Efficient Synthesis, Anticancer Evaluation of Triazole‐Thiadiazole/Benzo[<i>d</i>]Oxazole Scaffolds, and Investigation of Their Reactivity Properties Using Density‐Functional Theory Calculations and In Silico Docking

The present study describes a benzo[d]oxazole-functionalized conventional synthesis of novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles are formed by the condensation of 5 with bromo-substituted acetophenones and isothiocyanates. The structural elucidation of the newly synthesized compounds was accomplished using various spectroscopic techniques, for example, Fourier transform infrared, nuclear magnetic resonance (¹H/¹³C), and high-resolution mass spectrometry. We examined all the newly synthesized compounds for their in vitro anticancer potential against breast cancer cell lines. As the most prominent one, compound 6c showed the highest anticancer activity against the MDA-MB-231 cell line and a half-maximal inhibitory concentration (IC₅₀) value of 3.01 ± 0.45 µM, which was close to that of the positive control Doxorubicin (IC₅₀ value of 3.10 ± 0.27 µM). It was also observed that compound 8e (IC₅₀ = 3.92 ± 0.04 µM) exhibited superior activity against the T47D cell line, whereas compound 6f (IC₅₀ = 2.10 ± 0.21 µM) demonstrated better activity against the MCF-7 cell line. In silico docking investigations of the representative ligands further explored the characteristic binding orientations on conserved interactions with residues like LysA:55, ValA:60, ThrA:11, GluA:14, ProA:57, AlaA:15, SerA:51, and GlyA:58 from the breast cancer estrogen receptor beta enzyme (PDB code: 1U9E). We utilized density-functional theory (DFT) analyses to deduce the molecular structures and topologies of the more energetic molecules. Furthermore, the positive absorption, distribution, metabolism, excretion, and toxicity properties of these derivatives highlight their potential as therapeutics, calling for more research into possible clinical applications. The tested compounds' structure-activity relationships are in good agreement with molecular docking and DFT studies, which demonstrate that the primary cause of the high anticancer activity of 1,2,4-triazole hybrids is the presence of a lipophilic and heterocyclic substituent on the benzo[d]oxazole component.