Synthesis, Characterization, Bioactivity Evaluation, and POM/DFT/Docking Analysis of Novel Thiazolidine Derivatives as Potent Anticancer and Antifungal Agents
Ahmed A. Majed, Qeaser R. Abdalzahra, Hamsa Hussein Al-Hujaj, Dawood S. Abid, Abdulaziz Ali Alomari, Islam M. Abdellah, Ahmed A. Elhenawy
Abstract
Abstract A series of 2,2′‐(1,4‐phenylene)bis(N‐substituted phenylthiazolidine‐4‐amide) derivatives, denoted as (A 3–9 ), were synthesized, and characterized for their potential applications against prostate cancer cells (PC3), and Candida albicans fungi. These compounds incorporate various substituents on the phenyl ring such as 4‐NO 2 , 3‐NO 2 , 4‐COCH 3 , 4‐H, 4‐OCH 3 , 4‐OCH 2 CH 3 , and 4‐Cl. The chemical structures of these derivatives were confirmed by NMR, FTIR, and mass spectroscopy. Biological assays, utilizing the MTT assay for prostate cancer cells (PC3) and the disk diffusion assay for Candida albicans fungi, were conducted to evaluate the bioactivity of these compounds. The results revealed promising cytotoxic and antifungal activities. Specifically, compounds A 3 (IC 50 =69.74±0.96), A 4 (IC 50 =63.64±0.950), and A 9 (IC 50 =57.14±0.88 μg/mL) exhibited notable potency against PC3 cells, while A 7 and A 8 exhibited considerable antifungal efficacy against Candida albicans with MIC of 312 μg/mL. Moreover, density functional theory (DFT) simulations were used to study electronic properties and reactivity descriptors such as energy gap ( E g ), ionization potential ( IP ), electron affinity ( EA ), chemical potential (μ), chemical hardness ( η ), global softness (σ), electronegativity (χ), and electrophilicity (ω) to gain a better understanding of the Structure‐Activity Relationship (SAR). Molecular docking analysis against DNA Gyrase and EGFR tyrosine kinase enzymes revealed strong binding interactions of the investigated molecules within their active sites, making them valuable candidates for further development as therapeutic agents against prostate cancer and fungal infections. POM analysis indicates the presence of two antifungal pharmacophore sites (O1 δ− , O2 δ− ) and (O3 δ− , O4 δ− ), as well as two antitumor pharmacophore sites (O1 δ− , NH1 δ+ ) and (O4 δ− , NH2 δ+ ).