Synthesis of Deuterated Endochin-Like Quinolones

J Labelled Comp Radiopharm. 2024 May 15;67(5):186-196. doi: 10.1002/jlcr.4092. Epub 2024 Apr 25.

Abstract

Malaria continues to be a serious and debilitating disease. The emergence and spread of high-level resistance to multiple antimalarial drugs by Plasmodium falciparum has brought about an urgent need for new treatments that will be active against multidrug resistant malaria infections. One such treatment, ELQ-331 (MMV-167), an alkoxy carbonate prodrug of 4(1H)-quinolone ELQ-300, is currently in preclinical development with the Medicines for Malaria Venture. Clinical development of ELQ-331 or similar compounds will require the availability of isotopically labeled analogs. Unfortunately, a suitable method for the deuteration of these important compounds was not found in the literature. Here, we describe a facile and scalable method for the deuteration of 4(1H)-quinolone ELQ-300, its alkoxycarbonate prodrug ELQ-331, and their respective N-oxides using deuterated acetic acid.

Keywords: ELQ; deuterium exchange; endochin‐like quinolone; malaria; prodrug; quinolone.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Chemistry Techniques, Synthetic*
  • Deuterium* / chemistry
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology
  • Quinolones* / chemical synthesis
  • Quinolones* / chemistry

Substances

  • Quinolones
  • Deuterium
  • Prodrugs
  • Antimalarials