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Isonicotinohydrazones as inhibitors of alkaline phosphatase and ecto‐5′‐nucleotidase
Author(s) -
Channar Pervaiz Ali,
Shah Syed Jawad Ali,
Hassan Sidra,
Nisa Zaib un,
Lecka Joanna,
Sévigny Jean,
Bajorath Jürgen,
Saeed Aamer,
Iqbal Jamshed
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12861
Subject(s) - alkaline phosphatase , hypophosphatasia , chemistry , 5' nucleotidase , enzyme , isozyme , nucleotidase , microbiology and biotechnology , biochemistry , phosphatase , biology
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‐1 H ‐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.