RESUMO
A series of monobactam inhibitors of HCMV (N(o)) protease bearing a heterocycle linked by a methylene group at C-4 is described. Inhibitors containing a heterocycle such as a 2-furyl, 2-thiophenyl, 4-methyl-2-tetrazole and 2-benzothiazole were found to be active in a plaque reduction assay. Furthermore, 2-benzothiazole derivatives were shown to inhibit the HCMV protease activity inside cells by using a cell transfection assay, indicating that their antiviral activity in the plaque reduction assay could be attributed to protease inhibition.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Serina Endopeptidases/efeitos dos fármacos , Animais , Antivirais/química , Células COS , Citomegalovirus/enzimologia , Citomegalovirus/crescimento & desenvolvimento , Monobactamas/síntese química , Monobactamas/química , Monobactamas/farmacologia , Inibidores de Proteases/química , Análise Espectral , Ensaio de Placa ViralRESUMO
The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the beta-lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both tri- and tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.
Assuntos
Antivirais , Citomegalovirus/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase , Ureia , beta-Lactamas , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Bovinos , Linhagem Celular Transformada , Citomegalovirus/enzimologia , Citomegalovirus/fisiologia , Humanos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Suínos , Ureia/análogos & derivados , Ureia/síntese química , Ureia/química , Ureia/farmacologia , beta-Lactamas/síntese química , beta-Lactamas/química , beta-Lactamas/farmacologiaRESUMO
A series of novel monobactam inhibitors of human cytomegalovirus (HCMV) protease has been described that possess a heterocyclic thiomethyl side chain at C-4. Changes to the heterocycle did not significantly change the inhibitory activity of these compounds in an enzymatic assay, although improvements in solubility and cell culture activity were noted. A number of permutations between C-4 substitutions and N-1 derivatives led to the identification of several beta-lactams with antiviral activity in a plaque reduction assay. N-methyl thiotetrazole-containing compounds were found to be the most potent inhibitors in the enzymatic assay.
