Novel heteroarotinoids as potential antagonists of Mycobacterium bovis BCG.
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.
Brown
Chad W
CW
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071, USA.
Liu
Shengquan
S
Klucik
Jozef
J
Berlin
K Darrell
KD
Brennan
Patrick J
PJ
Kaur
Devinder
D
Benbrook
Doris M
DM
D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009163:Mycobacterium bovis / Q000187:drug effects*; D012176:Retinoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C483204:((1-aza-4-methyl-6-(1,2,2,4-tetramethyl(1,2-dihydroquinolyl))hexa-1,3,5-trienyl)amino)aminomethane-1-thione; C483202:2,2,4-trimethyl-2H-chromen-7-yl 4-(methoxycarbonyl)benzoate; D001565:Benzoates; D001578:Benzopyrans; D012176:Retinoids; C483203:ethyl 4-((N-(2,2,4,4-tetramethylchroman-6-yl)thiocarbamoyl)amino)benzoate; D013890:Thiourea