Novel phthalimide-pyrimidine hybrids as potent anti-tubercular agents

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 (6a-f) and 2-(6-amino-2-(2-(arylidene) hydrazineyl)pyrimidin-4-yl)isoindoline-1,3-dione (8a-f), respectively, as phthalimide-aminopyrimidine hybrids. Compounds showed a wide range of anti-tubercular activity against sensitive MDR and XDR M. tuberculosis strains, with 8f and 6a showing the highest activity. 8f and 6a inhibited sensitive M. tuberculosis with MIC =0.48 μg/ml and 0.98 μg/ml, respectively, comparable to isonizide (INH) (MIC =0.12 μg/ml). Both 8f and 6a inhibited MDR strain with MIC=1.95 μg/ml and 7.81 μg/ml, respectively, and XRD with MIC=7.81 μg/ml and 15.63 μg/ml, respectively. Both 8f and 6a could inhibit mycobacterial InhA enzyme in-vitro (IC₅₀ =0.717±0.033µM and 1.646±0.069µM, respectively). Molecular docking simulation revealed that 8f and 6a were also capable of interacting at the catalytic site of the InhA enzyme in a manner similar to the native ligand, via binding with NAD⁺ and Tyr158. Compounds 6a and 8f showed physicochemical properties of oral bioavailable drug-like compounds with high gastrointestinal absorption. Predictions showed that compounds have no side effects on the CNS and no anticipated hepatotoxicity, mutagenicity, or acute oral toxicity in models.