RESUMO
Synthesis of a series of fused pyrazole tetrahydrofluorenone analogs which are potent, ERbeta subtype selective ligands is described. Analogs possessing subnanomolar ERbeta binding, greater than 100-fold ERbeta-selectivity, and oral bioavailability are reported.
Assuntos
Receptor beta de Estrogênio/efeitos dos fármacos , Fluorenos/química , Pirazóis/química , Animais , Área Sob a Curva , Disponibilidade Biológica , Ciclização , Receptor beta de Estrogênio/metabolismo , Fluorenos/sangue , Fluorenos/metabolismo , RatosRESUMO
Synthesis and derivatization of a series of substituted tetrahydrofluorenone analogs giving potent, ERbeta subtype selective ligands are described. Several analogs possessing ERbeta binding affinities comparable to 17beta-estradiol but with greater than 75-fold selectivity over ERalpha are reported.
Assuntos
Receptor beta de Estrogênio/efeitos dos fármacos , Fluorenos/síntese química , Fluorenos/farmacologia , Linhagem Celular , Cristalografia por Raios X , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor beta de Estrogênio/química , Fluorenos/classificação , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.
Assuntos
Proteínas de Bactérias , Carbapenêmicos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Hexosiltransferases , Peptidil Transferases , Carbapenêmicos/química , Carbapenêmicos/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Resistência Microbiana a Medicamentos , Testes de Sensibilidade Microbiana , Muramilpentapeptídeo Carboxipeptidase/efeitos dos fármacos , Muramilpentapeptídeo Carboxipeptidase/metabolismo , Proteínas de Ligação às PenicilinasRESUMO
A series of 1beta-methyl-2-(naphthosultamyl)methyl-carbapenems bearing dicationic groups on the naphthosultamyl moiety was prepared and evaluated for activity against resistant gram-positive bacteria. Based on a combination of excellent in vitro antibacterial activity, acceptable mouse acute toxicity, and a desirable fragmentation pattern on beta-lactam ring opening, the analog 2g (L-786,392) was selected for extended evaluation.
Assuntos
Carbapenêmicos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Lactamas/farmacologia , Tiazóis/farmacologia , Animais , Carbapenêmicos/química , Carbapenêmicos/farmacologia , Carbapenêmicos/toxicidade , Resistência Microbiana a Medicamentos , Humanos , Lactamas/química , Lactamas/farmacocinética , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinéticaRESUMO
A carbapenem antibiotic, L-786,392, was designed so that the side chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain upon opening of the beta-lactam ring retained antibacterial activity while safely expelling the immunodominant epitope. L-786,392 was well tolerated in animal safety studies and had significant in vitro and in vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.
Assuntos
Proteínas de Bactérias , Carbapenêmicos/imunologia , Carbapenêmicos/farmacologia , Desenho de Fármacos , Hexosiltransferases , Lactamas/farmacologia , Peptidil Transferases , Tiazóis/farmacologia , Animais , Anticorpos/sangue , Carbapenêmicos/química , Carbapenêmicos/metabolismo , Carbapenêmicos/toxicidade , Proteínas de Transporte/metabolismo , Dipeptidases/metabolismo , Resistência Microbiana a Medicamentos , Resistência a Múltiplos Medicamentos , Enterococcus/efeitos dos fármacos , Eritrócitos/imunologia , Haptenos , Humanos , Epitopos Imunodominantes , Imunoglobulina G/sangue , Lactamas/síntese química , Lactamas/química , Lactamas/metabolismo , Ativação Linfocitária , Macaca mulatta , Camundongos , Camundongos Endogâmicos DBA , Testes de Sensibilidade Microbiana , Muramilpentapeptídeo Carboxipeptidase/metabolismo , Proteínas de Ligação às Penicilinas , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus/efeitos dos fármacos , Tiazóis/síntese química , Tiazóis/química , Tiazóis/metabolismoRESUMO
The syntheses of five thiols, including three dihydropyrrolotriazoliumthiol salts, 1,4-dimethyl-5-mercaptomethyl-1,2,4-triazolium trifluoromethanesulfonate, and 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium chloride; and the addition of these thiols to 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphono)oxy-6-[1(R)-hydroxyethyl]-1-met hylcarbapen-2-em-3-carboxylate and the subsequent hydrogenolysis of the addition products is described. The latter thiol provides a new route towards the preparation of L-627 (LJC 10,627). The compounds were evaluated in vitro against a panel of Gram-positive and Gram-negative bacteria and their antibacterial activities compared with imipenem. The compounds were measured for their hydrolytic stability to dehydropeptidase I (DHP-I) relative to imipenem. The five compounds generally had poorer Gram-positive and Pseudomonas activity than imipenem, although their Gram-negative activity was variably improved. The monocyclic triazolium analog was nearly comparable in overall activity to the four bicyclic heterarylium analogs evaluated, including L-627 (LJC 10,627). All compounds were more stable to DHP-I than imipenem, although minor differences existed among them.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Carbapenêmicos/síntese química , Carbapenêmicos/farmacologia , Antibacterianos/metabolismo , Carbapenêmicos/metabolismo , Dipeptidases/metabolismo , Estabilidade de Medicamentos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Tienamicinas/síntese química , Tienamicinas/farmacologiaRESUMO
delta 1-Thienamycin (2), a double-bond isomer of thienamycin, was prepared by isomerizing N-[[(p-nitrobenzyl)oxy]-carbonyl]thienamycin p-nitrobenzyl ester (5b) with DBU in Me2SO followed by hydrogenolysis of the protecting groups. When evaluated in a disc-diffusion antibacterial assay, delta 1-thienamycin was found to be essentially devoid of activity. The lack of antibacterial activity was ascribed to a chemically less reactive beta-lactam amide bond than that found in thienamycin.
Assuntos
Lactamas/síntese química , Tienamicinas , Bactérias/efeitos dos fármacos , Fenômenos Químicos , Química , Lactamas/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
A versatile stereocontrolled total synthesis of thienamycin starting from L-aspartic acid is reported. Stereocontrol is achieved by potassium tri-sec-butylborohydride reduction of a thermodynamically formed 3 alpha-acetylazetidinone intermediate. The key [3.2.0] bicyclic ring system is prepared by a metal catalyzed carbene insertion reaction.