Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides

J Med Chem. 2016 Sep 8;59(17):7950-62. doi: 10.1021/acs.jmedchem.6b00752. Epub 2016 Aug 25.


Phenotypic whole-cell screening in erythrocytic cocultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure-activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure-property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as 10b. Analogues 13h and 13i, with structural modifications at each site, were shown to possess excellent antimalarial activity in vivo. The (+)-(3S,4S) enantiomer of 13i and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-13i for further study as a preclinical candidate.

Publication types

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

MeSH terms

  • Anilides / chemical synthesis
  • Anilides / chemistry*
  • Anilides / pharmacology
  • Anilides / toxicity
  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry*
  • Antimalarials / pharmacology
  • Antimalarials / toxicity
  • Coculture Techniques
  • Erythrocytes / cytology
  • Erythrocytes / parasitology
  • Humans
  • Isoquinolines / chemical synthesis
  • Isoquinolines / chemistry*
  • Isoquinolines / pharmacology
  • Isoquinolines / toxicity
  • Mice
  • Microsomes, Liver / metabolism
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / physiology
  • Solubility
  • Stereoisomerism
  • Structure-Activity Relationship


  • Anilides
  • Antimalarials
  • Isoquinolines
  • N-(3-cyano-4-fluorophenyl)-1-oxo-3-(pyridin-3-yl)-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide