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In vitro antimalarial activity and molecular modeling studies of novel artemisinin derivatives

机译：新型青蒿素衍生物的体外抗疟活性和分子模型研究

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摘要

Cerebral malaria is a serious and sometimes fatal disease caused by a Plasmodium falciparum parasite that infects a female anopheles mosquito which feeds on humans. The parasites responsible for mosquito-borne infectious diseases are increasingly resistant to current drug approaches, and almost half of the world is at risk of contracting an illness. A series of twenty five new ether and ester derivatives of dihydroartemisinin (DHA) have been prepared based on in silico studies and in vitro antimalarial activity and later assessed against the chloroquine sensitive NF-54 strain of Plasmodium falciparum. In general the incorporation of nitro functionality in ester derivatives enhances the activity relative to artemisinin. Most of the ether derivatives were found to be as active as DHA, while 11-OH ether derivatives were not as active as DHA. The most potent analogue in the series was compound 21 which was several fold more active than artemisinin against P. falciparum used in the study. Molecular docking and ADMET studies were performed to explore the possible mode of interaction of active compounds in to the binding site pocket of malaria parasite target enzyme plasmepsin-II and evaluated compliance with oral bioavailability and pharmacokinetics parameters. The ester derivatives 19 and 20 were found to be twice active than DHA, having nitro functionality showing IC50 10.58 nM and 8.54 nM respectively.
机译：脑疟是由恶性疟原虫寄生虫感染的严重疾病，有时甚至是致命的疾病，这种寄生虫感染以人类为食的雌性按蚊。负责蚊媒传染病的寄生虫对目前的药物治疗方法越来越有抵抗力，世界上将近一半的人有染上疾病的风险。基于计算机研究和体外抗疟活性，已制备了一系列二十五种新的二氢青蒿素（DHA）醚和酯衍生物，随后评估了其对恶性疟原虫的氯喹敏感性NF-54菌株的作用。通常，相对于青蒿素，在酯衍生物中引入硝基官能团可增强活性。发现大多数醚衍生物的活性与DHA相同，而11-OH醚衍生物的活性与DHA不一样。该系列中最有效的类似物是化合物21，它对青蒿素的抗恶性疟原虫活性比青蒿素高出几倍。进行了分子对接和ADMET研究，以探索活性化合物与疟疾寄生虫靶酶纤溶酶II的结合位点口袋相互作用的可能模式，并评估其与口服生物利用度和药代动力学参数的依从性。发现酯衍生物19和20的活性是DHA的两倍，其硝基官能团的IC 50分别为10.58 nM和8.54 nM。

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