Design, Synthesis, and Characterization of Novel 1,3,4-Thiadiazole-Benzo[b]Oxepine Derivatives: Study of Their Antiproliferative Activity, Docking, DFT, and ADME-T Properties.

Driven by the urgent need for novel anticancer agents capable of overcoming limitations associated with conventional therapies, a new series of benzo[b]oxepine derivatives featuring 1,3,4-thiadiazole (5a-5k) linkers was successfully produced through a Vilsmeier-Haack reaction, thiazole formation, and C─N cross coupling or an Ullmann-type coupling reaction with the corresponding hydrazides. The structure of the synthesized compounds was confirmed through various spectroscopic techniques, such as NMR (¹H/¹³C) and HRMS. The cytotoxic activity of the newly synthesized congeners was investigated against MCF-7, MDA-MB-231, and T-47D (human breast cancer), A549, and PC-9 (lung cancer) cell lines. It is worth noting that the half maximal inhibitory concentration (IC₅₀) value of 5i against MDA-MB-231 cells was 3.50 ± 1.03 µg mL⁻¹, which was obviously superior to that of etoposide (4.03 ± 1.10 µg mL⁻¹). From the screening results, thiadiazole analogues 5a-5k showed excellent inhibitory activity against lung carcinoma in the range of IC₅₀ values 4.79 ± 1.14 to 40.86 ± 0.93 µg mL⁻¹. In this series, analogues 5a, 5i, and 5j show a remarkable antiproliferative profile on the T-47D cell line with IC₅₀ values of 5.70 ± 0.90, 4.25 ± 0.76, and 4.12 ± 1.35 µg mL⁻¹ by using etoposide as a standard, whose IC₅₀ is 5.65 ± 0.35 µg mL⁻¹. Moreover, molecules 5f, 5i, and 5j demonstrated the highest docking scores of -8.83, -8.93, and -9.20 kcal mol⁻¹ in in silico tests conducted on the most potent compounds. These therefore displayed the most hydrophobic, electrostatic, and hydrogen bonding with the estrogen receptor complex in breast cancer (PDB: 5T1Z) because of their highest docking score. 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. Additionally, DFT analysis identified electron-rich and electron-deficient areas on molecules, which were utilized in docking studies to compare polar and non-polar interactions with kinase. Collectively, these findings underscore the potential of 1,3,4-thiadiazole hybrids, particularly compounds 5i and 5j, as promising leads for the development of new anticancer agents.