate lifecycle of the parasite, coupled with the emergence of drug-resistant strains, has severely impacted the effectiveness of current anti-malarial treatments. In response, the present study attempts to demonstrate the blood-stage anti-plasmodial action of 30 triazole derivatives designed based on molecular hybridisation technique, and physicochemical properties. Each synthesised compound underwent thorough characterisation using various spectroscopic techniques. The in vitro blood-stage inhibitory activity of these 1,2,4-triazole amides was assessed against a mixed-stage culture of the human malarial parasite P. falciparum, Pf 3D7 using the SYBR 1 green assay. In the entire library, the meta-substituted derivatives displayed pronounced activity, with the 3,5-dimethyl (17), 3-Br (11) and 3-Cl (7) derivatives emerging as the most promising in the entire library with IC50 values of 0.87 μg/mL, 1.27 μg/mL and 2.17 μg/mL, respectively. These compounds also demonstrated significant activity against the chloroquine-resistant INDO strain of plasmodium, with IC50 values of 1.55 μg/mL, 5.70 μg/mL and 2.30 μg/mL, respectively. Compounds 17, 11, and 7 exhibited no hemolytic or cytotoxic effects on uninfected red blood cells, human Mo7e cells, and murine BA/F3 cells. In silico docking studies of the compounds with Plasmodium falciparum-dihydrofolate reductase displayed favourable interactions with the active site of the protein, providing further evidence of the anti-plasmodial potential of these compounds. This study represents the first report of 1,2,4-triazole amides as potent anti-plasmodial agents, offering a promising avenue for further exploration.