Quantitative Structure - Activity Relationship Study of some N-substituted -2-Isonicotinoyl Hydrazine Carboxamide Derivatives as Anti Tuberculosis Agents

Abstract

Tuberculosis (TB) is a chronic disease caused by Mycobacterium tuberculosis. The appearance of multidrug-resistant strains of Mycobacterium tuberculosis (M.tb) has led to an urgent search for new and effective anti-TB drugs. Isoniazid remains the main and most effective component of all the multiple therapeutic regimens recommended by the World Health Organization. In this work number of computer programs were used, such as ACD/Labs , MOE and SPSS. From previously published article , (21 compounds) of N-substituted -2-isonicotinoyl hydrazine carboxamide derivatives were divided into two groups, training set (15 compounds) and a test set(6 compounds) ,one of them was excluded). The biological activity (MIC) of data set was converted to logarithmic scale (pMIC) .The biological activity was correlated with selected descriptors were chosen according to correlation matrix to create a (QSAR) models. The models were used in study the relationship between structure and effectiveness by using the (MOE) program by (PLS) method. A number of equations were obtained in 2D ,3D and (2D+3D) dimensionals. The validity of the equations was confirmed by using the internal and external validation in addition to multiple linear regression (MLR) statistical analysis method to increase the strength and robustness of the equations. The equations were used to predicted the biological activity of data set compounds. The best equations in the (2D) dimensional with value of correlation coefficient R2 = 0.87. Also based on internal validation by using the training set (LOO, leave-one-out) method was obtained value Q2 =0.73 and the external investigation was conducted using the test set the value was R2pred= 0.70 and the equation is pMIC=8.00423-0.24582chiov-0.00617slog_VSA9-0.35165kier2 , And also the equation with a correlation coefficient R2=0.84, Q2=0.70, R2pred=0.71 pMIC=6.07370+0.10173kierA3-0.70720chi1v-0.21145logp(o/w) The best equation in the (3D) dimensional has the highest correlation coefficient R2 =0.96 values of Q2= 0.9 and R2pred= 0.70 according to the equation pMIC=10.25002-0.01536ASA-1.15755E_oop-2.58249npr1. In addition to in (2D+3D) dimensional pMIC=7.5644-1.1662E_oop-0.0103ASA-0.2475logp(o/w) with correlation coefficient R2=0.93 ,Q2=0.89 and R2pred=0.73 The Fifty eight new compounds were designed , the four equations were applied on the new designed compounds (58) of N-substituted -2-isonicotinoyl hydrazine carboxamide to predict the biological activity values ( pMIC) for them and compared to biological activity of Isoniazid (INH) pMIC = -0.3 . The compounds (XXIX, XXX, XXXII,XLI, XLIX) were showed biological activity values close to the biological activity value of Isoniazid (INH). The molecular docking was applied on the compounds of the data set and the 58 new designed compounds with (4TRO) protein. 4TRO protein was obtained from the Protein Data Bank (PDB) ,the designed compounds that were showed more interaction with 4TRO (VII, VIII XLVII, XXXVII, XL, LI,LII).