Synthesis, In Vitro and In Silico Molecular Docking Studies of Novel Phthalimide–Pyrimidine Hybrid Analogues to Thalidomide as Potent Antitubercular Agents
Abstract
Abstract Condensation reaction of aromatic aldehydes with 2-(6-amino-2-chloropyrimidin-4-yl)isoindoline-1,3-dione and 2-(6-amino-2-hydrazineylpyrimidin-4-yl)isoindoline-1,3-dione afforded 2-(2-chloro-6-((3 alkylbenzylidene)amino) pyrimidin-4-yl)isoindoline-1,3-dione derivatives 6a–f and 2-(6-amino-2-(2-(arylidene)hydrazinyl)pyrimidin-4-yl)isoindoline-1,3-dione derivatives 8a–f, respectively, as phthalimide–aminopyrimidine hybrids. The compounds showed a wide range of antitubercular activities against sensitive MDR and XDR M. tuberculosis strains, with 8f and 6a showing the highest activity; these compounds inhibited sensitive M. tuberculosis with MIC of 0.48 and 0.98 μg/mL, respectively, comparable to isonizide (INH) (MIC = 0.12 μg/mL). Both 8f and 6a inhibited the MDR strain with MIC of 1.95 and 7.81 μg/mL, respectively, and XRD with MIC of 7.81 and 15.63 μg/mL, respectively. Both 8f and 6a inhibited mycobacterial InhA enzyme in vitro (IC50 = 0.717± 0.033 μM and 1.646± 0.069 μM, respectively). Molecular docking simulations revealed that 8f and 6a were also capable of interacting at the catalytic site of the InhA enzyme via binding with NAD+ and Tyr158, in a manner similar to that of the native ligand. Compounds 6a and 8f exhibited physicochemical properties of oral bioavailable drug-like compounds with high gastrointestinal absorption. Predictions showed that the compounds are unlikely to have side effects on the CNS and no anticipated hepatotoxicity, mutagenicity, or acute…
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