甲磺酰胺苯乙胺类化合物抗心律失常活性的定量构效关系研究(Ⅰ)

QSARStudyonAntiarhythmicActivityofSomeMethanesulfonamidoPhenethylaminoDerivativesJiMin,LiuHong,JinSong,LiuLigang,HuaWeiyi,JiNianningDivisionofMedicinalChemistry,ChinaPharmaceuticalUniversity,Nanjing210009AbstractStructuresof12substitutedmethanesulfonamido

以ＰＯＬＹＧＥＮ软件中的ＣＨＡＲＭｍ程序和集团坐标轮换法，对合成的１２个甲磺酰胺苯乙胺类化合物的结构进行计算机分子模拟。根据所得化合物的能量最低构象，计算了其ＶＤＷ体积、偶极矩、总键能、总键角能、总非正则能以及氮原子电荷等值，并对这些化合物进行ＣＮＤＯ／２法量化计算，这些计算结果作为结构参数分别与１２个化合物抗心律失常活性进行相关分析，以逐步回归法建立了两个相关性较好的方程：ｌｇｌ／ＭＥＣ＝６．９９９１－０．３８４２Ｘ２＋３．６７９６Ｘ５［ｎ＝１２，ｒ＝０．８５５９７５，ｓ＝０．１８９６７２，Ｆ＝１２．３３４６４＞Ｆ１－０．０５（３，９）＝３．８６］；ｌｇｌ／ＭＥＣ＝１４．７０３８－２１３．２６９２Ｘ４－１０．４８２９Ｘ５［ｎ＝１２，ｒ＝０．９３１９１９，ｓ＝０．１３３０４７，Ｆ＝２９．７１３５４＞Ｆ１－０．０１（３，９）＝６．９９］。结果提示，这类化合物的抗心律失常活性与分子中的原子轨道杂化程度和氮原子对分子ＨＯＭＯ和ＬＵ－ＭＯ的贡献有关，可以看出。

Structures of 12 substituted methanesulfonamido phenethylamino derivatives were mimicked by computer aided molecular modeling. The POLYGEN software and the method of clique coordinate transformation were involved in these modeling processes. 12 parameters were calculated by the CHARMm optimized geometry and 10 parameters were calculated by CNDO/2 on the basis of dominant conformations of these compounds. Two significant correlation equations between antiarrhythmic activity(l gl/MEC) of the compounds and their structural parameters mentioned above, were established by stepwise regression analysis. lg l/MEC=6.9991-0.3842 X 2+3.6796X 5 n=12, r=0.855975, s=0.189672, F=12.33464>F 1-0.05 (3,9)=3.86 lg l/MEC=14.7038-213.269 2X 4-10.4829X 5 n=12, r=0.931919, s=0.133047, F=29.71354>F 1-0.01 (3,9)=6.99 The QSAR equations showed that the antiarrhythmic activity of these compounds increased with the increase of improper energy(IE) and the decrease of bond energy(BE) of molecules. The results also suggested that the antiarrhythmic activity of these methanesulfonamido phenethylamino derivatives might be mainly dependent upon their HOMO charge density and LUMO charge density for nitrogen atom in molecules.