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N ‐pyridin‐2‐yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro , in silico and in vivo evaluation
Author(s) -
Grewal Ajmer Singh,
Kharb Rajeev,
Prasad Deo Nandan,
Dua Jagdeep Singh,
Lather Viney
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13423
Subject(s) - benzamide , allosteric regulation , glucokinase , chemistry , in silico , in vivo , in vitro , pharmacology , enzyme , lead compound , small molecule , biochemistry , stereochemistry , biology , microbiology and biotechnology , gene
Glucokinase ( GK ) is the key enzyme controlling levels of blood glucose under normal physiological range, and GK activators are emerging class of drug candidates with promising hypoglycaemic activity. The current study was planned to design, synthesize and evaluate novel N ‐pyridin‐2‐yl benzamide analogues as allosteric activators of GK . A novel series of N ‐pyridin‐2‐yl benzamide analogues were synthesized starting from 3‐nitrobenzoic acid and evaluated in vitro for GK activation followed by in silico studies to predict the binding interactions of the designed molecules with GK protein. The selected synthesized molecules (compounds 5b , 5c , 5e , 5g , 5h and 6d ) which displayed excellent GK activity ( GK fold activation around 2) in GK assay and appreciable binding interaction with GK in docking studies were further evaluated for their antihyperglycaemic potential using oral glucose tolerance test ( OGTT ) in rats. Amongst the compounds tested in vivo ( OGTT assay) for antihyperglycaemic potential, compounds 5c , 5e and 5g displayed significant reduction in blood glucose levels. Compound 5e displayed most significant antidiabetic activity and comparable to that of standard drug in animal studies. The N ‐pyridin‐2‐yl benzamide analogues discovered in the current study can provide some lead molecules for the development of potent oral GK activators with minimum side‐effects for the management of type 2 diabetes.