Mustafa Alhaji Isa

Antimicrobial resistance (AMR) remains a global health crisis, necessitating the development of novel therapeutics against multidrug-resistant pathogens. In this study, ten (10) hybrid imine-benzalacetophenone derivatives (7a–7j), incorporating pyridine and thiophene scaffolds, were synthesized and structurally characterized using FTIR, ¹H-NMR, LC–MS, and elemental analysis. In vitro, antimicrobial screening demonstrated that compounds 7c and 7j displayed consistent and potent activity across Gram-positive and Gram-negative bacterial strains and fungal pathogens, with compound 7c achieving MICs as low as 25 µg/mL. Compound 7c exhibited significant antitubercular activity with 96% inhibition at 25 µg/mL against Mycobacterium tuberculosis H37Rv. A deep learning-based QSAR model, developed using a fully connected feedforward neural network trained on molecular descriptors (MolWt, LogP, TPSA, H-bond donors/acceptors, etc.), yielded predicted pMIC values closely matching experimental trends. SHAP analysis confirmed the multivariate contribution of key descriptors, validating the model’s interpretability despite dataset constraints. SwissADME-based pharmacokinetic profiling confirmed high gastrointestinal absorption, low PAINS alerts, and compliance with Lipinski and Veber rules for drug-likeness. Compounds 7c and 7j demonstrated balanced lipophilicity, low skin permeability, and favourable ADMET characteristics, aligning with their firm biological profiles. Molecular docking showed strong binding affinities for 7c (− 11.55 kcal/mol with CYP51) and 7j (− 9.97 kcal/mol with InhA), with multiple hydrogen bonds and hydrophobic interactions at catalytically relevant sites. These interactions were consistent with observed antimicrobial profiles. These docking predictions were validated by 200 ns molecular dynamics simulations, which confirmed the structural stability of 7c and 7j in complex with CYP51, InhA, PBP2a, and DNA Gyrase B. RMSD and RMSF trajectories, indicated stable ligand retention and minimized flexibility at the binding interface, particularly for 7c with CYP51 and InhA, and for 7j with DNA Gyrase B. These results support 7c and 7j as promising lead candidates with dual antimicrobial potential, favourable drug-like properties, and broad-spectrum activity profiles.