RESUMO
The synthesis of 6,6-dibromo-3alpha-(diphenylphosphate)oxymethyl-2,2-dimethyl penam sulfone (3a), 6alpha-chloro-3alpha-(diphenylphosphate)oxymethyl-2,2-dimethyl penam sulfone (3b), benzyl 6alpha-(diphenyl-phosphate)oxypenicillanate sulfone (4) and 6,6-dibromo-3alpha-(methylphosphate)carbonyl-2,2-dimethylpenam sulfone (12) are reported. When tested as inhibitors of human leukocyte elastase, the compound 4 proved to be the most active.
Assuntos
Elastase de Leucócito/antagonistas & inibidores , Sulfetos/síntese química , Sulfonas/síntese química , Ésteres/química , Humanos , Elastase de Leucócito/metabolismo , Fosfatos/química , Sulfetos/química , Sulfetos/farmacologia , Sulfonas/química , Sulfonas/farmacologiaRESUMO
The b-lactamases catalyze the hydrolysis of the b-lactam bond of a variety of b-lactam antibiotics destroying their antibacterial activity. During the last decades, there has been an inexorable spread of b-lactamase genes into species that previously were not known to possess them. One approach to combat the action of the b-lactamase is to inhibit the enzyme. However, inhibition of b-lactamase alone is not sufficient. The ability to penetrate the external membrane of Gram-negative bacteria, chemical stability, pharmacokinetics and other factors are also important in determining whether an inhibitor is suitable or not for therapeutic use. This review takes recent examples of synthetic b-lactam compounds developed as active-site serine b-lactamase inhibitors, emphasizing information on their structures and their activity against Ambler classes A, C and D b-lactamases. In addition, examples based on rational design by computerized molecular modeling of crystal structure of the native enzyme and mechanism of the enzyme action are highlighted.
Assuntos
Antibacterianos/química , Inibidores Enzimáticos/química , beta-Lactamases/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Sítios de Ligação , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Hidrólise , Serina/química , Estereoisomerismo , Inibidores de beta-Lactamases , beta-Lactamases/classificação , beta-LactamasRESUMO
The benzyl 6-fluoro-penicillanate sulfides 4a, 6a, 7a; and sulfones 6c, 7d were synthesized. The conversion to their free acids 4b, 6b, 6d, 7b, 7e and potassium salts 7c, 7f are described. These acids and salt 7c were evaluated as beta-lactamase inhibitors using beta-lactamase I from Bacillus cereus. The data indicate that substitution of the 6 alpha-hydrogen by a 6 alpha-fluorine atom on 6 beta-bromopenicillanic acid (1), leads to loss of beta-lactamase inhibitory activity. In the case of the isomers 6 beta- and 6 alpha-fluoropenicillanic acids the 6 beta-enantiomer proved to be considerably more potent. Potassium salts of 6 beta-fluoropenicillanate sulfide and sulfone were unstable in solid state and in water solution. The fragmentation of the sulfone in two parts in water solution is consistent with the hydrolytic behavior to the penicillanic acid sulfone (2) with 0.5 N NaOH.