New 6-amino-pyrido[2,3-d]pyrimidine-2,4-diones as novel agents to treat type 2 diabetes: A simple and efficient synthesis, α-glucosidase inhibition, molecular modeling and kinetic study

Adib, Mehdi; Peytam, Fariba; Rahmanian-Jazi, Mahmoud; Mahernia, Shabnam; Bijanzadeh, Hamid Reza; Jahani, Mehdi; Mohammadi-Khanaposhtani, Maryam; Imanparast, Somaye; Faramarzi, Mohammad Ali; Mahdavi, Mohammad; Larijani, Bagher

doi:10.1016/j.ejmech.2018.05.046

Cited by 83 publications

(25 citation statements)

References 23 publications

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“…The residue was puri ed by column chromatography using n-hexane/EtOAc (3:1) as eluent to afford pure product 6a. Molecular docking study Since the x-ray crystallographic structure S. cerevisiae α-glucosidase isn't accessible, the 3D structure of S.cerevisiae isomaltase with PDB ID: 3A4A was downloaded from RCSB web site with 84% similarity to S. cerevisiae α-glucosidase 15 . Docking studies were performed using Auto Dock Tools (version1.5.6), and the pdb structure of 3A4A was taken from theBrookhaven protein database (http://www.rcsb.org) as a complex bound with α-D-glucose.…”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis, Molecular Docking, and Kinetic Study of 3-Amino-2,4-Diarylbenzo[4,5]Imidazo[1,2-a]Pyrimidines as Novel, Potent Α-Glucosidase Inhibitor

Peytam

Takalloobanafshi

Saadattalab

et al. 2021

Preprint

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In an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a-ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their α-glucosidase inhibitory activities were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which may provide new drug candidates in the treatment of type II diabetes mellitus. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against α-glucosidase (IC50 = 16.4 ± 0.36 μM) which was 45.7 times more potent than acarbose as standard inhibitor (IC50 = 750.0 ± 1.5 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results.

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Section: Methodsmentioning

confidence: 99%

“…Over recent decade, various heterocyclic-based compounds possessing α-glucosidase inhibitory activities have been found [13][14][15][16][17][18][19][20][21][22][23][24] . For example, several pyrimidine derivatives have shown excellent inhibition potency [25][26][27][28] .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Molecular Docking, and Kinetic Study of 3-Amino-2,4-Diarylbenzo[4,5]Imidazo[1,2-a]Pyrimidines as Novel, Potent Α-Glucosidase Inhibitor

Peytam

Takalloobanafshi

Saadattalab

et al. 2021

Preprint

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“…Further, the active derivative 52 was found to be 10-fold more active in comparison to acarbose as standard (IC 50 = 750.0 ± 1.5 μm). Molecular modelling was also performed to confirm its binding to specific site (Adib et al, 2018). Toobaei and co-workers reported a series of poly-hydroxyl functionalized sub-structure and evaluated for α-Glucosidase and α-Amylase inhibition.…”

Section: Anti-diabetes Agentsmentioning

confidence: 99%

An overview on synthetic and pharmaceutical prospective of pyrido[2,3‐d]pyrimidines scaffold

Yadav

Shah

2020

Chem Biol Drug Des

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Pyrido[2,3-d]pyrimidine, a fused hetero-bicyclic nucleus containing pyridine and pyrimidine rings has attained the momentary attention in the sphere of multicomponent synthetic protocol and medicinal chemist. Pyrido[2,3-d]pyrimidine derived drugs have manifested diverse pharmacological activities, particularly, anti-inflammatory, cytotoxic, antimicrobial, phosphodiesterase inhibitors and cytokine inhibitors etc. The present review illustrates various modern synthetic strategies adopted, the structure-activity relationship (SAR) aspects and discloses the extensive crucial biological properties (anticancer, anti-infectious, anti-diabetics and CNS agents) of pyrido[2,3-d]pyrimidines. K E Y W O R D S anticancer, anti-diabetics, anti-infectious, CNS agents, pyrido[2,3-d]pyrimidines How to cite this article: Yadav P, Shah K. An overview on synthetic and pharmaceutical prospective of pyrido[2,3-d]pyrimidines scaffold.

