title: Diarylsulfonamides and their bioisosteres as dual inhibitors of alkaline phosphatase and carbonic anhydrase: Structure activity relationship and molecular modelling studies.
abstract: The effect of bioisosteric replacement of carboxamide linking group with sulfonamide linking group, on alkaline phosphatase (AP) and carbonic anhydrase (CA) inhibition activity of aromatic benzenesulfonamides was investigated. A series of carboxamide linked aromatic benzenesulfonamides 1a-1c, 2a-2d and their sulfonamide linked bioisosteres 3a-3d, 4a-4d was synthesized and evaluated for inhibitory activity against bovine tissue non-specific alkaline phosphatase (TNAP), intestinal alkaline phosphatase (IAP) and bCA II. A significant increase in CA inhibition activity was observed upon bioisosteric replacement of carboxamide linking group with a sulfonamide group. Some of these compounds were identified as highly potent and selective AP inhibitors. Compounds 1b, 2b, 3d, 4d 5b and 5c were found to be selective bTNAP inhibitors, whereas compounds 1a, 1c, 2a, 2c, 2d, 3a, 3c, 4a, 4b, 4c, 5a were found to be selective bIAP inhibitors. For most active AP inhibitor 3b, detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase (TNAP) and non-competitive mode of inhibition against intestinal alkaline phosphatase (IAP). Molecular docking studies were carried out to rationalize important binding site interactions.
authors: Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan. Electronic address: maria_al_rashida@hotmail.com.
authors: Mariya
authors: M
authors: Al-Rashida
authors: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
authors: Syeda Abida
authors: SA
authors: Ejaz
authors: Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan.
authors: Sharafat
authors: S
authors: Ali
authors: Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan.
authors: Aisha
authors: A
authors: Shaukat
authors: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
authors: Mehwish
authors: M
authors: Hamayoun
authors: Department of Chemistry, The Islamia University of Bahawalpur, Pakistan.
authors: Maqsood
authors: M
authors: Ahmed
authors: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan. Electronic address: jamshediqb@gmail.com.
authors: Jamshed
authors: J
authors: Iqbal
mesh_terms: D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000737:chemistry*; D002417:Cattle; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004952:Esters; D007700:Kinetics; D062105:Molecular Docking Simulation; D009928:Organ Specificity; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D004952:Esters; D013449:Sulfonamides; D000469:Alkaline Phosphatase; D024402:Carbonic Anhydrase II
keywords: Alkaline phosphatase inhibitors; Bioisosteres; Carbonic anhydrase inhibitors; Homology modeling; Intestinal alkaline phosphatase; Structure activity relationship (SAR); Tissue non-specific alkaline phosphatase