RESUMO
The prevention of aggrecan (a key component of cartilage) cleavage via the inhibition of aggrecanase-1 may provide a unique opportunity to stop the progression of cartilage degradation in osteoarthritis. The evaluation of a series of biphenylsulfonamides resulted in the identification of the ((4-keto)-phenoxy)methyl biphenyl-4-sulfonamides analogs (19-21 and 24) with improved Agg-1 inhibition and MMP-2, MMP-13 activity.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/metabolismo , Química Farmacêutica/métodos , Osteoartrite/tratamento farmacológico , Pró-Colágeno N-Endopeptidase/antagonistas & inibidores , Pró-Colágeno N-Endopeptidase/metabolismo , Sulfonamidas/síntese química , Proteína ADAMTS4 , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Modelos Químicos , Conformação Molecular , Proteoglicanas/química , Sulfonamidas/farmacologiaRESUMO
Deprotection of p-nitrobenzyl esters and valyl carbamates in carbapenem CL 192,276 produced the active compound OCA-983 in excellent yields. Straight chain alkanols such as 1-butanol, 1-pentanol and 1-hexanol in water at certain ratios were effective solvent systems. Alkyl acetates in water also resulted in simultaneous deprotection of PNB and PNZ side-chains albeit at slower rates. The deprotected carbapenem was isolated in excellent yield and purity after removal of the aqueous media. This procedure is applicable to sensitive compounds that are soluble in water without the need to use a buffer and allows for ease of isolation from the aqueous phase.
Assuntos
Antibacterianos/síntese química , Carbamatos/química , Carbapenêmicos/síntese química , Hidrogênio/química , Nitrobenzenos/química , Acetatos/química , Álcoois/química , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Ésteres/química , Estrutura Molecular , Solventes/química , Água/químicaRESUMO
The effect of introducing hydrophobic groups onto the disaccharide portion of the mannopeptimycins has been examined. Under acid-catalyzed conditions dimethyl acetals and ketals react on the terminal mannose of the disaccharide moiety of mannopeptimycin-alpha and the cyclohexylalanyl analogue 2. The preferentially formed monofunctionalized 4,6-acetals and -ketals display potent antibacterial activities against Gram-positive microorganisms, including MRSA, PRSP, and VRE pathogens.
Assuntos
Acetais/síntese química , Antibacterianos/síntese química , Glicopeptídeos , Bactérias Gram-Positivas/efeitos dos fármacos , Acetais/química , Acetais/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
A number of 6-O-ether and 4-O-ether derivatives of mannopeptimycin-alpha with different steric bulk and lipophilicity were synthesized for structure-activity relationship study. Novel iodo and bromo mannopeptimycin-alpha were also prepared. These compounds were synthesized via electrophilic aromatic substitution. Many of the new ether derivatives exhibited potent antibacterial activity against Gram-positive resistant strains including VRE, MRSA, and PRSP.
Assuntos
Antibacterianos/síntese química , Glicopeptídeos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Éter/química , Bactérias Gram-Positivas/efeitos dos fármacos , Halogênios/química , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
A series of benzoxazole derivatives of the mannopeptimycin glycopeptide antibiotics was synthesized via a novel benzoxazole formation reaction by treating aminophenol of mannopeptimycin-beta with an aldehyde and DDQ in DMF. Some of these derivatives (e.g., 5b, 5d, 5m, and 7b) showed good activity against Gram-(+) bacteria when compared to the parent compound mannopeptimycin-beta.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Glicopeptídeos , Bactérias Gram-Positivas/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Enterococcus/efeitos dos fármacos , Indicadores e Reagentes , Testes de Sensibilidade Microbiana , Espectrometria de Massas por Ionização por Electrospray , Staphylococcus aureus/efeitos dos fármacos , Streptococcus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Novel ether derivatives of mannopeptimycin glycopeptide were synthesized to probe their SAR. Many of these derivatives exhibited potent antibacterial activity against methicillin resistant and vancomycin resistant strains. These ether derivatives were prepared via reductive ring cleavage of acetals to give a mixture of 6-O, 4-O, 3-O, and 2-O-ether isomers. Both 6-O-ether and 4-O-ether showed significantly enhanced antibacterial activity over the parent and the isovalerate esters.
