Synthesis of New Quinazolinone-Based 1,2,3–Triazole Scaffolds as Potent Anticancer Agents: Molecular Docking and ADME Studies

Driven by the urgent need for novel anticancer agents capable of overcoming limitations associated with conventional therapies, a new series of quinazolinone derivatives featuring 1,2,3–triazole–acetamide linkers was successfully produced through a copper(I)-catalyzed azide alkyne cycloaddition (CuAAC)-catalyzed cyclocondensation of 3-ethyl-2-(prop-2-yn-1-ylsulfonyl) quinazolin-4(3H)-one with the corresponding 2-azido-N-phenylacetamides. The structures of the synthesized compounds were confirmed through 1H/13C NMR, IR, and HRMS spectroscopic techniques. The novel compounds were evaluated against human lung carcinoma (A549 and NCI-H460), human colorectal carcinoma (HT29 and HCT116), and also hepatocellular liver carcinoma (HepG-2) cell line. Among them, compound 6e demonstrated potent cytotoxicity against A549 (IC50 = 4.80 ± 1.04 μg. mL−1) and HT29 (IC50 = 5.40 ± 0.94 μg. mL−1) cell lines, showing efficacy comparable to doxorubicin (IC50 = 5.04 ± 1.15 and 5.80 ± 0.89 μg. mL−1, respectively). Notably, 6h inhibited the liver cancer cell line HepG-2 with an IC50 of 6.12 ± 0.56 μg. mL−1, when compared to DXN (7.12 ± 1.06 μg. mL−1). Additionally, the molecular modeling approach was employed to correlate the in vitro anticancer cell viability activity well with the in silico study, and the result obtained corroborated that active analogues established several key interactions at positions Arg483(A), Phe478(A), Leu484(A), Ile506(A), Thr458(A), Ser486(A), Asn485(A), and Gly527(A) with the active site of the lung cancer (PDB code: 1X2R). Extending our exploration, an analysis of the ADME-Tox profiling confirmed the safe use of these newly synthesized scaffolds, paving the way for promising therapeutic applications in the field of anticancer therapy. Collectively, these findings underscore the potential of 1,2,3-triazole hybrids, particularly compounds 6e and 6h, as the promising leads for the development of new anticancer agents.