2. Academic Validation
  3. Synthesis and evaluation of potent novel inhibitors of human sulfide:quinone oxidoreductase

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

  • Bioorg Med Chem Lett. 2021 Dec 15;54:128443. doi: 10.1016/j.bmcl.2021.128443.
Simon D P Baugh 1,  Michael R Jackson 2,  Adel Ahmed Rashad 2,  Allen B Reitz 1,  Patrick Y S Lam 1,  Marilyn Schuman Jorns 3
Affiliations

Affiliations

  • 1 Fox Chase Chemical Diversity Center, Inc., Doylestown, PA 18902, USA.
  • 2 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
  • 3 Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. Electronic address: [email protected].
PMID: 34763081 DOI: 10.1016/j.bmcl.2021.128443
Abstract

Here we report the first small-molecule inhibitors of human sulfide:quinone oxidoreductase (SQOR) that decrease the rate of breakdown of hydrogen sulfide (H2S), a potent cardioprotective signaling molecule. SQOR is a mitochondrial membrane-bound protein that catalyzes a two-electron oxidation of H2S to sulfane sulfur (S0), using glutathione (or sulfite) and coenzyme Q (CoQ) as S0 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 IC50 of 29 nM for SQOR inhibition and favorable pharmacokinetic and ADME properties required for in vivo efficacy testing.

Keywords

Heart failure; SAR development; Small-molecule inhibitors; Sulfide:quinone oxidoreductase (SQOR).

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