Synthesis, Biological Activity, and Molecular Modeling Studies of 1H-1,2,3-Triazole Derivatives of Carbohydrates as alpha-Glucosidases Inhibitors (original) (raw)
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1,4-Disubstituted-1,2,3-triazoles were synthesized by Cu(I) catalyzed click reaction, where the azides, with electron donating and electron withdrawing groups acted as 1,3-dipoles and 1- ethynyl-1-cyclohexanol served as the terminal alkyne. These synthesized triazoles were subjected to enzymatic assay which showed promising activity against α–glucosidase; 1-(2- Cyano-4-nitrophenyl)-4-(1-hydroxycyclohexyl)-1H-1,2,3-triazole 3m being the most active members of the library. Molecular docking studies of these triazoles with the homologymodeled α–glucosidase protein were also performed to delineate ligand-protein interactions at molecular level which suggested that Phe157, Arg312 and His279 are the major interacting residues in the biding site of the protein and may have a significant role in the inhibition of enzyme’s function.
Journal of Agricultural and Food Chemistry, 2020
Succinate dehydrogenase (SDH) is regarded as a promising target for fungicide discovery. To continue our ongoing studies on the discovery of novel SDH inhibitors as fungicides, novel pyrazole-thiazole carboxamides were designed, synthesized, and evaluated for their antifungal activity. The results indicated that compounds 9ac, 9bf 23 and 9cb showed excellent in vitro activities against Rhizoctonia cerealis with EC 50 values from 1.1 to 4.9 mg/L, superior to the commercial fungicide thifluzamide (EC 50 25 = 23.1 mg/L). Compound 9cd (EC 50 = 0.8 mg/L) was far more active than thifluzamide (EC 50 = 4.9 mg/L) against Sclerotinia sclerotiorum. Compound 9ac 27 exhibited promising in vivo activity against Rhizoctonia solani (90% at 10 mg/L), 28 which was better than thifluzamide (80% at 10 mg/L). The field experiment showed 29 that compound 9ac had 74.4% efficacy against R. solani at the 15 th day after 2 consecutive sprayings at an application rate of 4.80 g ai/667 m 2 , which was close to 31 thifluzamide (83.3%). Furthermore， molecular docking explained the possible binding mode of compound 9ac in the RcSDH active site. Our studies indicated that pyrazole-thiazole-carboxamide hybrid is a new scaffold of SDH inhibitors.
Experiences with the shikimate-pathway enzymes as targets for rational drug design
Biochemical Society Transactions, 2008
The background and current context of work on the shikimate-pathway enzymes as potential targets for anti-bacterial, anti-fungal and anti-parasitic drugs is reviewed. Recent work on the third enzyme of the pathway, dehydroquinase, which occurs in two structurally and mechanistically distinct forms, is used to illustrate the present state of studies into rational drug design.
1,4-Disubstituted-1,2,3-triazoles were synthesized by Cu(I) catalyzed click reaction, where the azides, with electron donating and electron withdrawing groups acted as 1,3-dipoles and 1-ethynyl-1-cyclohexanol served as the terminal alkyne. These synthesized triazoles were subjected to enzymatic assay which showed promising activity against a-glucosidase; 1-(2-cyano-4-nitrophenyl)-4-(1-hydroxycyclohexyl)- 1H-1,2,3-triazole 3m being the most active members of the library. Molecular docking studies of these triazoles with the homology-modeled a-glucosidase protein were also performed to delineate ligand– protein interactions at molecular level which suggested that Phe157, Arg312 and His279 are the major interacting residues in the biding site of the protein and may have a significant role in the inhibition of enzyme’s function.
Shikimic Acid:A Highly Prospective Molecule in Pharmaceutical Industry
Current Science, 2015
Shikimic acid (SA) is the key intermediate in the common pathway of aromatic amino acid biosynthesis (the shikimate pathway). The benzene ring, the basic unit of all aromatic compounds, is formed in plants and microorganisms through the shikimate pathway and the intermediate SA is an extremely essential compound in plants and microbes. The most important use of SA is as a substrate for the chemical synthesis of the drug oseltamivir, commercially known as Tamiflu ® , an efficient inhibitor of the human influenza virus H1N1 of swine origin, seasonal influenza virus types A and B, and avian influenza virus H5N1. The fruits of the Chinese star anise ( Illicium verum ) contain SA to the extent of 17.14% on dry wt. basis and this is now the main source for commercial production of SA. The demand for Tamiflu ® has increased tremendously and the pharmaceutical industry is unable to meet this demand due to shortage of SA. Therefore, significant attention needs to be paid towards the developm...
