Design, Synthesis, Characterization, and In silico Pharmacokinetic Evaluation of N-(2-(2-hydroxyquinolin-3-yl)-4-oxothiazolidin-3-yl) IsonicotinamideAnalogues as Antitubercular Agents

Introduction: Tuberculosis remains a major global health concern, particularly with the emergence of multidrug-resistant strains, necessitating the development of new therapeutic agents. A novel series of quinoline-isonicotinohydrazide derivative scaffolds, representing a versatile class of heterocycles, was designed, synthesized, and evaluated for structural, pharmacokinetic, and antitubercular potential via spectral characterization and in silico studies. Materials and Methods: A novel series of N-(2-(2-hydroxyquinolin-3-yl)-4-oxothiazolidin-3- yl) isonicotinamide derivatives (4a–4e) were designed, synthesized, and structurally characterized using IR, ¹H NMR, ¹³C NMR, and mass spectrometry. In silico studies were performed using molecular docking (GLIDE, Schrödinger Suite) against the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) enzyme. Molecular dynamics simulations (100 ns, DESMOND) were conducted to assess complex stability. ADME and pharmacokinetic properties were predicted using SwissADME. Results: All synthesized compounds displayed favorable docking affinities (–8.7 to –9.6 kcal/mol), significantly stronger than isoniazid (–5.6 kcal/mol). Compound 4b exhibited the highest binding energy (–9.6 kcal/mol), comparable to the native inhibitor (–9.8 kcal/mol), supported by stable RMSD values during MD simulations. ADME profiling indicated compliance with Lipinski’s Rule of Five, acceptable physicochemical parameters, and promising oral bioavailability. Compounds 4c and 4d demonstrated high gastrointestinal absorption and CYP enzyme inhibition potential, while compound 4e showed a balanced pharmacokinetic profile with no major toxicity alerts, highlighting it as the most promising lead. Discussion: The synthesized compound 4d exhibited the strongest interaction with a binding energy of –9.9 kcal/mol and maintained its orientation within the binding site, as confirmed by RMSD values. In silico metabolic analysis indicated that compounds likely underwent phase I and II biotransformations primarily via hepatic enzymes. Physicochemical parameters, including molecular weight, topological polar surface area (TPSA), and hydrogen bond donors/acceptors, were within acceptable ranges, supporting oral bioavailability. Conclusion: The synthesized quinoline-isonicotinohydrazide derivatives, particularly compounds 4b, 4d, and 4e, possess strong binding interactions with InhA and exhibit favorable pharmacokinetic properties. These findings suggest their potential as lead scaffolds for the development of next-generation antitubercular agents, warranting further biological evaluation.