Identification of 3-[(4-Acetylphenyl)(4-Phenylthiazol-2-Yl)Amino]Propanoic Acid Derivatives as Promising Scaffolds for the Development of Novel Anticancer Candidates Targeting SIRT2 and EGFR

Abstract

Background: A series of novel polysubstituted thiazole derivatives were synthesized, and their antiproliferative properties were evaluated using both 2D and 3D lung cancer models. Methods: The compounds were obtained via esterification, oximation, hydrazinolysis, and condensation reactions. Results: Structure–activity relationship analysis revealed that the antiproliferative activity was structure-dependent. Notably, oxime derivatives 21 and 22, along with carbohydrazides 25 and 26, exhibited low micromolar activity that was significantly greater than that of cisplatin (p < 0.005), a standard chemotherapeutic agent. These compounds demonstrated potent, antiproliferative activity against H69 small-cell lung carcinoma cells, as well as anthracycline-resistant H69AR cells. Moreover, compounds 21, 22, 25, and 26 effectively induced cell death in A549 agarose-based 3D spheroids, further supporting their potential therapeutic application. The in silico studies proposed that compound 22 is able to interact with human SIRT2 and EGFR via conserved amino acid residues. Conclusions: The ability of these thiazole derivatives to target both drug-sensitive and drug-resistant lung cancer models highlights their promise as scaffolds for further optimization and preclinical development. Future studies will focus on structural modifications to enhance potency, selectivity, and pharmacokinetic properties, paving the way for the development of novel thiazole-based antiproliferative agents.