Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation

Wang, Zhengyu; Shi, Xiaofan; Zhang, Huan; Yu, Liang; Cheng, Yanhua; Zhang, Hefeng; Zhang, Huibin; Zhou, Jinpei; Chen, Jing; Shen, Xu; Duan, Wenhu

doi:10.1016/j.ejmech.2017.07.051

Cited by 15 publications

(7 citation statements)

References 54 publications

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“…The 2D structures for the designed ligands were drawn in MarvinSketch and transformed to 3D with LigPrep 2.5 with OPLS2005 force field [59]. An analogous docking method was used for the molecular docking of the synthesized derivatives as described in detail in earlier publications using Glide and the ligand poses with most favorable docking score (Glide score and Glide energy) were selected [24, 25]. The binding interactions of the ligands with GK protein were analysed further for the docked poses of the ligands using PyMOL (the PyMOL molecular graphics system, Schrödinger, LLC).…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis and evaluation of novel 3,5-disubstituted benzamide derivatives as allosteric glucokinase activators

et al. 2019

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Glucokinase (GK) is the key enzyme expressed in β-cells of pancreas and liver hepatocytes and helps in the maintenance of blood glucose levels in normal range. Activators of GK are the novel category of drug candidates which activate GK enzyme allosterically and show their antidiabetic activity. A new series of 3,5-disubstituted benzamide analogues was designed, synthesized and evaluated as GK activators by in vitro assay as well as in silico docking studies followed by evaluation of antihyperglycemic activity in animal model. Amongst the synthesized derivatives, compounds 5c , 5f , 5i , 6c , 6e and 6h displayed excellent in vitro GK activation. Compounds 6c and 6e exhibited highest antihyperglycemic activity in oral glucose tolerance test in animal model. Compound 6e displayed most significant antihyperglycemic activity and comparable to that of standard drug in animal studies. In addition, antihyperglycemic activity of the synthesized molecules was further supported by the in silico docking studies of the synthesized derivatives in the allosteric site of GK protein.

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Section: Methodsmentioning

confidence: 99%

Design, synthesis and evaluation of novel 3,5-disubstituted benzamide derivatives as allosteric glucokinase activators

et al. 2019

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“…The 2D structures for the designed ligands were drawn in MarvinSketch and transformed to 3D with LigPrep 2.5 with OPLS2005 force field . A similar docking methodology was used for the molecular docking of the synthesized derivatives as described in detail in earlier publications using Glide, and the ligand poses with most favourable docking score were selected (Singh et al, 2016;Wang et al, 2017). The binding interactions were analysed further for the docked poses of the ligands using PyMOL (Charaya et al, 2018).…”

Section: Docking Studiesmentioning

confidence: 99%

“…GK activators are the novel category of therapeutic agents which activate GK allosterically and demonstrate their hypoglycaemic potential (Coghlan & Leighton, 2008;Matschinsky et al, 2011;Pal, 2009a;Perseghin, 2010). A broad variety of chemically different classes of compounds including substituted benzamide analogues (Charaya, Pandita, Grewal, & Lather, 2018;Iino et al, 2010;Li et al, 2011;Mao et al, 2012;Pike et al, 2011;Park et al, 2014Park et al, , 2013Singh et al, 2016;Wang et al, 2017;Zhang, Chen, et al, 2012), carboxamide derivatives such as acetamides, butanamides and other (Cheruvallath et al, 2013;Li et al, 2010;Mitsuya et al, 2009;Pfefferkorn, Tu, et al, 2012;Ye et al, 2012), acrylamides (Sidduri et al, 2010), heterocyclic compounds such as benzimidazole derivatives (Ishikawa et al, 2009;Takahashi et al, 2009), quinazolines derivatives (Iino et al, 2009), thiazole derivatives (Hinklin et al, 2013), pyrimidine derivatives (Filipski et al, 2013), and substituted urea compounds (Li et al, 2014;Zhang, Tian, et al, 2012) were developed recently to act as potent GK activators with antidiabetic effects. Several GK activators had been advanced to phase II clinical trials including piragliatin, AZD6370, AZD1656, MK-0941 and AMG151; although potent reduction of blood glucose efficacy had been reported, possible adverse effects had also been observed, including hypoglycaemia and raised triglyceride levels.…”

Section: Introductionmentioning

confidence: 99%

N‐pyridin‐2‐yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro, in silico and in vivo evaluation

et al. 2018

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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. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Grewal AS, Kharb R, Prasad DN, Dua JS, Lather V. N-pyridin-2-yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro, in silico and in vivo evaluation. Chem Biol Drug Des. 2019;93:364-372.

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“…The literature survey revealed that most of the drug discovery and development research associated with allosteric activators of human GK were mainly focused on the substituted benzamide analogs probably owing to their corresponding alignment outline and bonding connections with the residues of allosteric location of GK (Grewal et al, 2014;Pal et al, 2009b). Some of the benzamide derivatives reported recently as potent GK activators are shown in Figure 1 along with their GK activity (Bowler et al, 2013;Charaya et al, 2018;Ericsson et al, 2012;Grewal et al, 2019aGrewal et al, , 2019bLei et al, 2015;McKerrecher et al, 2018;Park et al, 2013Park et al, , 2014Pike et al, 2011;Sjostrand et al, 2013;Wang et al, 2017). Based on the above-mentioned facts, few newer N-benzothiazol-2-yl benzamide correspondents were proposed as potential activators of human GK.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and evaluation of some novel N-benzothiazol-2-yl benzamide derivatives as allosteric activators of human glucokinase

Sandeep¹,

Grewal²,

Sharma³

et al. 2021

J Appl Pharm Sci

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Some newer benzamide analogues of N-benzothiazol-2-yl were prepared and assessed for human glucokinase (GK) activation accompanied by molecular docking investigations for predicting the bonding connections of the these derivatives with residues in the allosteric site of GK. Among the derivatives synthesized, 6 and 7 strongly increased the catalytic action of GK (GK activation fold about 2.0 compared to control) in vitro. The outcomes of in vitro assay were supported by the molecular docking investigations of these analogues with allosteric site residues of the GK protein. Derivatives investigated in the present study can afford few lead compounds for the discovery of harmless and strong allosteric GK activating compounds for the management of type 2 diabetes.

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Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation

Cited by 15 publications

References 54 publications

Design, synthesis and evaluation of novel 3,5-disubstituted benzamide derivatives as allosteric glucokinase activators

Design, synthesis and evaluation of novel 3,5-disubstituted benzamide derivatives as allosteric glucokinase activators

N‐pyridin‐2‐yl benzamide analogues as allosteric activators of glucokinase: Design, synthesis, in vitro, in silico and in vivo evaluation

Design, synthesis, and evaluation of some novel N-benzothiazol-2-yl benzamide derivatives as allosteric activators of human glucokinase

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