Synthesis of novel inhibitors of α-glucosidase based on the benzothiazole skeleton containing benzohydrazide moiety and their molecular docking studies

• Published in: European Journal of Medicinal Chemistry
• Main Author: Taha M.; Ismail N.H.; Lalani S.; Fatmi M.Q.; Atia-Tul-Wahab; Siddiqui S.; Khan K.M.; Imran S.; Choudhary M.I.
• Format: Article
• Language: English
• Published: Elsevier Masson SAS 2015
• Online Access: https://www.scopus.com/inward/record.uri?eid=2-s2.0-84920848432&doi=10.1016%2fj.ejmech.2015.01.009&partnerID=40&md5=43b5ed99e419a1ce3031e5c687a043b1

In an effort to design and synthesize a new class of α-glucosidase inhibitor, we synthesized benzothiazole hybrid having benzohydrazide moiety (5). Compound 5 was reacted with various substituted aryl aldehyde to generate a small library of compounds 6-35. Synthesis of compounds was confirmed by the spectral information. These compounds were screened for their α-glucosidase activity. They showed a varying degree of α-glucosidase inhibition with IC50 values ranging between 5.31 and 53.34 μM. Compounds 6, 7, 9-16, 19, 21-30, 32-35 showed superior activity as compared to standard acarbose (IC50 Combining double low line 906 ± 6.3 μM). This has identified a new class of α-glucosidase inhibitors. The predicted physico-chemical properties indicated the drug appropriateness for most of these compounds, as they obey Lipinski's rule of five (RO5). A hybrid B3LYP density functional theory (DFT) was employed for energy, minimization of 3D structures for all synthetic compounds using 6-311 + G(d,p) basis sets followed by molecular docking to explore their interactions with human intestinal C- and N-terminal domains of α-glucosidase. All compounds bind to the prospective allosteric site of the C- terminal domain, and consequently, may be considered as mixed inhibitors. It was hypothesized that both the dipole moment and H-bond interactions govern the biological activation of these compounds. © 2015 Elsevier Masson SAS.