Design, Synthesis and Biological Evaluation of 2‐(naphthoyl) iminothiazolidin‐4‐ones as Potential Anticancer Agents

Abstract

A library of novel naphthyl bearing 2-iminothiazolidin-4-ones (2-ITZDs) (2 a-2 q) was designed and synthesized through a facile route involving regioselective heterocyclization of unsymmetrical thioureas (1 a-1 q). The synthesis was achieved at ambient temperature in good to excellent yields under catalyst free conditions. The molecular structures of 2-ITZDs were elucidated by spectroscopic techniques such as FT-IR, 1 H-NMR and 13 C-NMR. X-ray structural data was used to establish the structure (2 o) unequivocally and to define the geometry of exo double bond. The in vitro anticancer activity of 2-ITZDs (2 a-2 q) was investigated in several human cancer cell lines (A549, LNCap, PC-3, MDA-MB-231, BxPC3, MIA PaCa2). All compounds showed cytotoxicity with IC 50 values ranging from 6-23 μM in the tested cancer cell lines except MDA-MB-231. Compound 2 k (IC 50 = 7 μM) and the homologous analog 2 q (IC 50 = 6 μM) were found to be equipotent to 2 k and showed moderate cytotoxicity against human breast cell line (DA-MB-231). Furthermore, compound 2 k exhibited a medium permeability, enough metabolic stability and no significant inhibition of hERG channel. Compound 2 k inhibited cytochrome P450 activity below 50 % in 1 A2, 3 A4 and 2 C19, but not in 2 C9 and 2D6 at 10 μM. Structure-activity relationships (SAR) provided useful insights towards this class of compounds and tiled a way to design novel analogues with increased potency.[a] S.

Induction of Cyp450 enzymes by 4-thiazolidinone-based derivatives in 3T3-L1 cells in vitro

“…Recently, it has been reported that different thiazolidinone derivatives exerted CYP inhibition activity in several isoforms (CYP1A2, CYP3A4, and CYP2C19) at 10 μM, but there was no CYP inhibition activity of CYP2C9 and CYP2D6 in human and rat liver microsomes (Ashraf et al 2020 ). Unfortunately, the data on the CYP expression and/or activity after thiazolidinone treatment are limited.…”

Novel adamantyl clubbed iminothiazolidinones as promising elastase inhibitors: design, synthesis, molecular docking, ADMET and DFT studies

“…Thiazolidinone motifs are biologically significant five-membered heterocycle that is very common substructures in various pharmacological active molecules and known to exhibit a wide range of biological activities such as anticancer, antifungal, anti-inflammatory, antimicrobial, antidiabetic, inhibiting neuraminidase of influenza virus, and anti-HIV, 29 antischistosomal activity. Among these are inhibitors for necroptosis, selective GSK-3β inhibitor, anticancer activity, 30 aldose reductase inhibitor, 31 potent antiproliferative agent and inhibitor for non-membrane protein tyrosine phosphate. The aforesaid facts inspired us to synthesize novel ethyl 3-adamantanyl-2-((2-methyl benzoyl)imino)-4-oxothiazolidin-5-ylidene acetates (5a–j) for the appraisal of elastase inhibition assay.…”

Synthetic strategies and medicinal perspectives of 4‐thiazolidinones: Recent developments and structure–activity relationship studies

“…The MTT assay results revealed compound 169a as a promising derivative with IC 50 values of 19, 17, 7, 10, and 15 μM against A549, LNCap, MDA‐MB‐231, BxPC3, and MIAPaCa2, respectively. Further, the SAR study showed a better anticancer potential of the 2,6‐dichloro substituted derivative, compound 169a , as compared to trifluoromethyl, methoxy, and fluoro‐substituted thiazolidinone analogues [42].…”