Thioimidate Bond Formation Between Cardiac Troponin C and Nitrile-containing Compounds

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2020 May 20

PMID 32426091

Citations 2

Authors

Brittney A Klein

Ian M Robertson

Bela Reiz

Thomas Kampourakis

Liang Li

Brian D Sykes

Affiliations

Soon will be listed here.

Abstract

We have investigated the mechanism and reactivity of covalent bond formation between cysteine-84 of the regulatory domain of cardiac troponin C and compounds containing a nitrile moiety similar to the calcium sensitizer levosimendan. The results of modifications to the levosimendan framework ranged from a large increase in covalent bond formation to complete inactivity. We present the biological activity of one of the most potent compounds. Limitations, including compound solubility and degradation at acidic pH, have prevented thorough investigation of the potential of these compounds. Our studies reveal the efficacious nature of the malononitrile moiety in targeting cNTnC and its potential in future cardiotonic drug design.

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