Bulletin of the National Research Centre (Aug 2020)
Quantitative structure-activity relationship (QSAR) modelling study of some novel carboxamide series as new anti-tubercular agents
Abstract
Abstract Background QSAR modelling was performed on thirty-five (35) newly discovered compounds of N-(2-phenoxy) ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA) to predict their biological activities against Mycobacterium tuberculosis (MTB-H37Rv strain) by using some numerical data derived from structural and chemical features (descriptors) of the compounds. Results At first, the structure of the compounds was accurately drawn and optimized using the Spartan 14 software at DFT level of theory with B3LYP/6-31G** basis set in a vacuum. The diverse chemometric descriptors were computed from the optimized structures using the PaDEL descriptors software, and the division of the dataset into training and test sets was done based on Kennard-Stone’s algorithm. Five (5) models were generated from the training set using genetic function approximation, and model 1 was chosen as the best due to its robust internal and external validation metrics (R 2 train = 0.8563, R 2 adjusted = 0.8185, PRESS = 3.5724, average R ¯ m 2 $$ {\overline{R}}_m^2 $$ (LOO-train) = 0.6751, Q2 cv = 0.7534, R pred 2 = $$ {R}_{\mathrm{pred}}^2= $$ 0.7543, R 2 test = 0.6993) which passed the model criteria of acceptability. 6-Bromo-N-(2-(4-bromophenoxy) ethyl)-2-ethylimidazo[1,2-a] pyridine-3-carboxamide (compound 13) was used as the structural template for the in silico design due to its high pMIC, and it is within the model’s chemical space. Conclusion Based on the information obtained from model 1, six (6) designed compounds with higher anti-tubercular activity were obtained. Furthermore, the ADME and drug-likeness prediction of the designed molecules showed good pharmacokinetic properties which indicate the application prospect of these compounds as novel MTB-H37Rv inhibitors. This research could help the medicinal chemists and pharmaceutical practitioners in future designing and development of more potent drug candidates. Graphical abstract
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