Cytotoxic activity, molecular docking, and molecular dynamics simulation of new 2-Thioxo-1,3-thiazolidine-4,5-diones as building blocks for functionalization of N[sbnd]Nucleophiles with Oxamide moieties

Abstract

N-aryl/alkyl-substituted 2-thioxo-1,3-thiazolidine-4,5‑dione analogues as building blocks were evaluated for the functionalization of N-nucleophiles with oxalyl amide moieties. In this context, the improved method was applied to the simple preparation of carbazate/hydrazide derivatives functionalized with an oxalyl amide moiety. Ten 2-acylhydrazinyl-2-oxoacetamide analogues were isolated in good yields (78–95 %). The reactions occurred under mild conditions and in short times. The spectral data indicate that some 2-acylhydrazinyl-2-oxoacetamide derivatives have a tautomeric mixture with minor contributions of imin-ol forms (22–42 %). The mechanism revealed that the attack of the NH<inf>2</inf> group of hydrazide and carbazate nucleophiles to the carbonyl group on the 2-position of the ring leads to the ring-opening reaction. Then, the final products are produced by eliminating CS<inf>2</inf>. The in vitro anticancer activity assay demonstrated that four of the synthesized compounds were active against the cancer cell lines. The experimental study results were rationalized through molecular docking and molecular dynamics (MD) simulation. For this purpose, the binding potentials of the most active derivatives to 8-oxoguanine DNA glycosylase 1 (OGG1) were assessed. Compounds with similar scaffolds were found to be potent and selective OGG1 inhibitors. © 2025 Elsevier B.V., All rights reserved.