Design, Synthesis, Anticancer and Antimicrobial Studies of 2-Phenylthiazolidin-4-one Glycinamide Conjugates

Thiazolidin-4-one is a versatile nucleus that has been reported to exhibit a diverse array of biological activities, including anticancer and antimicrobial activities. In the current research study, a series of C2-(p-substituted phenyl)-thiazolidin-4-one compounds conjugated with anilines were designed and tested for drug-likeness behaviour. Subsequently, the designed compounds were synthesized, characterized, and tested for anticancer activity against three cancer cell lines, namely liver (HEP-G2 cells), breast (MDA-MB-231), and glioblastoma (U87MG cells), with gemcitabine as the reference positive control drug. Initially, the compounds were tested at 50 micromolar, while the MIC was determined for the selected active compounds. Among the three cell lines, MDA-MB-231 showed relatively higher sensitivity towards the tested compounds. Four compounds of the series exhibited comparable or superior cytotoxicity to the reference drug gemcitabine. Particularly, N-(p-tolyl)-2-(2-(4-methoxyphenyl)-4-oxothiazolidin-3-yl)acetamide (6 d) displayed highest cytotoxicity among the series. The anticancer activity of the selected compounds was also tested against 3D spheroid models, in which compound N-(4-chlorophenyl)-2-(2-(4-methoxyphenyl)-4-oxothiazolidin-3-yl)acetamide (6 a) induced apoptosis in brain tumour spheroids (MTS). Docking studies of compound 6 d were performed against different targets, namely dihydrofolate reductase, phosphoinositide 3-kinase, epidermal growth factor receptor, dihydroorotate dehydrogenase, and murine double minute 2, which illustrated inhibition of dihydroorotate dehydrogenase as a possible mechanism of toxicity. The compounds were also evaluated in vitro for antibacterial activity against two bacterial strains (E. coli and P. aeruginosa) and a Candida albicans fungal strain. The graphical abstract demonstrates the synthetic strategy of C2-(p-substituted phenyl) thiazolidin-4-one via multiple steps in the presence of various reactant and solvent. It also represents anticancer activity of synthesized thiazolidin-4-one conjugates against the different cell cancer lines, such as liver (HEP-G2 cells), breast (MDA-MB-231), and glioblastoma (U87MG cells).image