Design and evaluation of novel N-Aryl oxamic acid derivatives as potential anti-tubercular inhibitors: A comprehensive molecular modeling study

Abstract

The emergence of multidrug-resistant strains severely challenges tuberculosis (TB) management, necessitating the development of novel therapeutics targeting unexplored virulence pathways. The enzyme Protein Tyrosine Phosphatase B (PtpB), a critical contributor to the virulence of Mycobacterium tuberculosis , is an attractive target for developing new therapeutic inhibitors. This study describes the comprehensive computational design and evaluation of a series of novel N-aryl oxamic acid derivatives as potential PtpB inhibitors. A robust 2D-QSAR model was developed (R² = 0.911, Q² = 0.885) utilizing three key molecular descriptors (AATS6v, ATSC2p, SpMin8_Bhe) to predict anti-tubercular activity. Among 36 screened compounds, 18 and 8 emerged as top candidates, demonstrating superior MolDock scores (-112.006 and −108.369 kcal/mol, respectively) and stable interactions with critical PtpB residues (ARG63, ARG166) compared to the reference drug isoniazid. Molecular dynamics simulations confirmed the stability of the ligand-PtpB complexes over 100 ns. Ten new analogues of compound 18 were designed (18A-18I), with analogue 18E showing the strongest predicted binding to the target enzyme. Density Functional Theory (DFT) calculations revealed a lower energy gap (ΔE = 3.68 eV) for compound 18, indicating heightened reactivity, while Molecular Electrostatic Potential (MEP) and Non-Covalent Interaction (NCI) analyses provided insights into favourable interaction sites and intramolecular stability. All screened compounds, particularly 18, complied with Lipinski’s rules and displayed promising predicted ADMET properties, including high intestinal absorption and minimal toxicity risks. These findings collectively nominate the N-aryl oxamic acid derivative 18 as a highly promising, synthetically tractable lead candidate for further experimental development against drug-resistant tuberculosis. • Rational design of a new series of N-aryl oxamic acid derivatives targeting the virulence factor Protein Tyrosine Phosphatase B (PtpB) in Mycobacterium tuberculosis . • Development of a robust and validated 2D-QSAR model (R² = 0.911, Q² = 0.885) for accurate prediction of anti-tubercular activity. • Analogue 18E is identified as the top candidate with an exceptional predicted binding affinity (MolDock score: -136.549 kcal/mol), surpassing the lead compound 18 and the standard drug isoniazid. • All top candidates, especially 18E, exhibit excellent predicted pharmacokinetic and safety profiles, complying with Lipinski's rules and showing high intestinal absorption with low toxicity risks. • Integration of molecular docking, dynamics simulations (100 ns), DFT, MEP, and NCI analyses provides a comprehensive mechanistic understanding of binding stability, reactivity, and non-covalent interactions.