Thiazolidinone-based compounds as dual-purpose therapeutics: antimicrobial efficacy, cytotoxicity and pharmacokinetic potential

Abstract

Infectious diseases and cancer remain leading global health challenges, with rising resistance to existing antibiotics and limited selectivity of many cytotoxic agents. Heterocyclic scaffolds, particularly thiazolidinones, offer a promising platform for the development of novel antimicrobial and anticancer compounds.

The aim of the study. To evaluate the antimicrobial and cytotoxic properties of thiazolidinone-based compounds against a panel of pathogenic microorganisms and human cancer cell lines, and to identify the most promising derivatives with favorable safety, pharmacokinetic, and mechanistic profiles through molecular docking and dynamics studies. Materials and methods. A library of 5-enamine(hydrazine)-4-thiazolidinone derivatives was screened for antimicrobial activity against Gram-positive and Gram-negative bacteria and Candida albicans, and for cytotoxic activity against six human cancer cell lines. Minimum inhibitory concentrations (MIC) were determined, and IC₅₀ values were measured for selected compounds. Pharmacokinetic properties, including gastrointestinal absorption and lipophilicity, were assessed in silico. To investigate potential mechanisms of antibacterial action, molecular docking was performed against MurB (UDP-N-acetylenolpyruvylglucosamine reductase) and DNA gyrase subunit B (ATPase domain), followed by molecular dynamics (MD) simulations to evaluate the stability of the most promising complexes.

Results. Thirty-two compounds exhibited antimicrobial activity (MIC ≤ 200 µM), and ten (6, 7, 10, 12, 13, 16, 19, 21, 22, and 29) were identified as the most active. Compound 29, an isatin–oxadiazole hybrid, demonstrated potent activity against Enterococcus faecalis and vancomycin-resistant E. faecium (MIC = 3.13 µM), outperforming vancomycin. Compound 21 was highly active against Staphylococcus epidermidis (MIC = 1.56 µM), while compound 6 showed efficacy against methicillin-susceptible and -resistant S. aureus (MIC = 6.25 µM). Moderate antifungal activity was observed for compound 27 (MIC = 100 µM), whereas Gram-negative bacteria were largely resistant. Cytotoxicity screening revealed selective anticancer activity of compounds 12 and 27, with high therapeutic indices against CCRF-CEM cells and minimal effects on normal fibroblasts. Compound 2 exhibited strong cytotoxicity (IC₅₀ = 1.1 µM), while compound 29 combined non-cytotoxicity with favorable pharmacokinetic characteristics. Molecular docking supported MurB as the primary antibacterial target, with the most active compounds (21 and 29) showing the most favorable binding energies. Compound 29 also exhibited strong affinity for GyrB, indicating a potential dual-target mechanism. Molecular dynamics confirmed that MurB–compound 29 complexes were particularly stable, correlating well with experimental antibacterial activity. Conclusions. Thiazolidinone-based hybrids demonstrated promising antimicrobial and anticancer properties. Compound 29 emerged as a particularly attractive dual-purpose candidate due to its potent activity, safety profile, favorable pharmacokinetics, and validated interaction with essential bacterial enzymes. Together, biological and computational results support the potential of thiazolidinone scaffolds as a basis for the development of selective or multitarget therapeutic agents