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Dual Anti-Inflammatory and Anti-Bacterial Effects of Phenylhydrazide and Phenylhydrazone Derivatives
1  Jalal Soubhye, Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Campusplaine, CP 205/5, 1050 Brussels, Belgium. E-mail:

Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to the propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. The implementation of dynamic combinatorial libraries allowed to obtain several compounds derived from aromatic hydrazone with high activity on MPO. These inhibitors were found to be reversible and irreversible MPO inhibitors at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. In vivo evaluation in rats injected by carrageenan showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation.

On the other hand, paroxetine and p-aminobenzoic acid hydrazide are irreversible MPO inhibitors. The hydrazide group was identified as responsible for the irreversible activity. In addition, hydroxamic acid derivatives are good reversible inhibitors and the hydroxamate group is very similar to the hydrazide one in electronic density and ability to make bonds. Thus, starting from paroxetine, benzoic acid hydrazide, and hydroxamic acid, a new series of compounds has been  designed and synthesized. These compounds have shown very high activity on MPO with IC50 of 12-900 nM. Investigations on the mechanism of action has demonstrated that these compounds are irreversible MPO inhibitors. To see if these inhibitors impair the innate immunity, the effect of the compounds were tested on the neutrophils. The results showed that these inhibitors inhibit only the released MPO into the extracellular fluids.

Finally, hydrazide and hydrazine derivatives were tested as anti-bacterial agents. Surprisingly, all hydrazone derivatives showed high activity against Gram (-) bacteria and low activity on Gram (+). In contrast, hydrazide derivatives showed very high potency against Gram (+) but no effect was found on Gram (-).

Keywords: Anti-Inflammatory; Anti-Bacterial; Myeloperoxidase; Phenylhydrazide; Phenylhydrazone