Design, Synthesis, and Biological Evaluation of New Benzo[b]Oxepine-Based 1,2,3-Triazole Derivatives: Molecular Docking, DFT Analysis, In Silico Pharmacokinetics, and Identification of Antimicrobial Pharmacophore Sites.

A novel series of benzo[b]oxepine-1,2,3-triazole derivatives (8a-8k) was synthesized through a well-defined CuAAC pathway utilizing 5 as a key intermediate. Compounds 8a-8k were synthesized in good-to-excellent yield through a multi-component reaction of 1 with phosphoryl trichloride under the Vilsmeier-Haack reaction, followed by reduction, chlorination, azido-methylation, and triazole, respectively. The obtained products were physicochemically characterized by melting points, FT-IR, 1H nuclear magnetic resonance (NMR), 13C-NMR, and high-resolution mass spectrometry (electron ionization) analysis. Among them, compounds 8d, 8h, and 8j (ZI  =  37 ± 0.29, 36 ± 0.31, and 35 ± 0.15 mm, respectively) showed better activity against Escherichia coli than the reference drug MXF (ZI  =  33 ± 0.15 mm). In vitro antimicrobial activity results showed that compounds 8d and 8h exhibited potent activity against Pseudomonas aeruginosa (with MIC values of 1.8 and 2.2 µg mL-1, respectively), which was significantly stronger than MXF. Notably, the substituted triazoles 8b and 8h exhibited superior antifungal activity against Candida albicans, with MICs of 5.0 and 3.8 µg mL-1, compared to other compounds in the series. The density functional theory (DFT) study was performed to investigate various electronic properties such as geometry optimization, global reactivity parameters, and frontier molecular orbitals (FMOs). Furthermore, the docking studies were executed on the synthesized derivatives in order to explain the binding interface of compounds with the active sites of the antibacterial protein. In addition, the potent compounds were also subjected to ADME-Tox analysis to evaluate their pharmacokinetic properties, suggesting that all the compounds exhibited comparable results. These potent compounds observed in the current work may lead to promising candidates for future drug development.