Document Type

Article

Publication Date

2026

DOI

10.1016/j.molstruc.2025.144483

Publication Title

Journal of Molecular Structure

Volume

1352

Issue

Part 1

Pages

1444483

Abstract

Antimicrobial resistance (AMR) is a growing global health threat driven by multidrug-resistant bacteria (Staphylococcus aureus, Pseudomonas aeruginosa), and fungi (Candida albicans, and C. parapsilosis). This study evaluated six novel Schiff base derivatives (HSB-1 to HSB-6) through integrated in vitro antimicrobial activity and comprehensive computational studies. In vitro disk diffusion assay demonstrated the largest zones of inhibition against S. aureus for HSB-6 and HSB-1 (15–17 mm), activity against P. aeruginosa for HSB-5 and HSB-6 (12 mm), and moderate antifungal activity for HSB-4 (8–11 mm). Molecular docking results correlated with the in vitro findings with the binding energy ΔG = −12.3 kcal/mol for HSB-5 against LasR (P. aeruginosa), showing key interactions involving hydrogen bonding and hydrophobic contacts. Molecular dynamics (MD) simulations of 100 ns validated protein-ligand complex stability (low RMSD, compact Rg, and persistent hydrogen bonds). DFT calculations at the B3LYP/6-311G (d, p) level revealed electronic properties consistent with the reactivity: HSB-5 highlighted an intermediate HOMO-LUMO gap (ΔE = 3.74 eV) while HSB-6 and HSB-1 displayed lower gaps (3.09 and 3.12 eV, respectively); NBO and Fukui analyses identified electrophilic nitro/imine groups and nucleophilic π-carbons as likely interaction sites. ADMET profiling indicated drug-likeness for most compounds: high GI absorption for five derivatives (LogP 2.4–4.5); predicted BBB permeability for HSB-2 to HSB–4; CYP inhibition profiles consistent with metabolic stability; and LogS −3.4 to −5.9. Safety flags include Ames positivity for HSB-4 to HSB-6 and predicted hepatotoxicity for HSB-1. Overall, HSB-5 emerges as a balanced lead combining in vitro efficacy and favorable computational profiles which supports its prioritization for optimization against anti-microbial resistance.

Rights

© 2025 The Authors.

This is an open access article under the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Data Availability

Article states: "Data will be made available on request."

Original Publication Citation

Hussain, A., Akhter, S., Nasir, H., Shahzad, K., Arfan, M., & Park, S. H. (2026). Investigating the in vitro antimicrobial potential and comprehensive computational studies of new Schiff base derivatives. Journal of Molecular Structure, 1352(Pt. 1), Article 144483. https://doi.org/10.1016/j.molstruc.2025.144483

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