HIV-1逆转录酶抑制剂的三维定量构效关系

采用比较分子力场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)对一系列非核苷类HIV-1逆转录酶抑制剂(苯磺酰基亚胺噻唑类化合物)进行了三维定量构效关系的研究,获得了高可靠性的CoMFA和CoMSIA模型,其交叉验证相关系数q2值分别为0.748和0.607.通过对CoMFA和CoMSIA模型三维等势图的分析,确定了该类化合物抗HIV-1活性的结构要求.研究结果表明,对苯磺酰基亚胺噻唑类化合物而言,在苯环的C-5位引入体积大和电负性强的基团能增加其抑制活性;苯环的C-2位的氢键给体基团对活性有利;噻唑环的R2取代基疏水性增大会降低生物活性.研究结果表明,可以指导新HIV-1逆转录酶抑制剂的设计和合成.     

HIV-1逆转录酶抑制剂2-氨基6-苯磺酰基苄腈及其类似物活性OSAR研究

首先利用半经验AM I量子化学方法计算了54个2-氨基-6-苯磺酰基苄腈及其类似物的物理化学、电子结构、指示变量等共28个参数,然后使用偏最小二乘,穷举回归和混沌遗传乘法训练的人工神经网络方法建立了这些参数和其抑制H IV-1逆转录酶活性之间的定量构效关系模型,为设计、合成更高生物活性的该类化合物提供了理论参考。     

Novel 2-chloro-8-arylthiomethyldipyridodiazepinone derivatives with activity against HIV-1 reverse transcriptase

Based on the molecular modeling analysis against Y181C HIV-1 RT, dipyridodiazepinone derivatives containing an unsubstituted lactam nitrogen and 2-chloro-8-arylthiomethyl were synthesized via an efficient route. Some of them were evaluated for their antiviral activity against HIV-1 RT subtype E and were found to exhibit virustatic activity comparable to some clinically used therapeutic agents.     

Sommelet-hauser rearrangement of an ammonium ylide derived from the HIV-1 reverse transcriptase inhibitor nevirapine

Functionalization at the 3-position of the dipyridodiazepinone nevirapine ( 1 ) has been accomplished by Sommelet-Hauser rearrangement of an ylide derived from 1 . Treatment of N-cyanomethylpyrrolidinium salt 4 with potassium tert-butoxide in a mixture of dimethylsulfoxide and tetrahydrofuran at ?10°, followed by acid hydrolysis, afforded a mixture of compounds 5 and 6 in a ratio of 1:1.8. Upon treatment of 4 with sodium amide in liquid ammonia, 5 and 6 were obtained in a ratio of 1.5:1 and a combined yield of 83%. Compound 5 is the desired product resulting from Sommelet-Hauser rearrangement of 4 , whereas 6 derives from competing Stevens rearrangement and intramolecular cyclization of the aldehyde produced upon hydrolysis. Baeyer-Villiger oxidation of 5 afforded the 3-hydroxy derivative 2 , a recently identified metabolite of nevirapine.