Discovery and molecular characterization of a potent thiazolyl-pyrazole hybrid targeting EGFR for breast cancer therapy.

Herein, a novel compound 2-(3-methyl-5-oxo-1-phenyl-1,5-dihydro-4H-pyrazolylidene)-3-phenylthiazolidin-5-one )2(was synthesized and reacted with different aromatic aldehydes 3a-f via Knoevenagel condensation reaction to give the corresponding 4-arylidene-2-(5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)thiazolidin-5-one hybrids 4a-f. The chemical structures were described by spectroscopic tools, IR, (1)H NMR, (13)C NMR, and MS. Their frontier molecular orbitals configuration and electron distribution were estimated to utilize DFT. The cytotoxicity of thiazolyl-pyrazole analogues 2 and 4a-f demonstrated in vitro antitumor activity toward breast cells; MCF-7 and MDA-MB231. Among the prepared analogues, the thiazolyl-pyrazole 2 revealed potent inhibitory toward the two cancer cells, particularly MDA-MB231 (IC(50) = 22.84 µM). SwissADME studies showed the pharmacokinetic parameters, drug-like qualities, and bioavailability of these derivatives, revealing their potential in anticancer applications. Additionally, disease and drug target predictions and construction of the protein-protein interaction (PPI) network identified PPARG, EGFR, and PPARA as major targets. Moreover, other studies were carried out on the most potent conjugate 2 to evaluate the potential interactions against PPARG, EGFR, and PPARA proteins for molecular docking and against EGFR only for molecular dynamic simulation. The mechanism of the most effective analogue 2 was proven experimentally by inhibiting wound healing and EGFR expression in MDA-MB231 culture media. The findings provide more credence to compound 2's potential in current medication development initiatives.