Natural product derived antiprotozoal agents: synthesis, biological evaluation, and structure-activity relationships of novel chromene and chromane derivatives

J Med Chem. 2013 Sep 26;56(18):7442-8. doi: 10.1021/jm401007p. Epub 2013 Sep 9.

Abstract

Various natural products with the chromane and chromene scaffold exhibit high antiprotozoal activity. The natural product encecalin (7) served as key intermediate for the synthesis of different ethers 9, amides 11, and amines 12. The chromane analogues 14 and the phenols 15 were obtained by reductive amination of ketones 13 and 6, respectively. Angelate 3, ethers 9, and amides 11 did not show considerable antiprotozoal activity. However, the chromene and chromane derived amines 12, 14, and 15 revealed promising antiprotozoal activity and represent novel lead compounds. Whereas benzylamine 12a and α-methylbenzylamine 12g were active against P. falciparum with IC50 values in the range of chloroquine, the analogous phenols 15a and 15b were unexpectedly 10- to 25-fold more potent than chloroquine with selectivity indexes of 6760 and 1818, respectively. The phenylbutylamine 14d based on the chromane scaffold has promising activity against T. brucei rhodesiense and L. donovani.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / chemistry*
  • Antiprotozoal Agents / pharmacology*
  • Biological Products / chemical synthesis
  • Biological Products / chemistry*
  • Biological Products / pharmacology*
  • Chemistry Techniques, Synthetic
  • Chromans / chemical synthesis
  • Chromans / chemistry*
  • Chromans / pharmacology*
  • Inhibitory Concentration 50
  • Structure-Activity Relationship

Substances

  • Antiprotozoal Agents
  • Biological Products
  • Chromans