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1.
Eur J Med Chem ; 43(9): 1989-96, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18207286

ABSTRACT

In the present study, a novel series of 4-pyrrol-1-yl benzoic acid hydrazide analogs, some derived 5-substituted-2-thiol-1,3,4-oxadiazoles, 5-substituted-4-amino-1,2,4-triazolin-3-thione and 2,5-dimethyl pyrroles have been synthesized in good yields and characterized by IR, NMR, mass spectral and elemental analyses. Compounds were evaluated for their preliminary in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria and compounds were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain by broth dilution assay method. Some compounds showed very good antibacterial and antitubercular activities.


Subject(s)
Benzoic Acid/chemical synthesis , Benzoic Acid/pharmacology , Oxadiazoles/chemistry , Pyrroles/chemistry , Triazoles/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Benzoic Acid/chemistry , Drug Design , Mycobacterium tuberculosis/drug effects
2.
J Biol Chem ; 255(19): 9067-74, 1980 Oct 10.
Article in English | MEDLINE | ID: mdl-7410412

ABSTRACT

The (+)- and (-)-enantiomers of benzo[a]pyrene 7,8-oxide are hydrated stereospecifically at C-8 to (-)- and (+)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene, respectively, by rat hepatic epoxide hydrolase. The (-)-enantiomer of benzo[a]pyrene 7,8-oxide is metabolized by microsomal epoxide hydrolase at a rate 3- to 4-fold greater than the (+)-enantiomer. At low conversion of racemic substrate, however, benzo[a]pyrene 7,8-oxide is metabolized to the dihydrodiol at a rate equal to that of the (+)-enantiomer. An analysis of the enantiomeric composition of the dihydrodiol formed from the racemic substrate revealed preferential formation of (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo-[a]pyrene. At low substrate conversion (< 20% metabolism), the enantiomeric purity of the dihydrodiol was much higher than at high substrate conversion (> 50% metabolism). Similar results were obtained with microsomes from hamster, rabbit, guinea pig, mouse, and human liver. These results indicate that epoxide hydrolase has a higher affinity for (+)-benzo[a]pyrene 7,8-oxide than for the (-)-enantiomer. The kinetics of hydration of (+)- and (-)-benzo[a]pyrene 7,8-oxide by purified epoxide hydrolase in detergent solution showed the (+)- and (-)-enantiomers to have apparent Km values of 1.7 and greater than or equal to 20 microM, respectively. Tumorigenicity studies with benzo[a]pyrene 7,8-oxide on mouse skin and in newborn mice revealed that (+)-benzo[a]pyrene 7,8-oxide, the metabolic precursor of the more tumorigenic (-)-7,8-dihydrodiol, is significantly more tumorigenic than the (-)-enantiomer. However, racemic benzo[a]pyrene 7,8-oxide was more tumorigenic than either enantiomer alone, indicating an enantiomeric synergism in the carcinogenicity of benzo[a]pyrene 7,8-oxide. The data are discussed in relation to the complete sequence of metabolic pathways leading to an ultimate carcinogen from benzo[a]pyrene.


Subject(s)
Benzopyrenes/metabolism , Carcinogens , Epoxide Hydrolases/metabolism , Microsomes, Liver/enzymology , Skin Neoplasms/chemically induced , Animals , Cricetinae , Female , Humans , Kinetics , Male , Mice , Microsomes, Liver/drug effects , Neoplasms, Experimental/chemically induced , Phenobarbital/pharmacology , Rabbits , Rats , Species Specificity , Stereoisomerism , Structure-Activity Relationship
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