Novel heteroarotinoids as potential antagonists of Mycobacterium bovis BCG

J Med Chem. 2004 Feb 12;47(4):1008-17. doi: 10.1021/jm0303453.

Abstract

A series of 15 heteroarotinoids has been prepared and evaluated for activity against Mycobacterium bovis BCG with the thiourea-containing isoxyl (7) (0.5 microg/mL) as the standard. 2,2,4-Trimethyl-2H-chromen-7-yl 4-(methoxycarbonyl)benzoate (8) displayed the most significant activity (2.0-4.0 microg/mL) in terms of the lowest concentration (microg/mL) (MIC, minimum inhibitory concentration) required to produce a 99% reduction in the number of colonies on a plate as compared to that system free of the agent at the same dilution of the culture suspension. Ethyl 4-[[N-(2,2,4,4-tetramethylchroman-6-yl)thiocarbamoyl]amino]benzoate (9) and [[(1E,3Z,5E)-1-aza-4-methyl-6-(1,2,2,4-tetramethyl(1,2-dihydroquinolyl))hexa-1,3,5-trienyl]amino]aminomethane-1-thione (10) exhibited activity at 5.0-10.0 and 10.0-20.0 microg/mL, respectively, while the other examples had MIC values of 20 microg/mL or greater. The inhibitory ability of 8 may occur via the inhibition of mycolic acid synthesis in a like manner as found with 7, but this requires further study. The heteroarotinoids are the first examples to exhibit inhibitory ability against the growth of Mycobacterium bovis BCB.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Benzoates / chemical synthesis*
  • Benzoates / chemistry
  • Benzoates / pharmacology
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology
  • Microbial Sensitivity Tests
  • Mycobacterium bovis / drug effects*
  • Retinoids / chemical synthesis*
  • Retinoids / chemistry
  • Retinoids / pharmacology
  • Structure-Activity Relationship
  • Thiourea / analogs & derivatives
  • Thiourea / chemical synthesis*
  • Thiourea / chemistry
  • Thiourea / pharmacology

Substances

  • ((1-aza-4-methyl-6-(1,2,2,4-tetramethyl(1,2-dihydroquinolyl))hexa-1,3,5-trienyl)amino)aminomethane-1-thione
  • 2,2,4-trimethyl-2H-chromen-7-yl 4-(methoxycarbonyl)benzoate
  • Benzoates
  • Benzopyrans
  • Retinoids
  • ethyl 4-((N-(2,2,4,4-tetramethylchroman-6-yl)thiocarbamoyl)amino)benzoate
  • Thiourea