Synthesis, Conformational Analysis and Evaluation of the 2-aryl-4-(4-bromo-2-hydroxyphenyl)benzo[1,5]thiazepines as Potential α-Glucosidase and/or α-Amylase Inhibitors

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-10, Vol.27 (20), p.6935
• Main Authors: Nkoana, Jackson K, Maluleka, Marole M, Mphahlele, Malose J, Mampa, Richard M, Choong, Yee Siew
• Format: Article
• Language: English
• Subjects: 2,3-dihydrobenzo[b][1,5]thiazepines; Absorption; Acarbose; Alzheimer's disease; Amylases; Aromatic compounds; Benzodiazepines; Binding sites; Bioavailability; Biological activity; Blood-brain barrier; Carbohydrates; Computational neuroscience; computational studies; Conformation; Conformational analysis; DFT; Diabetes; Enzymes; Glucose; Glucosidase; Hydrogen bonding; Hydrogen bonds; Hydroxyl groups; Hyperglycemia; Kinases; Membrane permeability; Metabolism; Methods; Nitrogen; NMR; Nuclear magnetic resonance; Organic compounds; Physiological aspects; Proteins; Single crystals; Spectroscopy; Spectrum analysis; Structure; Testing; Vapor phases; X-ray diffraction; X-ray structure; α-Amylase; α-Glucosidase
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27206935

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 1H-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 2b as a representative example in the gas phase. Compounds 2a (Ar = -C6H5), 2c (Ar = -C6H4(4-Cl)) and 2f (Ar = -C6H4(4-CH(CH3)2) exhibited increased inhibitory activity against α-glucosidase compared to acarbose (IC50 = 7.56 ± 0.42 µM), with IC50 values of 6.70 ± 0.15 µM, 2.69 ± 0.27 µM and 6.54 ± 0.11 µM, respectively. Compound 2f, which exhibited increased activity against α-glucosidase, also exhibited a significant inhibitory effect against α-amylase (IC50 = 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.