Design of Some Benzimidazoles as Target for α-Glucosidase Inhibitors

Abstract

Diabetes mellitus is rising globally touching more than 180 million people worldwide. This is prevailing mostly in type 2 diabetes and according to WHO report the incidence is likely to be more than doubled by 2030. α-Glucosidase inhibitors work by reducing the amount of glucose that the intestines absorb from food. In this work, forty-five benzimidazole analogues were studied using 3D QSAR, HQSAR, pharmacophore mapping and based on their results 60 compounds were designed. The results show that the best Comparative Molecular Field Analysis (CoMFA) model has q2 = 0.742 and r2 = 0.973, and the best Comparative Molecular Similarity Indices Analysis (CoMSIA) model has q2 = 0.679 and r2 = 0.918. For HQSAR the best model has q2 = 0.773 and r2 = 0.964. The r2 value for boostrap for CoMFA and CoMSIA are 0.98 and 0.97 respectively. Pharmacophore mapping revealed varied bioactive regions of ligand. Thus, these compounds could be used as lead for designing the synthesis of potent alpha-glucosidase inhibitors.
 Keywords: Acarbose, Alpha-glucosidase inhibition, Benzimidazoles, Molecular modelling, Post-prandial hyperglycemia

Design, synthesis, in silico, and in vitro evaluation of benzylbenzimidazolone derivatives as potential drugs on α-glucosidase and glucokinase as pharmacological targets

“…One of the main aspects in the discovery and generation of new drugs, is the design of specific and effective structures against a pharmacologic target, using atoms and functional groups that have been reported with biological relevance against pharmacologic targets related to the control of hyperglycemia states like α-glu and GK. 13,27 Therefore, in silico evaluation play a critical role in identifying novel molecules that can control blood glucose levels, using molecular docking to show the interactions with biological relevance amino acids in the union site, which helps to predict the possible biological activity. 28 The molecular docking analysis suggests good affinity energy (values < −5 Kcal mol −1 ); these values could be explained in the amino acid residues interaction, where the evaluated compounds present hydrogen, electrostatic and hydrophobic bond with catalytic or biological important residues of the active or allosteric site.…”

“…Currently, there are no docking studies of benzimidazolones derivatives against GK, and only a few against α-glu; however, Mentense et al in 2020, Aispuro-Pérez et al in 2019, Kadhase et al in 2019 and Singh et al in 2019, performed studies of heterocyclic compounds with structural similarity than benzimidazolones; their results showed affinity energy values lower than these derivatives (−11.1 to −8.0 Kcal mol –1 ), which suggest that the evaluated compounds have better potential than the compound reported by these authors. 4,8,25,27…”

Water‐SDS‐Ionic Liquid Catalytic System for the Synthesis of Pyrano‐chromenes and in‐silicio Approach to Predict Inhibitory Activity Against Mpro of SARS‐CoV‐2**

“…The reported compounds have molecular weights ranging from 316.31-366.37 i. e. lies within the acceptable range. The topological polar surface area (TPSA) of drug-like compounds ranges from 20 to 130 Å 2 [64] and the reported compound values ranged from 89.25 to 135.07.This value is somewhat in excess for compounds 5 j and 5 k, but it is within the range for the remaining compounds. The range of rotatable bonds for a drug-like molecule should be 0-9, and the range for selected hits was 1-2.…”

Design, synthesis and spectroscopic and structural characterization of novelN-(2-hydroxy-5-methylphenyl)-2,3-dimethoxybenzamide: DFT, Hirshfeld surface analysis, antimicrobial activity, molecular docking and toxicology

“…Molar refraction (MR) is the total polarization capacity of one mole of a compound. It depends on temperature, pressure and refractive index (Mishra & Dahima, 2019). The octanol-water partition coefficient (logP) is related to the polar or hydrophobic character of a compound.…”