Yadav Dharmendra Kumar, Dhawan Sangeeta, Chauhan Akanksha, Qidwai Tabish, Sharma Pooja, Bhakuni Rajendra Singh, Dhawan Om Prakash, Khan Feroz
Metabolic & Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.-CIMAP, Kukrail Picnic Spot Road, Lucknow-226015 (U.P.) India.
Curr Drug Targets. 2014;15(8):753-61. doi: 10.2174/1389450115666140630102711.
To screen the active antimalarial novel artemisinin derivatives, a QSAR modeling approach was used. QSAR model showed high correlation (r(2)= 0.83 and rCV(2)= 0.81) and indicated that Connectivity Index (order 1, standard), Connectivity Index (order 2, standard), Dipole Moment (debye), Dipole Vector X (debye) and LUMO Energy (eV) well correlate with activity. High binding likeness on antimalarial target plasmepsin was detected through molecular docking. Active artemisinin derivatives showed significant activity and indicated compliance with standard parameters of oral bioavailability and ADMET. The active artemisinin derivatives namely, β-Artecyclopropylmether HMCP (A3), β- Artepipernoylether (PIP-1) (A4) and 9-(β-Dihydroartemisinoxy)methyl anthracene (A5) were semi-synthesized and characterized based on its (1)H and (13)C NMR spectroscopic data and later activity tested in vivo on mice infected with multidrug resistant strain of P. yoelii nigeriensis. Predicted results were successfully validated by in vivo experiments.
为筛选具有抗疟活性的新型青蒿素衍生物，采用了定量构效关系（QSAR）建模方法。QSAR模型显示出高度相关性（r(2)= 0.83和rCV(2)= 0.81），表明连接性指数（一阶，标准）、连接性指数（二阶，标准）、偶极矩（德拜）、偶极向量X（德拜）和最低未占分子轨道能量（电子伏特）与活性具有良好的相关性。通过分子对接检测到对抗疟靶点胃蛋白酶具有较高的结合相似性。活性青蒿素衍生物显示出显著活性，并表明符合口服生物利用度和药物代谢动力学、药物毒性、药物分布、药物排泄及药物相互作用（ADMET）的标准参数。活性青蒿素衍生物，即β-环丙甲基醚蒿甲醚（A3）、β-哌啶基醚蒿甲醚（PIP-1）（A4）和9-(β-二氢青蒿素氧基)甲基蒽（A5）进行了半合成，并根据其氢核磁共振（(1)H）和碳核磁共振（(13)C）光谱数据进行了表征，随后在感染了约氏疟原虫耐多药菌株的小鼠体内进行了活性测试。预测结果通过体内实验成功验证。
