Nα-arylsulfonyl histamines as selective β-glucosidase inhibitors (original) (raw)

Nα-arylsulfonyl histamines as selective βglucosidase inhibitors

2018

N a-benzenesulfonylhistamine, a new semi-synthetic b-glucosidase inhibitor, was obtained by bioactivityguided isolation from a chemically engineered extract of Urtica urens L. prepared by reaction with benzenesulfonyl chloride. In order to identify better b-glucosidase inhibitors, a new series of N a ,N s-diarylsulfonyl and N a-arylsulfonyl histamine derivatives was prepared. Biological studies revealed that the b-glucosidase inhibition was in a micromolar range for several N a-arylsulfonyl histamine compounds of the series, N a-4-fluorobenzenesulfonyl histamine being the most powerful compound. Besides, this reversible and competitive inhibitor presented a good selectivity for b-glucosidase with respect to other target enzymes including a-glucosidase.

Synthesis and bioevaluation of glycosyl ureas as α-glucosidase inhibitors and their effect on mycobacterium

Bioorganic & Medicinal Chemistry, 2003

Glycosyl amino esters (2-13) on reaction with different isocyanates resulted in quantitative conversion to glycosyl ureas (14--32). Few of the selected ureas (15-20, 22-28, 30 and 32) on cyclative amidation with DBU/TBAB/4 Å MS gave respective dihydropyrimidinones in fair to good yields (33-47). The compounds were screened for a-glucosidase inhibitory activity and two (19 and 23) of them showed strong inhibition against rat intestinal a-glucosidase. The compounds were also screened against Mycobacterium aurum, however, only one (19) of them exhibited marginal antitubercular activity.

Synthesis of new 2-{2,3-dihydro-1,4-benzodioxin-6-yl[(4-methylphenyl) sulfonyl]amino}-N-(un/substituted-phenyl)acetamides as α-glucosidase and acetylcholinesterase inhibitors and their in silico study

Brazilian Journal of Pharmaceutical Sciences, 2019

The aim of the present research work was to investigate the enzyme inhibitory potential of some new sulfonamides having benzodioxane and acetamide moieties. The synthesis was started by the reaction of N-2,3-dihydrobenzo[1,4]-dioxin-6-amine (1) with 4-methylbenzenesulfonyl chloride (2) in the presence of 10% aqueous Na 2 CO 3 to yield N-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)-4-methylbenzenesulfonamide (3), which was then reacted with 2-bromo-N-(un/substituted-phenyl)acetamides (6a-l) in DMF and lithium hydride as a base to afford various 2-{2,3-dihydro-1,4-benzodioxin-6-yl[(4-methylphenyl)sulfonyl] amino}-N-(un/substituted-phenyl)acetamides (7a-l). All the synthesized compounds were characterized by their IR and 1 H-NMR spectral data along with CHN analysis data. The enzyme inhibitory activities of these compounds were tested against a-glucosidase and acetylcholinesterase (AChE). Most of the compounds exhibited substantial inhibitory activity against yeast a-glucosidase and weak against AChE. The in silico molecular docking results were also consistent with in vitro enzyme inhibition data.

Discovery of B-Glucosidase Inhibitors from a Chemically Engineered Extract Prepared through Ethanolysis

A series of vegetal extracts have been chemically altered by ethanolysis. The effect of the reaction on the inhibition of the enzyme -glucosidase properties of the mixtures was studied using thin layer chromatography (TLC) with biodetection. Glucosidase inhibitory activity guided fractionation of one of the produced chemically engineered extracts led to the isolation of apigenin and ethyl p-cumarate. Both compounds were generated during the chemical modification step.

Three New Acrylic Acid Derivatives from Achillea mellifolium as Potential Inhibitors of Urease from Jack Bean and α-Glucosidase from Saccharomyces cerevisiae

Molecules, 2022

  1. Background: Achillea mellifolium belongs to a highly reputed family of medicinal plants, with plant extract being used as medicine in indigenous system. However, limited data is available regarding the exploitation of the medicinal potential of isolated pure compounds from this family; (2) Methods: A whole plant extract was partitioned into fractions and on the basis of biological activity, an ethyl acetate fraction was selected for isolation of pure compounds. Isolated compounds were characterized using different spectroscopic techniques. The compounds isolated from this study were tested for their medicinal potential using in-vitro enzyme assay, coupled with in-silico studies; (3) Results: Three new acrylic acid derivatives (1-3) have been isolated from the ethyl acetate fraction of Achillea mellifolium. The characterization of these compounds (1-3) was carried out using UV/Vis, FT-IR, 1D and 2D-NMR spectroscopy ( 1 H-NMR, 13 C-NMR, HMBC, NOESY) and mass spectrometry. These acrylic acid derivatives were further evaluated for their enzyme inhibition potential against urease from jack bean and α glucosidase from Saccharomyces cerevisiae, using both in-silico and in-vitro approaches. In-vitro studies showed that compound 3 has the highest inhibition against urease enzyme (IC 50 =10.46 ± 0.03 µM), followed by compound 1 and compound 2 with percent inhibition and IC 50 value of 16.87 ± 0.02 c and 13.71 ± 0.07 µM, respectively, compared to the standard (thiourea-IC 50 = 21.5 ± 0.01 µM). The investigated IC 50 value of compound 3 against the urease enzyme is two times lower compared to thiourea, suggesting that this compound is twice as active compared to the standard drug. On the other hand, all three compounds (1-3) revealed mild inhibition potential against α-glucosidase. In-silico molecular docking studies, in combination with MD simulations and free energy, calculations were also performed to rationalize their time evolved mode of interaction inside the active pocket. Binding energies were computed using a MMPBSA approach, and the role of individual residues to overall binding of the inhibitors inside the active pockets were also computed; (4) Conclusions: Together, these studies confirm the inhibitory potential of isolated acrylic acid derivatives against both urease and α-glucosidase enzymes; however, their inhibition potential is better for urease enzyme even when compared to the standard.

