Synthesis and evaluation of potent novel inhibitors of human sulfide:quinone oxidoreductase

Simon D P Baugh; Michael R Jackson; Adel Ahmed Rashad; Allen B Reitz; Patrick Y S Lam; Marilyn Schuman Jorns

doi:10.1016/j.bmcl.2021.128443

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Synthesis and evaluation of potent novel inhibitors of human sulfide:quinone oxidoreductase

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Synthesis and evaluation of potent novel inhibitors of human sulfide:quinone oxidoreductase

Simon D P Baugh, Michael R Jackson, Adel Ahmed Rashad, Allen B Reitz, Patrick Y S Lam and Marilyn Schuman Jorns

Bioorganic & medicinal chemistry letters, v 54, pp 128443-128443

15 Dec 2021

DOI: https://doi.org/10.1016/j.bmcl.2021.128443

PMID: 34763081

Featured in Collection : UN Sustainable Development Goals @ Drexel

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Abstract

Dose-Response Relationship, Drug

Enzyme Inhibitors - chemical synthesis

Enzyme Inhibitors - chemistry

Enzyme Inhibitors - pharmacology

Humans

Hydrocarbons, Aromatic - chemical synthesis

Hydrocarbons, Aromatic - chemistry

Hydrocarbons, Aromatic - pharmacology

Molecular Structure

Oxidoreductases Acting on Sulfur Group Donors - antagonists & inhibitors

Oxidoreductases Acting on Sulfur Group Donors - metabolism

Small Molecule Libraries - chemical synthesis

Small Molecule Libraries - chemistry

Small Molecule Libraries - pharmacology

Structure-Activity Relationship

Here we report the first small-molecule inhibitors of human sulfide:quinone oxidoreductase (SQOR) that decrease the rate of breakdown of hydrogen sulfide (H S), a potent cardioprotective signaling molecule. SQOR is a mitochondrial membrane-bound protein that catalyzes a two-electron oxidation of H S to sulfane sulfur (S ), using glutathione (or sulfite) and coenzyme Q (CoQ) as S and electron acceptor, respectively. Inhibition of SQOR may constitute a new approach for the treatment of heart failure with reduced ejection fraction. Starting from top hits identified in a high-throughput screen, we conducted SAR development guided by docking of lead candidates into our crystal structure of SQOR. We identified potent SQOR inhibitors such as 19 which has an IC of 29 nM for SQOR inhibition and favorable pharmacokinetic and ADME properties required for in vivo efficacy testing.

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Title: Synthesis and evaluation of potent novel inhibitors of human sulfide:quinone oxidoreductase
Creators: Simon D P Baugh - Fox Chase Chemical Diversity Center
Michael R Jackson - Drexel University
Adel Ahmed Rashad - Drexel University
Allen B Reitz - Fox Chase Chemical Diversity Center
Patrick Y S Lam - Fox Chase Chemical Diversity Center
Marilyn Schuman Jorns - Drexel University
Publication Details: Bioorganic & medicinal chemistry letters, v 54, pp 128443-128443
Publisher: Elsevier
Grant note: R41 HL134435 / NHLBI NIH HHS
Resource Type: Journal article
Language: English
Academic Unit: Biochemistry and Molecular Biology; Microbiology and Immunology; Pharmacology and Physiology; [Retired Faculty]
Web of Science ID: WOS:000722162300004
Scopus ID: 2-s2.0-85119119487
Other Identifier: 991019168874604721

UN Sustainable Development Goals (SDGs)

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Web of Science research areas: Chemistry, Medicinal; Chemistry, Organic

Synthesis and evaluation of potent novel inhibitors of human sulfide:quinone oxidoreductase

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UN Sustainable Development Goals (SDGs)

InCites Highlights

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