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Synthesis, Biological Evaluation and Molecular Docking of Deferasirox and Substituted 1,2,4‐Triazole Derivatives as Novel Potent Urease Inhibitors: Proposing Repositioning Candidate
Author(s) -
Salehi Ashani Razieh,
Azizian Homa,
Sadeghi Alavijeh Nahid,
Fathi Vavsari Vaezeh,
Mahernia Shabnam,
Sheysi Niloofar,
Biglar Mahmood,
Amanlou Massoud,
Balalaie Saeed
Publication year - 2020
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201900710
Subject(s) - acetohydroxamic acid , chemistry , urease , docking (animal) , stereochemistry , deferasirox , pyrimidine , enzyme , combinatorial chemistry , tetrazole , active site , triazole , carboxylate , biochemistry , organic chemistry , medicine , nursing , thalassemia
A series of new deferasirox derivatives were synthesized through the reaction of monosubstituted hydrazides with 2‐(2‐hydroxyphenyl)‐4 H ‐benzo[ e ][1,3]oxazin‐4‐one. For the first time, deferasirox and some of its derivatives were evaluated for their in vitro inhibitory activity against Jack bean urease. The potencies of the members of this class of compounds are higher than that of acetohydroxamic acid. Two compounds, bearing tetrazole and hydrazine derivatives (bioisoester of carboxylate group), represented the most potent urease inhibitory activity with IC 50 values of 1.268 and 3.254 μ m , respectively. In silico docking studies were performed to delineate possible binding modes of the compounds with the enzyme, urease. Docking analysis suggests that the synthesized compounds were anchored well in the catalytic site and extending to the entrance of binding pocket and thus restrict the mobility of the flap by interacting with its crucial amino acid residues, CME592 and His593. The overall results of urease inhibition have shown that these target compounds can be further optimized and developed as a lead skeleton for the discovery of novel urease inhibitors