Format

Send to

Choose Destination
Eur J Med Chem. 2016 Jun 10;115:484-94. doi: 10.1016/j.ejmech.2016.02.073. Epub 2016 Mar 3.

2-Alkoxy-3-(sulfonylarylaminomethylene)-chroman-4-ones as potent and selective inhibitors of ectonucleotidases.

Author information

1
Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, 54600, Lahore, Pakistan. Electronic address: maria_al_rashida@hotmail.com.
2
Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, 54600, Lahore, Pakistan.
3
Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.
4
Département de Microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Canada; Centre de Recherche du CHU de Québec, Université Laval, Québec, QC, G1V 4G2, Canada.
5
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
6
Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan. Electronic address: drjamshed@ciit.net.pk.

Abstract

A facile method for the modulation of 2-alkoxy side chain of 3-formylchromone enamines has been exploited for the synthesis of a series of 2-alkoxy-3-(sulfonylarylaminomethylene)-chroman-4-ones. This modulation was achieved by simply changing the alcoholic reaction media from methanol to ethanol, iso-propanol and n-butanol while reacting various 3-formylchromones with aminobenzenesulfonamides. Alcohols are sufficiently nucleophilic and add into the C2-C3 olefinic bond of 3-formylchromones without causing any ring cleavage. The resulting 2-alkoxy-3-(sulfonylarylaminomethylene)-chroman-4-ones were found to be potent and selective inhibitors of ecto-5'-nucleotidase and alkaline phosphatases (TNAP and IAP). Detailed enzyme kinetics studies revealed competitive inhibition against alkaline phosphatases and un-competitive inhibition against rat and human ecto-5'-nucleotidase. The most active TNAP inhibitor 23 (Ki = 0.078 ± 0.001 μM), exhibited 28 times more selectivity for TNAP over IAP (Ki = 2.18 ± 0.12 μM). Compound 9 was most active IAP inhibitor (Ki = 0.24 ± 0.01 μM), and was 300 times more selective towards IAP than TNAP (Ki = 72.9 ± 1.68 μM). Compound 40 was most active human ecto-5'-nucleotidase inhibitor exhibiting inhibition in low nanomolar range (Ki = 14 nM).

KEYWORDS:

Chromones; Ecto-5′-nucleotidase; Ectonucleotidase inhibitors; Intestinal alkaline phosphatase; Sulfonamides; Tissue non-specific alkaline phosphatase

PMID:
27054295
DOI:
10.1016/j.ejmech.2016.02.073
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center