In search of better α-glucosidase inhibitors, a series of bis-indolylmethane sulfonohydrazides derivatives (1-14) were synthesized and evaluated for their α-glucosidase inhibitory potential. All derivatives exhibited outstanding α-glucosidase inhibition with IC50 values ranging between 0.10 ± 0.05 to 5.1 ± 0.05 μM when compared with standard drug acarbose having IC50 value 856.28 ± 3.15 μM. Among the series, analog 7 (0.10 ± 0.05 μM) with tri-chloro substitution on phenyl ring was identified as the most potent inhibitor of α-glucosidase (∼ 8500 times). The structure activity relationship has been also established. Molecular docking studies were also performed to help understand the binding interaction of the most active analogs with receptors. From the docking studies, it was observed that all the active bis-indolylmethane sulfonohydrazides derivatives showed considerable binding interactions within the active site (acarbose inhibition site) of α-glucosidase. We also evaluated toxicity of all derivatives and found none of them are toxic.

Understanding the detailed mechanisms of enzyme-catalyzed hydrolysis of the glycosidic bond is fundamentally important, not only to the design of tailored cost-efficient, stable and specific catalysts, but also to the development of specific glycoside hydro-lase inhibitors as therapeutics. Retaining glycosidases employ two key carboxylic acid residues, typically glutamic acids, in a double-displacement mechanism involving a covalent glycosyl-enzyme intermediate. One Glu functions as a nucleophile while the other acts as a general acid/base. A significant part of enzymatic proficiency is attributed to a "perfect match" of the electrostatics provided by these key residues, a hypothesis that has been remarkably difficult to prove in model systems or in enzymes them-selves. We experimentally probe this synergy by preparing synthetic variants of a model glycosidase, Bacillus circulans -xylanase (Bcx) with the nucleophile Glu78 substituted by 4-fluoro or 4,4-difluoroglutamic acid to progressively reduce nucleophilicity. These Bcx variants were semi-synthesized by preparation of optically pure fluoroglutamic acid building blocks, incorporation into synthetic peptides and ligation onto a truncated circular permutant of Bcx. By measuring the effect of altered electrostatics in the active site on enzyme kinetic constants, we show the influence of nucleophile pKa on pH-dependent activity. Linear free energy correlations using substrates of varying leaving group ability demonstrate that by reducing nucleophilic catalysis, the concerted mechanism of the enzyme is disturbed. This represents the first example of site-specific introduction of fluorinated glutamic acids into any protein.

Diabetes has turned out to be an epidemic in the recent years all over the world, and today it has become a burden on the healthcare system. Over the years, with technological advancements, different classes of antidiabetic medications have emerged, like sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones, but these are often loaded with serious aftermaths like hypoglycemia, weight gain, cardiovascular and renal issues. Dipeptidyl peptidase-4 (DPP-4) inhibition is an exciting and new approach in the treatment of type-2 diabetes. DPP-4 inhibitors or "gliptins" are weight neutral, pose lesser risk of hypoglycemia, and provide a long-term post-meal glycemic control. In this review, an attempt has been made to investigate novel potential compounds that can be added to the existing list of anti-diabetic drugs.

The data presented in this article are related to the research article under the title "in vitro anti-diabetic activity of flavonoids and pheophytins from Allophylus cominia Sw. on PTP1B, DPPIV, alpha-glucosidase and alpha-amylase enzymes" (Semaan et al., 2017) [3]. This article defines the kinetics of inhibition of flavonoids and pheophytin A extracts from A. cominia which showed an inhibition of the PTP1B enzyme activity. The main reason to make these results public is to confirm that this study was followed up and no more experiments are needed, also to confirm that these compounds can be reported as PTP1B inhibitors.

Stereoselective and efficient synthesis of hydroxymethyl-substituted rac-quercitols (13-15) was achieved, starting from cis-furan (Kobayashi, 2008) with photooxygenation reaction, which is readily available by the reduction of cis-phtalic anhydride. α- and β-Glucosidase enzyme activity of the target molecules was evaluated and good inhibitor activity was seen. One- and two-dimensional NMR spectroscopy, IR spectroscopy and X-ray crystallography were utilized in the structure characterization of products.

The hydrolysis of starch is a key step in plant germination, which also has relevance in the malting and brewing processes for beer and spirit production. Gaps in knowledge about this metabolic process exist that cannot easily be addressed using traditional genetic techniques, due to functional redundancy in many of the enzyme activities required for alpha-glucan metabolism in cereal crop species. Chemical inhibitors provide opportunities to probe the role of carbohydrate-active enzymes and the phenotypes associated with inhibition of specific enzymes. Iminosugars are the largest group of carbohydrate-active enzyme inhibitors and represent an underused resource for the dissection of plant carbohydrate metabolism. Herein we report a method for carrying out a reverse chemical genetic screen on α-glucosidase, the enzyme that catalyzes the final step in starch degradation during plant germination, namely the hydrolysis of maltose to release glucose. This chapter outlines the use of a high-throughput screen of small molecules for inhibition of α-glucosidase using a colorimetric assay which involves the substrate p-nitrophenyl α-D-glucopyranoside. Identified inhibitors can be further utilized in phenotypic screens to probe the roles played by amylolytic enzymes. Furthermore this 96-well plate-based method can be adapted to assay exo-glycosidase activities involved in other aspects of carbohydrate metabolism.

Dengue fever is a leading cause of illness and mortality in the tropics and subtropics. There are no therapeutics currently available and a recently approved vaccine is not very efficacious demanding an urgent need to develop an effective antiviral. The path to successful dengue drug development depends on availability of relevant preclinical testing models and better understanding of dengue pathogenesis. In recent years, efforts to develop dengue therapeutics have focused on both repurposing approved drugs as well as discovery of new chemical entities that act via virus or host targeted mechanisms. Here, we discuss the various innovative approaches, their outcome, and the lessons gleaned from the development efforts.

Targeting the host-cell endoplasmic reticulum quality control (ERQC) pathway is an effective broad-spectrum antiviral strategy. The two ER resident α-glucosidases whose sequential action permits entry in this pathway are the targets of glucomimetic inhibitors. Knowledge of the molecular details of the ER α-glucosidase II (α-Glu II) structure was limited. We determined crystal structures of a trypsinolytic fragment of murine α-Glu II, alone and in complex with key catalytic cycle ligands, and four different broad-spectrum antiviral iminosugar inhibitors, two of which are currently in clinical trials against dengue fever. The structures highlight novel portions of the enzyme outside its catalytic pocket which contribute to its activity and substrate specificity. These crystal structures and hydrogen-deuterium exchange mass spectrometry of the murine ER alpha glucosidase II heterodimer uncover the quaternary arrangement of the enzyme's α- and β-subunits, and suggest a conformational rearrangement of ER α-Glu II upon association of the enzyme with client glycoproteins.

Prediabetes is an intermediate stage of hyperglycaemia, characterized by impaired fasting glucose, impaired glucose tolerance and/ or an HbA1c ranging from 5.7-6.4%. Prediabetes is associated with an increased risk of progression to overt diabetes and increased risk of cardiovascular disease. Several intervention studies have demonstrated that onset of diabetes can be prevented or delayed with intensive lifestyle modification and oral antidiabetic agents including metformin, thiazolidinediones and alpha-glucosidase inhibitors. Prediabetes management should focus on lifestyle modification and multiple risk factor management. In cases at high risk, use of oral antidiabetic agents may be considered.