Abstract

A couple of N-(4)-morpholine/pyrrolidine-substituted thiosemicarbazones (TSCs) of fluorene-2-carboxaldehyde (FM and FP), and their corresponding thiadiazoles (TDZs) (CFM and CFP), were synthesized and characterized (elemental analysis, ultraviolet–visible [UV–Visible], Fourier transform infrared [FT-IR], nuclear magnetic resonance [NMR; 1H & 13C], high-resolution mass spectrometry [HRMS], and single-crystal X-ray diffraction [SCXRD]) for the evaluation of their anticancer potential. The TDZs were obtained unexpectedly and are possibly formed via single-step metal (copper)-mediated oxidative cyclizations of the TSCs. The synthesized compounds are fairly stable in phosphate buffer at the biological pH of 7.4. The density functional theory [DFT] studies were performed to predict the optimized structures and physicochemical properties of these compounds. The compounds were further subjected to computational and experimental biomolecular investigations in order to evaluate their anticancer activity in detail. CFM had the most potent activity against human breast adenocarcinoma (MCF-7) and human urinary bladder (T24) cancer cells, with IC50 values of 12.00 and 24.80 ?M, respectively. In contrast, CFM had negligible cytotoxicity (IC50 = 98.70 ?M) against kidney epithelial cells extracted from an African green monkey (Vero) normal cells. This outcome was preferable to that of the widely used medicine Cisplatin. Molecular docking studies were performed with the breast cancer protein “cytochrome P450 1A1” (CYP1A1) and bovine serum albumin (BSA) to predict how effectively the compounds bind to the receptor. The ADMET findings suggest that these compounds have considerable drug-likeness and oral bioavailability. These insights may open the door for additional medical research into the bioactivities of TSCs and TDZs produced from bioactive carbonyl compounds. © 2023 John Wiley & Sons Ltd.