- Design and synthesis of newer N-benzimidazol-2yl benzamide analogues as allosteric activators of human glucokinase
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Allosteric activators of human glucokinase (GK) had revealed significant hypoglycemic effects for therapy of type-2 diabetes (T2D) in animal as well as human models. Some newer N-benzimidazol-2yl substituted benzamide analogues were prepared and assessed for activation of GK accompanied by molecular docking investigations for predicting the bonding interactions of these derivatives with the residues in allosteric site of GK protein. Amongst the derivatives synthesized, compounds 2 and 7 strongly increased catalytic action of GK (GK activation fold >2.0 in comparison to control) in vitro. The results of in-vitro testing were supported by the molecular docking investigations of these analogues with GK protein’s allosteric site residues (showed appreciable H-bond interactions with Arg63 residue of GK). Derivatives investigated in present study afforded few lead compounds for the discovery of harmless and strong allosteric GK activating compounds for treating T2D.
- Singh, Sukhbir,Arora, Sandeep,Dhalio, Ervon,Sharma, Neelam,Arora, Kunal,Grewal, Ajmer Singh
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p. 760 - 770
(2021/01/20)
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- Synthesis,docking and evaluation of phenylacetic acid and trifluoro-methylphenyl substituted benzamide derivatives as potential ppar? agonists
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Background: Peroxisome proliferator-activated receptor (PPAR) ? is a type of PPARs belonging to the steroid or nuclear hormone receptor super family. Activation of PPAR? leads to metabolism of fat instead of glucose by body for energy requirements. PPAR? represent an emerging pharmacological target for the treatment of metabolic syndrome (MS). Many selective and potent PPAR? agonists had been synthesized with a potential role in the treatment of various disorders associated with MS including type 2 diabetes and inflammation. Objective: The present work was designed to synthesize and evaluate the antidiabetic and anti-inflammatory activity of some newer phenylacetic acid and trifluoromethylphenyl substituted benzamide derivatives as potential PPAR? agonists. Methods: This work involved the synthesis of newer sulfamoyl benzamide derivatives and their evaluation by molecular docking studies to determine the binding interactions for the best fit conformations in the binding site of the PPAR? protein. Based on the results of the in silico studies, the selected compounds were tested for their antidiabetic and anti-inflammatory activity in the animal models. Results: Amongst the synthesized molecules, compound 7 showed higher anti-diabetic activity and compound 19 showed higher anti-inflammatory activity. The experimental results were found to be in concordance with that of the in silico results. Most of the synthesized molecules were found to have drug like properties as devised by Lipinski's rule of five. Conclusion: These molecules can act as the starting hits for the design of safe, effective and bioavailable PPAR? agonists for the potential treatment of MS and related diseases.
- Grewal, Ajmer Singh,Lather, Viney,Pandita, Deepti,Bhayana, Garima
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p. 1239 - 1251
(2017/11/14)
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- CHEMOKINE RECEPTOR BINDING HETEROCYCLIC COMPOUNDS
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Tertiary amines containing a multiplicity of heteroaromatic substituents are useful as chemokine receptor modulators.
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- β-Amino-thiols inhibit the zinc metallopeptidase activity of tetanus toxin light chain
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Tetanus neurotoxin is a 150-kDa protein produced by Clostridium tetani, which causes the lethal spastic paralytic syndromes of tetanus by blocking inhibitory neurotransmitter release at central synapses. The toxin light chain (50 kDa) has a zinc endopeptidase activity specific for synaptobrevin, an essential component of the neuroexocytosis apparatus. Previous unsuccessful attempts to block the proteolytic activity of this neurotoxin with well-known inhibitors of other zinc proteases led us to study the design of specific inhibitors as a possible drug therapy to prevent the progressive evolution of tetanus following infection. Starting from the synaptobrevin sequence at the level of the cleavage site by tetanus neurotoxin (Gln76- Phe77)a thiol analogue of glutamine demonstrated inhibitory activities in the millimolar range. A structure-activity relationship performed with this compound led us to determine the requirement for the correct positioning of the thiol group, the primary amino group, and a carboxamide or sulfonamide group on the side chain. This resulted in the design of a β-amino(4- sulfamoylphenyl)glycine-thiol, the first significantly efficient inhibitor of tetanus neurotoxin with a K(i) value of 35 ± 5μM.
- Martin, Lo?c,Cornille, Fabrice,Coric, Pascale,Roques, Bernard P.,Fournié-Zaluski, Marie-Claude
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p. 3450 - 3460
(2007/10/03)
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