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“…All experiments were performed at least three times. Dock Tools (version 1.5.6) to study ligand-enzyme interactions 21,80 . Briefly, crystal structures of isomaltase from Saccharomyces cerevisiae (PDB code 3A4A), with 72% identical and shares 85% similarity with the Saccharomyces cerevisiae α-glucosidase, was designated for building modeled α-glucosidase.…”

Section: Chemistrymentioning

confidence: 99%

An efficient and targeted synthetic approach towards new highly substituted 6-amino-pyrazolo[1,5-a]pyrimidines with α-glucosidase inhibitory activity

Peytam

Adib

Shourgeshty

et al. 2020

Sci Rep

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In an attempt to find novel α-glucosidase inhibitors, an efficient, straightforward reaction to synthesize a library of fully substituted 6-amino-pyrazolo[1,5-a]pyrimidines 3 has been investigated. Heating a mixture of α-azidochalcones 1 and 3-aminopyrazoles 2 under the mild condition afforded desired compounds with a large substrate scope in good to excellent yields. All obtained products were evaluated as α-glucosidase inhibitors and exhibited excellent potency with IC 50 values ranging from 15.2 ± 0.4 µM to 201.3 ± 4.2 µM. Among them, compound 3d was around 50-fold more potent than acarbose (IC 50 = 750.0 ± 1.5 µM) as standard inhibitor. Regarding product structures, kinetic study and molecular docking were carried out for two of the most potent ones. Recently, the world health organization (WHO) has identified the diabetes mellitus (DM) as a critical health challenge in the 21st century. The prevalence of diabetes has been increasing at alarming rate over the past three decades. This metabolic disorder, characterized by chronic hyperglycemia, leads to further severe damages like abnormally great thrust, excessive appetite, overweigh, blindness, excessive urination, cardiovascular complications, as well as renal and neurodegenerative diseases 1-6. There are three main diabetes types among which type 2 or non-insulin dependent (T2DM) is the most common one, mainly treated by controlling the digestive enzyme activities such as α-glucosidase 7-9. α-Glucosidase, found in the brush-border surface membrane of intestinal cells, plays catalyzing role in the carbohydrate digestion process by which the postprandial blood glucose levels increases. Preventing the glucose release in the bloodstream, the α-glucosidase inhibitors control T2DM 10. Additionally, this enzyme has a pivotal role in the biosynthesis of glycoprotein, therefore, its inhibitors have possessed anticancer, antitumor, antiviral, and immunoregulatory properties 11-15. Acrabose, miglitol, voglibose, and deoxynojirimycin have clinically been used to restrict the α-glucosidase activity 16. Considering the side effects and absorption problems associated with these drugs, new scaffolds should be synthesized and evaluated by medicinal chemists to extend the library of compounds 17-25. Pyrazoles are common structural motif in numerous drugs 26 and biologically active compounds showing activities such as anti-cancer 27,28 , anti-inflammatory 29 , anti-hypertensive 30 , cannabinoid receptor antagonist 31 , dopaminergic receptor antagonist 32 , and α-glucosidase inhibitors 33. Pyrazoles have been used to synthesize

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New 6-amino-pyrido[2,3-d]pyrimidine-2,4-diones as novel agents to treat type 2 diabetes: A simple and efficient synthesis, α-glucosidase inhibition, molecular modeling and kinetic study

Cited by 83 publications

References 23 publications

Design, Synthesis, Molecular Docking, and Kinetic Study of 3-Amino-2,4-Diarylbenzo[4,5]Imidazo[1,2-a]Pyrimidines as Novel, Potent Α-Glucosidase Inhibitor

Design, Synthesis, Molecular Docking, and Kinetic Study of 3-Amino-2,4-Diarylbenzo[4,5]Imidazo[1,2-a]Pyrimidines as Novel, Potent Α-Glucosidase Inhibitor

An overview on synthetic and pharmaceutical prospective of pyrido[2,3‐d]pyrimidines scaffold

An efficient and targeted synthetic approach towards new highly substituted 6-amino-pyrazolo[1,5-a]pyrimidines with α-glucosidase inhibitory activity

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