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Chem Biodivers. 2020 Mar 18. doi: 10.1002/cbdv.201900710. [Epub ahead of print]

Synthesis, Biological Evaluation and Molecular Docking of Deferasirox and Substituted 1,2,4-Triazole Derivatives as Novel Potent Urease Inhibitors: Proposing Repositioning Candidate.

Author information

1
K.N. Toosi University of Technology, Chemistry Department, PO Box 15875-4416, 15875-4416, Tehran, IRAN (ISLAMIC REPUBLIC OF).
2
KN Toosi University of Technology, Peptide chemistry research center, PO Box 15875-4416, Tehran, IRAN (ISLAMIC REPUBLIC OF).
3
Tehran University of Medical Sciences, Department of medicinal chemistry, Hemmat, Tehran, IRAN (ISLAMIC REPUBLIC OF).
4
KN Toosi University of Technology, Peptide chemistry research center, P.O. Box 15875-4416, Tehran, IRAN (ISLAMIC REPUBLIC OF).
5
KN Toosi University of Technology, Peptide Chemistry Research Center, P.O. Box 15875-4416, Tehran, IRAN (ISLAMIC REPUBLIC OF).
6
Tehran University of Medical Sciences, Drug Design and Development Research Center, Enghelab street, Tehran, IRAN (ISLAMIC REPUBLIC OF).
7
Tehran University of Medical Sciences, Department of medicinal chemistry, Enghelab Street, Tehran, IRAN (ISLAMIC REPUBLIC OF).
8
Tehran University of Medical Sciences, Drug Design and Development Research Center, Enghelab Street, Tehran, IRAN (ISLAMIC REPUBLIC OF).

Abstract

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 greater than that of acetohydroxamic acid. Compounds 7d and 7e, analogs 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 µM, 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 key 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 discovery of novel urease inhibitors.

KEYWORDS:

Cyclization; Deferasirox analoges; Heterocycles; Inhibitors; Repositioning candidate

PMID:
32187446
DOI:
10.1002/cbdv.201900710

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