title: 2-Alkoxy-3-(sulfonylarylaminomethylene)-chroman-4-ones as potent and selective inhibitors of ectonucleotidases.
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).
authors.affiliation: Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, 54600, Lahore, Pakistan. Electronic address: maria_al_rashida@hotmail.com.
authors.forename: Mariya
authors.initials: M
authors.lastname: al-Rashida
authors.affiliation: Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, 54600, Lahore, Pakistan.
authors.forename: Gazala
authors.initials: G
authors.lastname: Batool
authors.affiliation: Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, 54600, Lahore, Pakistan.
authors.forename: Almas
authors.initials: A
authors.lastname: Sattar
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.
authors.forename: Syeda Abida
authors.initials: SA
authors.lastname: Ejaz
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.
authors.forename: Samiullah
authors.initials: S
authors.lastname: Khan
authors.affiliation: 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.
authors.forename: Joanna
authors.initials: J
authors.lastname: Lecka
authors.affiliation: 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.
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Hameed
authors.affiliation: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan. Electronic address: drjamshed@ciit.net.pk.
authors.forename: Jamshed
authors.initials: J
authors.lastname: Iqbal
mesh_terms: D002839:Chromans / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009708:Nucleotidases / Q000037:antagonists & inhibitors*
chemical_list: D002839:Chromans; D004791:Enzyme Inhibitors; D009708:Nucleotidases
keywords: Chromones; Ecto-5′-nucleotidase; Ectonucleotidase inhibitors; Intestinal alkaline phosphatase; Sulfonamides; Tissue non-specific alkaline phosphatase