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, ¹H NMR, ¹³C 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 (IC₅₀ = 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.

ADME; Breast cancer; EGFR; Molecular Docking; Molecular dynamics; PPI network; Thiazolyl-pyrazole analogues.