title: Isonicotinohydrazones as inhibitors of alkaline phosphatase and ecto-5'-nucleotidase.
abstract: A series of isonicotinohydrazide derivatives was synthesized and tested against recombinant human and rat ecto-5'-nucleotidases (h-e5'NT and r-e5'NT) and alkaline phosphatase isozymes including both bovine tissue-non-specific alkaline phosphatase (b-TNAP) and tissue-specific calf intestinal alkaline phosphatase (c-IAP). These enzymes are implicated in vascular calcifications, hypophosphatasia, solid tumors, and cancers, such as colon, lung, breast, pancreas, and ovary. All tested compounds were active against both enzymes. The most potent inhibitor of h-e5'NT was derivative (E)-N'-(1-(3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)isonicotinohydrazide (3j), whereas derivative (E)-N'-(4-hydroxy-3-methoxybenzylidene)isonicotinohydrazide (3g) exhibited significant inhibitory activity against r-e5'NT. In addition, the derivative (E)-N'-(4'-chlorobenzylidene)isonicotinohydrazide (3a) was most potent inhibitor against calf intestinal alkaline phosphatase and the derivative (E)-N'-(4-hydroxy-3-methoxybenzylidene)isonicotinohydrazide (3g) was found to be most potent inhibitor of bovine tissue-non-specific alkaline phosphatase. Furthermore, putative binding modes of potent compounds against e5'NT (human and rat e5'NT) and AP (including b-TNAP and c-IAP) were determined computationally.
authors: Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan.
authors: Pervaiz Ali
authors: PA
authors: Channar
authors: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
authors: Syed Jawad Ali
authors: SJ
authors: Shah
authors: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
authors: Sidra
authors: S
authors: Hassan
authors: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
authors: Zaib Un
authors: ZU
authors: Nisa
authors: Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, Canada.|Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, Canada.
authors: Joanna
authors: J
authors: Lecka
authors: Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, Canada.|Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, Canada.
authors: Jean
authors: J
authors: Sévigny
authors: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.
authors: Jürgen
authors: J
authors: Bajorath
authors: Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan.
authors: Aamer
authors: A
authors: Saeed
authors: Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan.
authors: Jamshed
authors: J
authors: Iqbal
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D007538:Isoniazid / Q000737:chemistry; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D000469:Alkaline Phosphatase; D015720:5'-Nucleotidase; C548241:NT5E protein, human; C548243:Nt5e protein, rat; D007538:Isoniazid
keywords: biological screening; drug discovery; molecular modeling