Rudrapal Mithun, Chetia Dipak, Singh Vineeta
a Department of Pharmaceutical Sciences , Dibrugarh University , Dibrugarh , India.
b Parasite Bank, National Institute of Malaria Research (ICMR) , Sector 8 , Dwarka , New Delhi , India.
J Enzyme Inhib Med Chem. 2017 Dec;32(1):1159-1173. 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 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.
在三个系列的1,2,4 - 三恶烷衍生物中，有五种化合物表现出良好的体外抗疟活性，其中三种化合物对恶性疟原虫抗性（RKL9）菌株的活性比对敏感（3D7）菌株的活性更好。两种最佳化合物一种来自芳基系列，另一种来自杂芳基系列，对敏感和抗性菌株的IC值分别为1.24 μM和1.24 μM以及1.06 μM和1.17 μM。此外，基于Lipinski的五规则以及其他物理化学和ADMET参数，三恶烷衍生物对恶性疟原虫半胱氨酸蛋白酶疟原虫蛋白酶2受体（PDB编号：3BPF）表现出良好的结合亲和力，具有明确的类药物和药代动力学性质。鉴于具有抗疟潜力，本文报道的1,2,4 - 三恶烷衍生物作为新型抗疟先导物，在未来抗疟候选药物的发现和开发中，作为恶性疟原虫疟原虫蛋白酶2抑制剂对抗抗性疟疾可能是有用的。
