From Dynamic Combinatorial Chemistry to in Vivo Evaluation of Reversible and Irreversible Myeloperoxidase Inhibitors

Abstract

The implementation of dynamic combinatorial libraries allowed the determination of highly active reversible and irreversible inhibitors of myeloperoxidase (MPO) 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. Finally, in vivo evaluation showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation. KEYWORDS:Myeloperoxidase, reversible and irreversible inhibitors, dynamic combinatorial chemistry, molecular docking, kinetic study N eutrophils represent the first line of the human innate immune defense system by phagocytosing and killing invading pathogens.1 Optimal antimicrobial action in neutrophils relies on the action of hypochlorous acid (HOCl), the product of the myeloperoxidase (MPO, EC 1.11.2.2)−hydrogen peroxide−chloride system. In certain inflammatory events, MPO and/or HOCl are released from neutrophils causing oxidative damage of host tissue and modification of biomolecules.2−4 Consequently, MPO has become a new target for designing anti-inflammatory drugs. 5−7From a general point of view, the development of pharmacophores typically proceeds according to a conventional pathway, namely, the structural design and synthesis of analogues from a "hit" molecule followed by the evaluation of structure−activity relationships. 6,8 However, this classical method is particularly costly and time-consuming. Another innovative strategy consists in the generation and screening of a dynamic combinatorial library (DCL). 9 In the realm of dynamic combinatorial chemistry (DCC), DCL constitutes a rational alternative in drug discovery, opening thus new horizons for medicinal chemists. Indeed, the in situ reaction of simple building blocks is able to give rise to a wide range of new molecules through reversible covalent bond formation. In the last 10 years, this strategy allowed for the creation and the identification of ligands that specifically recognize targets such as proteins and nucleic acids. 10With this in mind, we decided to apply this approach in order to develop new irreversible inhibitors of MPO. Recently, we evaluated a new family of scaffolds, i.e., hydralazine 11 and isoniazid, endowed with the ability to inhibit MPO irreversibly but with high IC 50 values (0.9 and 5 μM, respectively) ( Figure 1). Keen to improve these substrates, we decided to take advantage of the high reactivity of hydrazine and hydrazide functionalities toward aldehyde partners in order to prepare

The many roles of myeloperoxidase: From inflammation and immunity to biomarkers, drug metabolism and drug discovery

“…Studies have come quite a long way since hydrazides, and there is considerable chemical heterogeneity for MPO inhibitors. Computational and experimental screening efforts directed towards identifying reversible and irreversible MPO inhibitors have led to diverse scaffolds [ [196] , [197] , [198] , [199] ]. These chemical scaffolds include triazolopyridine macrocyclics, peptides, ferulic acids, indole alkylamines, thioxanthines, thioxodihydroquinazolinones, triazolopyridines, and thiopyrimidinones [ 3 ].…”

A patent review of myeloperoxidase inhibitors for treating chronic inflammatory syndromes (focus on cardiovascular diseases, 2013-2019)

“…It has been suggested that the circulating MPO in the blood is a leftover of neutrophils and its concentration increases in the inflammatory cases where the high level of MPO in plasma has been found to be a risk factor for CVD [92][93][94]. Thus, the suicidal inhibitors are preferred rather than the reversible ones as the frequency of drug administration is lower when the drug acts irreversibly [95]. However, besides the activity, the safety profile is the most important property for the inhibitor in order to enter clinical use and with this good tolerance, the compound can be administrated even in a relatively high-dose or high-frequency schedule [96].…”

Crystal packing and theoretical analysis of halogen- and hydrogen-bonded hydrazones from pharmaceuticals. Evidence of type I and II halogen bonds in extended chains of dichloromethane

“…The synthesis of the substituted hydrazones was performed under conventional conditions (Soubhye et al, 2017). Isoniazid was stirred in refluxing ethanol with an equimolar amount of 4-iodo-or 4-bromobenzaldehyde, resulting in the acyl hydrazones IsI and IsBr in 88 and 77% yields, respectively (Hearn et al, 2009).…”

“…As a preliminary study, we decided to investigate the selfassembly properties of halogenated hydrazones and their hydroxyl-substituted analogues derived from two well known pharmaceuticals, isoniazid and hydralazine. Hydrazones are an important class of molecules endowed with a wide range of applications that are used for their photo/chemical switching properties (Aprahamian, 2017), their pH-responsive behaviour in drug delivery systems (Sonawane et al, 2017) or as inhibitors of myeloperoxidase (Soubhye et al, 2017) and metal ligands (Mandal et al, 2017). Here, the supramolecular organizations of 4-iodo-, 4-bromo-and 4-hydroxyhydrazones ( Fig.…”