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

A series of new deferasirox derivatives were synthesized through the reaction of monosubstituted hydrazides with 2-(2-hydroxyphenyl)-4H-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 IC50 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 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.

Synthesis and Study of Multifunctional Cyclodextrin-Deferasirox Hybrids.

Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress, protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal-selective chelation therapy. Deferasirox, 4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions. Cyclodextrins are cyclic glucose units that are extensively used in the pharmaceutical industry as formulating agents as well as for encapsulating hydrophobic molecules such as in the treatment of Niemann-Pick type C or for hypervitaminosis. We conjugated deferasirox, via an amide coupling reaction, to both 6A -amino-6A -deoxy-ß-cyclodextrin and 3A -amino-3A -deoxy-2A (S),3A (S)-ß-cyclodextrin, at the upper and lower rim, respectively, creating hybrid molecules with dual properties, capable of both metal chelation and cholesterol encapsulation. Our findings emphasize the importance of the conjugation of ß-cyclodextrin with deferasirox to significantly improve the biological properties and to decrease the cytotoxicity of this drug.