title: Synthesis of novel inhibitors of α-glucosidase based on the benzothiazole skeleton containing benzohydrazide moiety and their molecular docking studies.
abstract: 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 = 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.
authors.affiliation: Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia; Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia. Electronic address: taha_hej@yahoo.com.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Taha
authors.affiliation: Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia; Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia.
authors.forename: Nor Hadiani
authors.initials: NH
authors.lastname: Ismail
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Salima
authors.initials: S
authors.lastname: Lalani
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology (CIIT), Park Road, Chak Shahzad, Islamabad 45600, Pakistan.
authors.forename: Muhammad Qaiser
authors.initials: MQ
authors.lastname: Fatmi
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.lastname: Atia-Tul-Wahab
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Salman
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Khalid Mohammed
authors.initials: KM
authors.lastname: Khan
authors.affiliation: Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor, Malaysia; Faculty of Applied Science UiTM, 40450 Shah Alam, Selangor, Malaysia.
authors.forename: Syahrul
authors.initials: S
authors.lastname: Imran
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Muhammad Iqbal
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D065089:Glycoside Hydrolase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D000520:alpha-Glucosidases / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D065089:Glycoside Hydrolase Inhibitors; D000520:alpha-Glucosidases; C005465:benzothiazole
keywords: Benzothiazole derivatives; DFT calculations; Docking studies; Physico-chemical properties; α-Glucosidase