Pharmacophoric model building for antitubercular activity of the individual Schiff bases of small combinatorial library

Synthesis and evaluation of anti-TB activity of individual compounds of Schiff bases combinatorial library were done against Mycobacterium tuberculosis H37Rv at a single concentration of 6.25 μg/mL according to the protocol of TAACF. Compounds 2C and 3D produced 99% inhibitory activity on the investigated organism, while the other tested compounds showed lower activity ranging from 35 to 84%. It was found that there are no relation between the anti-TB activity of the tested compounds and their lipophilicity expressed by C log P of these compounds. A 3D pharmacophoric model has been generated by Molecular Operating Environment (MOE) using a training set of 10 reported anti-TB compounds and testing the synthesized compounds (1A, 1B, 1D, 1E, 2C, 3A, 3C, 3D, 3E and 4A–4E). The generated pharmacophoric features include, F1: hydrogen bond donors (Don), F2: aromatic rings (Aro), F3: hydrogen bond acceptors (Acc)/metal ligator (ML), F4: Aro/hydrophobic (Hyd). In all hit set, it was found that the amidic nitrogen CONH–NC fitted the region of the Don, F1, while the amidic carbonyl group fitted the region of the Acc/ML, F3. The distances bridging F1 to F2, F3 and F4 were essential for anti-TB activity in the developed pharmacophore model, as it was confirmed from model validation procedure.

Graphical abstractA 3D pharmacophoric model has been generated by Molecular Operating Environment (MOE) using a training set of 10 reported anti-TB Schiff bases and testing the synthesized ones.Figure optionsDownload full-size imageDownload as PowerPoint slide