RESUMO
Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogues that displayed inhibition constants ranging from 5 to 120 nM against the enzyme. Two of these compounds exhibited low micromolar activity against Mtb with half maximal effective inhibitory concentrations of 1.7 and 4.0 µM. Our selectivity and preliminary pharmacokinetic studies showed that the compounds possess a higher degree of specificity against MtbAdoK when compared with the human counterpart and are well tolerated in rodents, respectively. Finally, crystallographic studies showed the molecular basis of inhibition, potency, and selectivity and revealed the presence of a potentially therapeutically relevant cavity unique to the MtbAdoK homodimer.
Assuntos
Adenosina Quinase/metabolismo , Adenosina/análogos & derivados , Desenho de Fármacos , Mycobacterium tuberculosis/enzimologia , Inibidores de Proteínas Quinases/síntese química , Adenosina/metabolismo , Adenosina/farmacocinética , Adenosina Quinase/química , Animais , Antituberculosos/síntese química , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Domínio Catalítico , Feminino , Camundongos , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-AtividadeRESUMO
A new class of inhibitors for cysteine proteases cathepsin B, L, K and S is described. These inhibitors are based on the beta-lactam ring designed to interact with the nucleophilic thiol of the cysteine in the active site of cysteine proteases. Some 3-acylamino-azetidin-2-one derivatives showed very potent inhibition activities for cathepsins L, K and S at the nanomolar or subnanomolar IC(50) values.
Assuntos
Azetidinas/síntese química , Inibidores de Cisteína Proteinase/síntese química , Azetidinas/farmacologia , Catepsina B/antagonistas & inibidores , Catepsina K , Catepsina L , Catepsinas/antagonistas & inibidores , Cisteína Endopeptidases , Inibidores de Cisteína Proteinase/farmacologia , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Lactamas/química , Elastase de Leucócito/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
A series of 6-substituted amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one compounds was designed and synthesized as a new class of inhibitors for cysteine proteases cathepsins B, L, K, and S. One compound (5S,6S)-6-(N-benzyloxycarbonyl-L-phenylalanyl) amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one showed excellent cathepsin L and K inhibition activity with IC(50) at a low nanomolar range.
Assuntos
Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Lactamas/química , Lactamas/farmacologia , Catepsinas/antagonistas & inibidores , Desenho de Fármacos , Concentração Inibidora 50 , Modelos Moleculares , Papaína/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis of a new series of 6-acylamino penam derivatives and their inhibition of cysteine proteases cathepsins B, L, K, and S is described. The 6-acylamino-penam sulfone compounds showed excellent cathepsin L, K, and S inhibition activity with IC(50) values in the nanomolar and subnanomolar range.
