Synthesis, molecular docking, molecular dynamic simulation and biological evaluation of novel 3,4-dihydropyridine derivatives as potent antituberculosis agents.

Abstract

Antibiotic resistance is an increasing threat to global public health. Developing new antibiotics and alternative treatments is crucial for combating resistant strains and reducing the global health burden. Hence, we synthesized and evaluated the antitubercular potential of dihydropyridine derivatives. A simplified Biginelli condensation method was employed to synthesize novel 3,4-dihydropyrimidine derivatives (4a-4m) via a one-pot three-component reaction using various substituted benzaldehydes. Reaction completion was monitored via thin-layer chromatography. The structures of the compounds were confirmed by FT-IR, mass spectrometry, ¹H NMR, and ¹³C NMR spectroscopy, and melting points were determined by differential scanning calorimetry. ADMET screening was performed for all synthesized compounds. Selected compounds were tested for their antibacterial and anti-tubercular activity against gram-positive and gram-negative bacteria. ADMET screening identified eight potential compounds: 4c, 4e, 4f, 4g, 4i, 4j, 4k, and 4m. The literature emphasized DprE1 as a critical target for anti-tubercular activity. Molecular docking studies revealed promising binding affinities for compounds 4g (- 7.67), 4d (- 7.316), 4e (- 7.062), and 4c (- 7.042) against DprE1. Furthermore, to study the binding stability and interaction patterns of protein-ligand complexes, a molecular dynamics simulation was performed. The stability of the protein-ligand complex was confirmed by low protein RMSD values and minimal fluctuations in ligand RMSD, indicating a stable binding pose throughout the 200 ns simulation. These compounds also exhibited significant antibacterial activity against gram-positive and gram-negative bacteria compared to standard drugs. In-vitro antitubercular assays against the H37Rv strain demonstrated moderate to notable efficacy relative to the standard reference drug. The findings suggest that these compounds could serve as promising drug candidates. Further development may lead to their use as effective antituberculosis agents in future research.