Synthesis of diethyl 4-substituted-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates as a new series of inhibitors against yeast α-glucosidase

Huma Niaz; Hamdy Kashtoh; Jalaluddin A J Khan; Ajmal Khan; Atia-tul- Wahab; Muhammad Tanveer Alam; Khalid Mohammed Khan; Shahnaz Perveen; M Iqbal Choudhary

doi:10.1016/j.ejmech.2015.03.018

Synthesis of diethyl 4-substituted-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates as a new series of inhibitors against yeast α-glucosidase

Eur J Med Chem. 2015 May 5:95:199-209. doi: 10.1016/j.ejmech.2015.03.018. Epub 2015 Mar 11.

Authors

Huma Niaz¹, Hamdy Kashtoh², Jalaluddin A J Khan², Ajmal Khan¹, Atia-tul- Wahab³, Muhammad Tanveer Alam¹, Khalid Mohammed Khan⁴, Shahnaz Perveen⁵, M Iqbal Choudhary⁶

Affiliations

¹ H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
² Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia.
³ Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
⁴ H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: khalid.khan@iccs.edu.
⁵ PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan.
⁶ H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan; Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21412, Saudi Arabia; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: iqbal.choudhary@iccs.edu.

PMID: 25817770
DOI: 10.1016/j.ejmech.2015.03.018

Abstract

1,4-Dihydropyridine-3,5-dicarboxylate derivatives (1-25) were synthesized in high yields via Hantzsch reaction and evaluated for their α-glucosidase inhibitory activity. Compounds 1, 2, 6-8, 11, 13-15, and 23-25 showed a potent inhibitory activity against yeast α-glucosidase with IC50 values in the range of 35.0-273.7 μM, when compared with the standard drug acarbose (IC50 = 937 ± 1.60 μM). Their structures were characterized by different spectroscopic techniques. The kinetics, selectivity, and toxicity studies on these compounds were also carried out. The kinetic studies on most active compounds 14 and 25 determined their modes of inhibition and dissociation constants Ki. Compound 14 was found to be a non-competitive inhibitor with Ki = 25.0 ± 0.06, while compound 25 was identified as a competitive inhibitor with Ki = 66.0 ± 0.07 μM.

Keywords: 1,4-Dihydropyridine-3,5-dicarboxylates; Anti-hyperglycemic activity; Hantzsch reaction; Type II diabetes; α-Glucosidase inhibition.

Publication types

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

MeSH terms

Animals
Carbonic Anhydrase II / antagonists & inhibitors
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / pharmacology
Carboxylic Acids / chemical synthesis*
Carboxylic Acids / pharmacology*
Cell Proliferation / drug effects*
Cells, Cultured
Dose-Response Relationship, Drug
Fibroblasts / cytology
Fibroblasts / drug effects*
Glycoside Hydrolase Inhibitors / chemical synthesis*
Glycoside Hydrolase Inhibitors / pharmacology*
Kinetics
Molecular Structure
Phosphodiesterase I / antagonists & inhibitors
Phosphodiesterase Inhibitors / chemical synthesis
Phosphodiesterase Inhibitors / pharmacology
Pyridines / chemical synthesis*
Pyridines / pharmacology*
Rats
Saccharomyces cerevisiae / enzymology*
Structure-Activity Relationship
alpha-Glucosidases / chemistry*

Substances

Carbonic Anhydrase Inhibitors
Carboxylic Acids
Glycoside Hydrolase Inhibitors
Phosphodiesterase Inhibitors
Pyridines
diethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
diethyl 2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Phosphodiesterase I
alpha-Glucosidases
Carbonic Anhydrase II