Novel synthesis of dihydropyrimidines for α-glucosidase inhibition to treat type 2 diabetes: in vitro biological evaluation and in silico docking

Muhammad Yar; Marek Bajda; Lubna Shahzadi; Sohail Anjum Shahzad; Maqsood Ahmed; Muhammad Ashraf; Umber Alam; Islam Ullah Khan; Ather Farooq Khan

doi:10.1016/j.bioorg.2014.05.003

Novel synthesis of dihydropyrimidines for α-glucosidase inhibition to treat type 2 diabetes: in vitro biological evaluation and in silico docking

Bioorg Chem. 2014 Jun:54:96-104. doi: 10.1016/j.bioorg.2014.05.003. Epub 2014 May 15.

Authors

Muhammad Yar¹, Marek Bajda², Lubna Shahzadi³, Sohail Anjum Shahzad⁴, Maqsood Ahmed⁵, Muhammad Ashraf⁶, Umber Alam⁶, Islam Ullah Khan⁷, Ather Farooq Khan³

Affiliations

¹ Interdisciplinary Research Center in Biomedical Materials, COMSATS Institute of Information Technology, Lahore 54000, Pakistan. Electronic address: drmyar@ciitlahore.edu.pk.
² Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland; Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Cracow, Poland.
³ Interdisciplinary Research Center in Biomedical Materials, COMSATS Institute of Information Technology, Lahore 54000, Pakistan.
⁴ Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: sohail_chem@yahoo.com.
⁵ Department of Chemistry, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
⁶ Department of Biochemistry & Biotechnology, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan.
⁷ Department of Chemistry, GC University, Lahore 54000, Pakistan.

PMID: 24880489
DOI: 10.1016/j.bioorg.2014.05.003

Abstract

A convenient and efficient new method has been established for the synthesis of dihydropyrimidines by inexpensive and non-toxic N-acetyl glycine (NAG) catalysed reaction of aromatic aldehydes with ethyl acetoacetate and urea/thiourea. This method is applicable for various substituted aldehydes as well as urea and thiourea. It has also been used to synthesize bicyclic oxygen-bridged pyrimidine derivatives (4d, 4j). The biological assay revealed that the majority of compounds synthesized displayed modest inhibitory activity against α-glucosidase at low micro-molar concentrations. Molecular docking studies were also performed on the most active compound, 4f (with IC50 value 112.21±0.97 μM), to show the enzyme - inhibitor interactions.

Keywords: Acarbose; Biginelli reaction; Dihydropyrimidine; N-acetyl glycine; α-Glucosidase inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Crystallography, X-Ray
Diabetes Mellitus, Type 2 / drug therapy*
Dose-Response Relationship, Drug
Glycoside Hydrolase Inhibitors / chemical synthesis
Glycoside Hydrolase Inhibitors / chemistry
Glycoside Hydrolase Inhibitors / pharmacology*
Molecular Docking Simulation*
Molecular Sequence Data
Molecular Structure
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Saccharomyces cerevisiae / enzymology
Sequence Alignment
Structure-Activity Relationship
alpha-Glucosidases / metabolism*

Substances

1,4-dihydropyrimidine
Glycoside Hydrolase Inhibitors
Pyrimidines
alpha-Glucosidases