A novel 1,3-diazetidine-2-thione derivative with antibacterial and immunomodulatory activity against Proteus mirabilis: in vitro, in vivo, ADMET, docking, and molecular dynamics evaluation.

Authors

Najeeb Mohammed Hussein, Ali Abd Sharad, Mohammed F Hamdi

Published in

In silico pharmacology. Volume 14. Issue 3. Pages 265. Epub Oct 23, 2026.

Abstract

The functional group of 1,3-diazetidine-2-thione is a four-membered heterocyclic ring that is not a very common functional group. Unlike the β-lactam ring, in which the carbonyl group is C=O, the diazetidine-thione scaffold contains a C=S group and two nitrogen atoms within the four-membered ring. As β-lactam resistance is currently a major pharmaceutical issue, β-lactam-inspired heterocyclic modification may provide useful scaffolds for antibacterial development. This study aimed to synthesize and evaluate, computationally and experimentally in vitro and in vivo, the biological activity of a novel 1,3-diazetidine-thione derivative. Molecular docking and ADMET profiling were performed before the laboratory work. Compound-1 was prepared through a Schiff base reaction starting from 4-aminobenzoic acid, and Compound-2 was obtained through cyclization with 1-chloro-4-isothiocyanatobenzene. The available structural characterization was based on ¹H-NMR and ¹³C-NMR spectra, supported by the observed melting point and chromatographic behavior. Antibacterial screening by agar diffusion showed concentration-dependent growth-inhibition zones against P. mirabilis, with the largest mean zone observed at 25% Compound-2. MIC and MBC were not determined; accordingly, these findings are interpreted as preliminary agar-based evidence of growth inhibition rather than a quantitative measure of antibacterial potency or bactericidal activity. The PMN-related endpoint showed no significant adverse change across the treated groups under the tested conditions. This limited finding was not interpreted as confirmation of systemic safety, particularly because the ADMET model generated high alerts for drug-induced liver injury and carcinogenicity. Phagocytosis activity was markedly enhanced at higher concentrations, indicating activation of innate immune responses. Moreover, migration inhibition assays revealed a concentration-dependent reduction in MIF levels, suggesting a regulatory role in macrophage-mediated inflammation. A single 100 ns MD trajectory was used to examine the behavior of Compound-2 within the selected 2WAE reference complex. The ligand remained associated with the modeled binding region and maintained recurring contacts during the trajectory. As no independent replicate trajectories or MM-PBSA/MM-GBSA calculations were available, the MD findings were interpreted descriptively and were not used as quantitative validation of binding affinity. Because 2WAE is not a Proteus mirabilis-specific structure, the computational findings were treated as reference-structure observations rather than evidence of target engagement in the tested organism. Overall, Compound-2 showed preliminary antibacterial activity in the agar diffusion assay together with immunomodulatory effects at the tested concentrations, while quantitative antibacterial susceptibility and bactericidal endpoints remain to be established.

PMID:
42927066
Bibliographic data and abstract were imported from PubMed on 25 Oct 2026.

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