RESUMO
Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 µg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.
Assuntos
Antibacterianos/farmacologia , Benzoatos/farmacologia , Enterococcus/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Timina/análogos & derivados , Resistência a Vancomicina/efeitos dos fármacos , Antibacterianos/síntese química , Benzoatos/síntese química , Domínio Catalítico , Cristalografia por Raios X , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Núcleosídeo-Fosfato Quinase/metabolismo , Relação Estrutura-Atividade , Timina/síntese química , Timina/farmacologiaRESUMO
The diastereoselectivity in the alkylation and Michael addition of "naked" 6-substituted delta-lactolates has been studied by density functional (B3LYP) calculations with ab initio (MP2) energy refinements. The resulting proposed model for the origins of stereocontrol in this reaction has been tested by experiment. The reactions lead to a high cis diastereoselectivity across the THP ring due to the preference for both the alkoxide and the 6-substituent to sit equatorial in the alkylation transition structure. In the oxy-Michael addition of these lactolates to beta-substituted nitroolefins, we propose that the high diastereoselectivity beta- to the nitro group is a result of a combination of steric, stereoelectronic and solvation factors.
RESUMO
The "naked" anion of (S)-6-methyl delta lactol undergoes efficient oxy-Michael addition to alpha,beta-disubstituted nitro olefins to give the THP* protected Henry products with excellent (95-->98% de) stereocontrol at the beta-position and moderate (up to 3 : 1) stereocontrol at the alpha-position in favour of the syn-diastereoisomer. Nitro group reduction with in situN-Boc protection and THP* removal provides alpha,beta-disubstituted ethanolamine derivatives, while treatment with tetrapropylammonium perruthenate gives THP* protected alpha-hydroxy ketone derivatives in high diasteromeric excess.
Assuntos
Alcenos/química , Cetonas/química , Fenilpropanolamina/química , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , EstereoisomerismoRESUMO
[reaction: see text] The highly diastereoselective oxy-Michael addition of the "naked" anion of (6S)-methyl delta lactol to alkylidiene-, arylidene-, and heteroarylidenemalonate derivatives leading to the direct formation of THP-protected beta-hydroxy ester derivatives is described. Subsequent acid-mediated deprotection affords the enantioenriched aldol products in quantitative yields.