Phenylthiazolidin-4-one piperazine Conjugates: Design, Synthesis, anticancer and antimicrobial studies

Abstract

In current research study, a series of ten novel phenylthiazolidin-4-one glycinamide conjugates with piperazines compounds (7a-j) were designed by combining the crucial pharmacophoric features from the reported potential anticancer hit molecules, subsequently evaluated for the drug-likeness behaviour. Designed candidates were synthesized, purified, and characterized by non-spectral and spectral methods. Further, compounds were evaluated for anticancer activity against three cells line; as HEP-G2 cells (liver cancer cells line), MDA-MB-231 (breast cancer cells line) and U87MG cells (brain cancer cells line). Compound 7j exhibited encouraging antineoplastic activity against MDA-MB-231 and HEP-G2 cell line with IC50 of 4.02 and 15.04 µM, comparable to positive control, gemcitabine (IC50: 2.81 and 15.94 µM, respectively). The compound 7j displayed better anticancer activity against U87M with IC50 value of 13.96 µM in comparison to gemcitabine (IC50: 34.26 µM). SAR studies of the series illustrating the effect of different substitutions on the anticancer activity is discussed. Further, cytotoxicity of compound 7j was tested against the brain tumour spheroids (MTS), in which it showed significant apoptosis of MTS cells as compared to gemcitabine. To find the mechanistic basis of cytotoxicity, computational studies were performed against the six probable targets, in which compound 7j showed excellent binding affinity towards DHFR and hDHODH targets, illustrating both as probable targets of the compounds. Additionally, the synthesized compounds were tested for antimicrobial activity against bacterial (E. coli and P. aeruginosa) and fungal strains (C. albicans), in which majority of compounds showed moderate to weak activity.

Keywords

• Anticancer
• Antimicrobials
• Drug-likeness
• Piperazine
• 3D Spheroid models
• 4-Thiazolidinone