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Design, Synthesis and Activity Evaluation of New Irreversible Myeloperoxidase Inhibitors Derived From Benzodioxole
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: 02 November 2015 by MDPI in 1st International Electronic Conference on Medicinal Chemistry session ECMC-1

The essential role of Myeloperoxidase (MPO) in the immunity system is the oxidation of the pathogenic agents inside the neutrophils. In some cases, this enzyme causes oxidative damages for the host tissues contributing in the development of inflammatory syndromes. Thus, the inhibition of MPO in the circulation can be useful in the treatment of several inflammatory diseases. In the last decade, we described some potent reversible MPO inhibitors derived from fluorotryptamine. In addition we have reported that the SSRI agent (paroxetine) can irreversibly inhibit MPO at low nanomolar range. With the docking experiments, the important chemical groups in both paroxetine and fluorotryptamine derivatives were determined and general structure of the new series was designed.

After determination of the general structure, several modifications, including the length of the side chain, the functional group, the aromatic ring and the dioxole group, were applied to study the SAR of this series. Docking experiments for these designed compounds indicated that the length of the side chain must be between 3 and 6 carbons, the functional groups must be amine or amide, the best aromatic group is benzene and two hydroxyl groups give the compound an interaction with active site higher than dioxole.

These compounds were synthesized and tested in vitro by taurine chloramine test in order to determine the IC50 values. The results confirmed the docking test for several compounds where it is found that the IC50 of the compounds with amine are the lowest values among all the functional groups (IC50= 10-60 nM). It is shown also that 5 carbons on the side chain give the best activity for the compounds with amine while those of amide the best activity was in the compound with 3 carbons. Unlike the docking, the in vitro test showed that the compound with 2 OH instead of dioxole hasn’t any activity. Kinetic study showed that all of the active compounds reduced the Compound I of MPO (MPO-Porphyrin•+-Fe(IV)=O) to the inactive form Compound II (MPO-Porphyrin-Fe(IV)=O) in very fast way. Where Compound I of MPO is the oxidized form that reacts with the halogen ions to give HOX. Then the inhibitor reacts irreversibly with the enzyme causing destruction of the heme. The compound with 2 OH reacts with both Compounds I and II in very fast way to regenerate the native enzyme which in turn is oxidized to Compound I that produces HOCl (the active oxidative molecule of MPO).  

Keywords: Myeloperoxidase inhibitors; irreversible inhibitors; paroxitine; Benzodioxole