| Summary: | The ambident electrophilic character of the 5-bromo-2-hydroxychalcones and the binucleophilic nature of 2-aminothiophenol were exploited to construct the 2-aryl-4-(4-bromo-2-hydroxyphenyl)benzo[1,5]thiazepines. The structures and conformation of these 2-aryl-4-(4-bromo-2-hydroxyphenyl)benzo[1,5]thiazepines were established with the use of spectroscopic techniques complemented with a single crystal X-ray diffraction method. Both <sup>1</sup>H-NMR and IR spectroscopic techniques confirmed participation of the hydroxyl group in the intramolecular hydrogen-bonding interaction with a nitrogen atom. SC-XRD confirmed the presence of a six-membered intramolecularly hydrogen-bonded pseudo-aromatic ring, which was corroborated by the DFT method on <b>2b</b> as a representative example in the gas phase. Compounds <b>2a</b> (Ar = -C<sub>6</sub>H<sub>5</sub>), <b>2c</b> (Ar = -C<sub>6</sub>H<sub>4</sub>(4-Cl)) and <b>2f</b> (Ar = -C<sub>6</sub>H<sub>4</sub>(4-CH(CH<sub>3</sub>)<sub>2</sub>) exhibited increased inhibitory activity against α-glucosidase compared to acarbose (IC<sub>50</sub> = 7.56 ± 0.42 µM), with IC<sub>50</sub> values of 6.70 ± 0.15 µM, 2.69 ± 0.27 µM and 6.54 ± 0.11 µM, respectively. Compound <b>2f</b>, which exhibited increased activity against α-glucosidase, also exhibited a significant inhibitory effect against α-amylase (IC<sub>50</sub> = 9.71 ± 0.50 µM). The results of some computational approaches on aspects such as noncovalent interactions, calculated binding energies for α-glucosidase and α-amylase, ADME (absorption, distribution, metabolism and excretion) and bioavailability properties, gastrointestinal absorption and blood–brain barrier permeability are also presented.
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