Novel series of 1,2,4-trioxane derivatives as antimalarial agents

• Published in: Journal of enzyme inhibition and medicinal chemistry 2017-01, Vol.32 (1), p.1159-1173
• Main Authors: Rudrapal, Mithun, Chetia, Dipak, Singh, Vineeta
• Format: Article
• Language: English
• Subjects: antimalarial; Antimalarial activity; Antimalarial agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Cysteine proteinase; Dose-Response Relationship, Drug; Drug development; Erythrocytes; falcipain 2 inhibitors; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Malaria; Malaria - drug therapy; Molecular Docking Simulation; Molecular Structure; P. falciparum; Parasitic Sensitivity Tests; Plasmodium falciparum - drug effects; Research Paper; resistance; Structure-Activity Relationship; trioxane derivatives
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2017.1363742

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 IC 50 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.