Novel phthalimide-pyrimidine hybrids as potent anti-tubercular agents

Abstract

<title>Abstract</title> 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 <bold>(6a-f) </bold>and 2-(6-amino-2-(2-(arylidene) hydrazineyl)pyrimidin-4-yl)isoindoline-1,3-dione <bold>(8a-f)</bold>,<bold> </bold>respectively, as phthalimide-aminopyrimidine hybrids. Compounds showed a wide range of anti-tubercular activity against sensitive MDR and XDR <italic>M. tuberculosis</italic> strains, with <italic><bold>8f</bold></italic> and <italic><bold>6a</bold></italic> showing the highest activity. <italic><bold>8f</bold></italic> and <italic><bold>6a</bold></italic> inhibited sensitive <italic>M. tuberculosis</italic> with MIC =0.48 μg/ml and 0.98 μg/ml, respectively, comparable to isonizide (INH) (MIC =0.12 μg/ml). Both <italic><bold>8f</bold></italic> and <italic><bold>6a</bold></italic> 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.<italic> </italic>Both<italic> </italic><italic><bold>8f</bold></italic><bold> </bold>and <italic><bold>6a</bold></italic> could inhibit mycobacterial InhA enzyme <italic>in-vitro</italic> (IC₅₀ =0.717±0.033µM and 1.646±0.069µM, respectively). Molecular docking simulation revealed that <italic><bold>8f</bold></italic><bold> </bold>and <italic><bold>6a</bold></italic> 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 <italic><bold>6a </bold></italic>and <italic><bold>8f</bold></italic> 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.