New oxa/thiadiazole-chalcone hybrids linked via a clickable 1,2,3-triazole bridge with dual EGFR/VEGFR-2 kinase inhibitory activity and antiproliferative effects.
TL;DR
A novel series of pyridine-1,3,4-oxa/thiadiazole-chalcone hybrids, linked via a clickable 1,2,3-triazole moiety, were synthesized and elucidated by FT-IR, NMR, and HRMS and showed configurations that were pose-consistent with key hinge interactions within the target enzymes.
Abstract
The growing global incidence of cancer, coupled with the limitations of many current therapies, such as cytotoxicity, resistance, and poor selectivity, drives the need for new therapeutic agents. In this study, a novel series of pyridine-1,3,4-oxa/thiadiazole-chalcone hybrids, linked via a clickable 1,2,3-triazole moiety (7a-k and 8a-d), were synthesized and elucidated by FT-IR, NMR, and HRMS. These target compounds were screened in vitro for anticancer activity against three human cancer cell lines (A549, MCF-7, HCT-116) and for EGFR/VEGFR-2 inhibitory activity. The HCT-116 cells were the most sensitive. Notably, compounds 7b,7d, 7j, 8b, and 8d exhibited promising cytotoxic activity with IC50 values ranging from 0.79 to 19.23 μM against the three tested cell lines. Moreover, the safety of derivatives 7b, 7d, 7f, 7j, 8b, and 8d was confirmed by screening them against a normal colon cell line (FHC), which exhibited a favorable selectivity profile within the HCT-116/FHC model. Additionally, compounds 7d and 8d showed inhibitory activity against EGFRWT (0.084, 0.068 μM, respectively), EGFRT790M (0.287 ± 0.01, 0.154 ± 0.004 μM, respectively), and VEGFR-2 (0.075, 0.071 μM, respectively). Compound 7d exhibited potent inhibitory activity against resistant NCI-H1975 cell line, with an IC₅₀ value of 11.64 ± 0.31 μM. Against SW1463 cells, 7d and 8d showed IC₅₀ of 2.74 ± 0.08 and 7.180 ± 0.23 μM, respectively, outperforming erlotinib (IC₅₀ = 12.335 ± 0.40 μM). Compound 8d exhibited potent inhibition of both EGFRT790M and EGFRWT expression, reducing their levels to 2.164 ± 0.08 ng/mL (78.8% reduction) and 220.88 ± 8.33 pg/mL (76.0% reduction), respectively, showing activities comparable to erlotinib. Compounds 7d, 7j, 8b, and 8d appeared to induce cell cycle arrest at G₀/G₁ phase and promote apoptosis; however, these findings are preliminary, derived from a single experiment, and hypothesis-generating. Computational studies for the most active compounds showed configurations that were pose-consistent with key hinge interactions within the target enzymes. Furthermore, the lipophilicity (log P) of the compounds, 7f and 8d, was experimentally determined to provide additional insight into their predicted ADME properties.