Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones

Roth, Aaron; Ott, Sean; Farber, Kelli M.; Palazzo, Teresa A.; Conrad, Wayne E.; Haddadin, Makhluf J.; Tantillo, Dean J.; Cross, Carroll E.; Eiserich, Jason P.; Kurth, Mark J.

doi:10.1016/j.bmc.2014.09.044

Cited by 22 publications

(18 citation statements)

References 45 publications

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“…Expanding the toolkit for 1,2-dihydro-3 H -indazol-3-one (indazolone) construction is highly desirable because these heterocycles afford a plethora of interesting biological activities with valuable pharmaceutical applications (Figure 1). 1 For example, 1 and 2 have antiviral and antibacterial activities, 2 3 has shown antihyperglycemic properties, 3 4 is an antitumor agent, 4 5 is an angiotensin II receptor antagonist, 5 and other cases in the literature. 6…”

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confidence: 99%

Photochemical Preparation of 1,2-Dihydro-3H-indazol-3-ones in Aqueous Solvent at Room Temperature

Zhu

Kraemer

et al. 2018

J. Org. Chem.

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o-Nitrosobenzaldehyde is a reactive intermediate useful in the synthesis of nitrogen heterocycles. Previous strategies for using o-nitrosobenzaldehyde involve its isolation via chromatography and/or formation under harsh conditions. Herein, this intermediate was photochemically generated in situ from o-nitrobenzyl alcohols in a mild, efficient manner for the construction of 1,2-dihydro-3H-indazol-3-ones using an aqueous solvent at room temperature. This convenient reaction offers several advantages over reported methods. The commercially available photoreactor employed 3 × 18 W bulbs outputting broad emission above 365 nm.

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confidence: 99%

Photochemical Preparation of 1,2-Dihydro-3H-indazol-3-ones in Aqueous Solvent at Room Temperature

Zhu

Kraemer

et al. 2018

J. Org. Chem.

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“…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).…”

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confidence: 99%

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

Soubhye

Gelbcke

Antwerpen

et al. 2016

ACS Med. Chem. Lett.

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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

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“…The two-step, one-pot Davis-Beirut reaction has been used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study has been undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H 2 O 2 consumption assays [14]. Fourteen compounds were found to be potent inhibitors with IC 50 values below 1 lM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H 2 O 2 / HOCl/HOBr system.…”

Section: Library Applicationsmentioning

confidence: 99%

Combinatorial Chemistry Online Volume 17, Issue 2, February 2015

Terrett

2015

Combinatorial Chemistry - an Online Journal

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Inhibition of myeloperoxidase: Evaluation of 2H-indazoles and 1H-indazolones

Cited by 22 publications

References 45 publications

Photochemical Preparation of 1,2-Dihydro-3H-indazol-3-ones in Aqueous Solvent at Room Temperature

Photochemical Preparation of 1,2-Dihydro-3H-indazol-3-ones in Aqueous Solvent at Room Temperature

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

Combinatorial Chemistry Online Volume 17, Issue 2, February 2015

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