4H-甲基咪唑苯二氮(艹卓)酮类抗HIV-1药物的量子化学研究

用分子力学MM3方法、量子化学MNDO法和从头算STO-3G基组计算了20个4H-甲基咪唑苯二氮(廿卓)酮HIV-1逆转录酶抑制剂的优势构型和电子结构,用逐步回归方法和BP神经网络方法得到其抗HIV-1活性与电子结构的定量构效关系.结果表明:(1)TIBO类衍生物的体积越大,极性越小,即流水性越大对抑制HIV-1活性越有利.(2)C环N上H原子可能是化合物的正电活性部位.(3)R′原子与受体作用时可能作为电子给予体,前线轨道中S的贡献比O大得多,故含S的TIBO化合物比含O化合物的活性高.(4)苯环上连接吸电子基团对活性有利,由于分子的正负电荷中心距离较近,极性较小,疏水性较大,故3位取代比2位取代活性更高.

Quantum Chemistry Studies on Tetrahydroimidazobenzodiazepinone Inhibitors of HIV-1

The optimization of geometries and electronic structures of 20 TIBO (Tetrahy-droimidazobenzodiazepinone) HIV-1 inhibitors had been performed by MNDO and ab initio quantum chemical methods. Asignificant QSARwas obtained as below:P_c= -10. 425+4. 216×10^-2V-19. 935Q_N12-4. 211Q_3x. The BP artificial neural network method can be used to predict the activities more accurately. The results show that (1) the activities of TIBO derivations will increase due to the larger volume and less polarity of molecules; (2) the hydrogen atom connected to nitrogen atom in ring Cmay be the active atom taking positive charge; (3) the R' atom(Sor O) is the electron donor to acceptor. The frontier molecular orbital component of Sis much bigger than that of O, and Sis more puweiful election donor than O, which indicate why the sulfur has a better activity than oxygen; (4) the electron acceptor substituents in ring Acan enhance the activity of TIBOderivations. Since smaller distance between positive and negative charge center leads to small polarity, 3-substituted derivations show better activities than 2-substituted derivations.