The 4-(dimethylaminoalkyl)piperazine inhibitors of α-glucosidase: allosteric enzyme inhibition and identification of interacting chemical groups

Turkish Journal of Chemistry

Intestinal α-glucosidases are a class of enzymes that are essential for digestion of dietary carbohydrates [1]. One of the treatment approaches for controlling hyperglycemia manifested in diabetes mellitus is inhibition of α-glucosidase [2]. The current therapeutic regime for treatment of diabetes includes only a limited number of oral α-glucosidase inhibitors namely acarbose, miglitol, and voglibose. Their low efficacy and gastrointestinal side effects are major obstacles to achieving promising therapeutic outcome. Unfortunately, no significant progress has been made in the drug development of oral α-glucosidase inhibitors. Therefore, this area needs attention to develop new α-glucosidase inhibitors with better efficacy, less side effects, and more therapeutic benefits [3-4]. Carbamate and piperazine moieties have been shown to exhibit promising biological activities for treatment of Alzheimer's disease and a number of other central nervous system (CNS) disorders [5]. Dithiocarbamate, an isostere of carbamate, is a promising pharmacophore in the drug development of CNS-related disorders especially for drug delivery due to its lipophilic properties [6]. Moreover, the piperazine moiety exhibits diverse biological activities such as antiparasitic, antimicrobial, antipsychotic, antidepressant, and anxiolytic activities [7]. Furthermore, compounds bearing the piperazine moiety are also known to possess potent inhibitory activity against α-glucosidase including chiral piperazine diones [8], 2-furoic piperazides [9], triazole-containing piperazines [10], and phenylpiperazines [11]. Presently, there are a very limited number of reports on dithiocarbamates as inhibitors of α-glucosidase that include coumarin-containing dithiocarbamates [12], and benzyl carbamates [13]. Nevertheless, these derivatives are a promising class of emerging compounds that exhibit potent inhibition of α-glucosidase. Our recent work on dithiocarbamates α-glucosidase inhibitors

and β-Glucosidase inhibitors: chemical structure and biological activity

Tetrahedron, 2006

Glycoside trimming enzymes are crucially important in a broad range of metabolic pathways, including glycoprotein and glycolipid processing and carbohydrate digestion in the intestinal tract. Amongst the large array of enzymes, glucosidases are postulated to be a powerful therapeutic target since they catalyze the cleavage of glycosidic bonds releasing glucose from the non-reducing end of an oligo-or polysaccharide chain involved in glycoprotein biosynthesis. Glucosidase inhibitors are currently of interest owing to their promising therapeutic potential in the treatment of disorders such as diabetes, human immunodeficiency virus (HIV) infection, metastatic cancer, and lysosomal storage diseases. Glucosidase inhibitors have also been useful in probing biochemical pathways and understanding structure-activity relationship patterns required for mimicking the enzyme transition state. Amongst the various types of glucosidase inhibitors, disaccharides, iminosugars, carbasugars, thiosugars, and non-sugar derivatives have received great attention. This review is aimed at highlighting the main chemical classes of glucosidase inhibitors, as well as their biological activities toward aand b-glucosidases, but it is not intended to be an exhaustive review on the subject. Inhibition data on the compounds covered in this review are included in a tabular form as an Appendix, where the type of each glucosidase associated with a specific inhibitor is also given.

α- and β-Glucosidase Inhibitors: Chemical Structure and Biological Activity

ChemInform, 2007

Glycoside trimming enzymes are crucially important in a broad range of metabolic pathways, including glycoprotein and glycolipid processing and carbohydrate digestion in the intestinal tract. Amongst the large array of enzymes, glucosidases are postulated to be a powerful therapeutic target since they catalyze the cleavage of glycosidic bonds releasing glucose from the non-reducing end of an oligo-or polysaccharide chain involved in glycoprotein biosynthesis. Glucosidase inhibitors are currently of interest owing to their promising therapeutic potential in the treatment of disorders such as diabetes, human immunodeficiency virus (HIV) infection, metastatic cancer, and lysosomal storage diseases. Glucosidase inhibitors have also been useful in probing biochemical pathways and understanding structure-activity relationship patterns required for mimicking the enzyme transition state. Amongst the various types of glucosidase inhibitors, disaccharides, iminosugars, carbasugars, thiosugars, and non-sugar derivatives have received great attention. This review is aimed at highlighting the main chemical classes of glucosidase inhibitors, as well as their biological activities toward aand b-glucosidases, but it is not intended to be an exhaustive review on the subject. Inhibition data on the compounds covered in this review are included in a tabular form as an Appendix, where the type of each glucosidase associated with a specific inhibitor is also given.