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Abstract
Among three series of 1,2,4-trioxane derivatives, five compounds showed good in vitro antimalarial activity, three compounds of which exhibited better activity against P. falciparum resistant (RKL9) strain than the sensitive (3D7) one. Two best compounds were one from aryl series and the other from heteroaryl series with IC50 values of 1.24 µM and 1.24 µM and 1.06 µM and 1.17 µM, against sensitive and resistant strains, respectively. Further, trioxane derivatives exhibited good binding affinity for the P. falciparum cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski’s rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, 1,2,4-trioxane derivative(s) reported herein may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as P. falciparum falcipain 2 inhibitors against resistant malaria.
Highlights
Malaria continues to be a major lethal infectious disease of human beings, affecting around 200–300 million people and causing approximately 430,000 deaths every year globally
Our study was aimed at developing 1,2,4-trioxane derivatives as newer synthetic peroxide-based antimalarial agents having comparatively simpler molecular framework than conventional antimalarial drug molecules with activity against resistant malaria parasites
Newer series of 1,2,4-trioxane derivatives reported have potential in vitro antimalarial effectiveness and further studies are required for the evaluation of their toxicity, antimalarial efficacy, and pharmacokinetics in animal models
Summary
Malaria continues to be a major lethal infectious disease of human beings, affecting around 200–300 million people and causing approximately 430,000 deaths every year globally. Considering all above facts, development of peroxide-based synthetic compounds is expected to provide effective antimalarials agents with limited toxicity issues and ready to be available at affordable cost. SS R97193 therapeutic option for the treatment of malaria with good clinical outcomes (desired potency with optimal pharmacokinetics) and resistant preventing action It may represent a new class of synthetic, new-generation and orally active peroxides, with optimal antimalarial potency against resistant P. falciparum malaria. C, 4-pyridyl), 188.42 (C1⁄4O); MS (ESþ), m/z (%): 247.47 (100), [M]þ, 204.78 (67), 172.09 (38), 156.20 (24); CHN anal. for C13H13NO4 (247.25), calc. (%): C, 63.15; H, 5.30; N, 5.67; O, 25.88, found (%):C, 63.87; H, 5.06; N, 6.12; O, 25.06
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