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Synthesis and evaluation of potent novel inhibitors of human sulfide:quinone oxidoreductase
Journal article   Open access   Peer reviewed

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
url
https://doi.org/10.1016/j.bmcl.2021.128443View
Accepted (AM)Open Access (License Unspecified),  Open

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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7 citations in Web of Science
6 citations in Scopus

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Web of Science research areas
Chemistry, Medicinal
Chemistry, Organic
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