European journal of medicinal chemistry, 2018
Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC 50 values of 0.64-51.09 mM. The preliminary structure-activity relationships indicated that the methylcatechol moiety and arylsulfonyl substituents generated better compounds than both the benzodioxole and alkylsulfonyl chains. Molecular dynamics studies of compound 6d showed that the interaction with the peripheral binding site of AChE was similar to donepezil, which may explain its low IC 50 (0.64 mM). Furthermore, the drug-likeness of 6d suggests that the compound may have appropriate oral absorption and brain penetration. Compound 6d also presented antiradical activity and was not cytotoxic to LL24 cells, suggesting that this compound might be considered safe. Our findings indicate that arylsulfonylhydrazones may be a promising scaffold for the design of new drug candidates for the treatment of AD.
Bioorganic & Medicinal Chemistry, 2013
Bacterial resistance remains a significant threat and a leading cause of death worldwide, despite massive attempts to control infections. In an effort to develop biologically active antibacterial and antifungal agents, six novel aryl-substituted-1,2,3-triazoles linked to carbohydrate units were synthesized through the Cu(I)-catalyzed azide-alkyne cycloaddition CuAAC of substituted-arylazides with a selection of alkyne-functionalized sugars. The chemical structures of the new derivatives were verified using different spectroscopic techniques. The novel clicked 1,2,3-triazoles were evaluated for in vitro antibacterial activity against Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa, and the obtained results were compared with the activity of the reference antibiotic "Ampicillin". Likewise, in vitro antifungal activity of the new 1,2,3-triazoles was investigated against Candida albicans and Aspergillus niger using "Nystatin" as a reference drug. The results of the biological evaluation pointed out that Staphylococcus aureus was more susceptible to all of the tested compounds than other examined microbes. In addition, some tested compounds exhibited promising antifungal activity.
Molecular Diversity, 2020
We have created a novel series of mushroom tyrosinase inhibitors with 1,2,4-triazole as fundamental skeleton. The target compound 1,2,4-triazol-3-ylthio)-N-phenyl acetamide derivatives 9(a-l) were synthesized by the reaction of 4-and 5-substituted 1,2,4-triazole-3-thiol derivatives 6(a-c) with 2-chloro-N-sub/un-substituted phenyl acetamide derivatives 8(a-d) under basic condition. By using the analytical techniques for instance, FTIR, LC-MS, 1 H NMR and 13 C NMR, the structural verification was evaluated. The novel series of the target compounds 9(a-l) has been scanned for biological activity (mushroom tyrosinase inhibition potential) which demonstrates adequate results. Interestingly, compound 9k (IC 50 = 0.0048 ± 0.0016 µM) exhibits 3500 times more activity compared with standard drug kojic acid (IC 50 = 16.8320 ± 1.1600 µM) against mushroom tyrosinase inhibitor. Furthermore, the cytotoxicity experiment was carried out for the highly effective target compounds (9d, 9i, 9j and 9k) by using MTT assay method for A375 human melanoma cells to define the nontoxic performance of the most effective compounds ranging from 1 to 25 µM. Furthermore, the molecular docking study delivers the thought concerning the interface of the ligand with an enzyme. Also, the dynamic simulation was accomplished for compound 9k to govern the plausible binding model.
RSC Advances, 2023
Benzimidazolones have shown biological activities, including antihyperglycemic and hypoglycemic, by inhibiting or activating of a-glu and GK. The aim of this study is the rational design of compounds using in silico assays to delimitate the selection of structures to synthesize and the in vitro evaluation of benzimidazolone derivatives in blood glucose control. A docking of 23 benzimidazolone derivatives was performed; selecting the compounds with better in silico profiles to synthesize by microwaveirradiation/conventional heat and evaluate in enzymatic in vitro evaluation. Compounds 2k, 2m, 2r, and 2s presented the best in silico profiles, showing good affinity energy (−10.9 to −8.6 kcal mol −1) and binding with catalytic-amino acids. They were synthesized at 70°C and 24 h using DMF as the solvent and potassium carbonate (yield: 22-38%). The results with a-glu showed moderate inhibition of 2k (14 ± 1.23-29 ± 0.45), 2m (12 ± 2.21-36 ± 0.30), 2r (7 ± 2.21-13 ± 1.34), and 2s (11 ± 0.74-35 ± 2.95) at evaluated concentrations (0.1 to 100 mg mL −1). The GK activation assay showed an enzymatic activity increase; compound 2k increased 1.31 and 2.83 more than normal activity, 2m (2.13-fold), 2s (2.86 and 3.74-fold) at 100 and 200 mg mL −1 respectively. The present study showed that the 2s derivative presents moderate potential as an a-glu inhibitor and a good activator potential of GK, suggesting that this compound is a good candidate for blood glucose control through antihyperglycemic and hypoglycemic mechanisms.