RESUMO
New quinolonyl diketo acid compounds bearing various substituents at position 6 of the quinolone scaffold were designed and synthesized as potential HIV-1 integrase inhibitors. These new compounds were evaluated for their antiviral and anti-integrase activity and showed inhibitory potency similar to that of 6-bromide analog 2. Molecular modeling and docking studies were performed to rationalize these data and to provide a detailed understanding of the mechanism of inhibition for this class of compounds.
Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV/efeitos dos fármacos , Cetoácidos/farmacologia , Quinolonas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Domínio Catalítico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Integrase de HIV/química , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Cetoácidos/síntese química , Cetoácidos/química , Modelos Moleculares , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Ethyl [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl]-4-hydroxy-2-oxo-3-butenoate 1 and [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl)]-4-hydroxy-2-oxo-3-butenoïc acid 2 were synthesized as potential HIV-1 integrase inhibitors and evaluated for their enzymatic and antiviral activity, acidic compound 2 being more potent than ester compound 1. X-ray diffraction analyses and theoretical calculations show that the diketoacid chain of compound 2 is preferentially coplanar with the quinolinone ring (dihedral angle of 0-30 degrees ). Docking studies suggest binding modes in agreement with structure-activity relationships.
Assuntos
4-Quinolonas/química , Butiratos/química , Inibidores de Integrase de HIV/química , Integrase de HIV/química , 4-Quinolonas/síntese química , 4-Quinolonas/farmacologia , Butiratos/síntese química , Butiratos/farmacologia , Domínio Catalítico , Simulação por Computador , Cristalografia por Raios X , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Humanos , Conformação Molecular , Ligação Proteica , Teoria Quântica , Relação Estrutura-AtividadeRESUMO
Several 5-ethyl-6-methyl-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized and evaluated for their anti HIV-1 activities against wild-type virus and clinically relevant mutant strains. A racemic mixture (10) with methyl substituents at positions 3 and 5 of the cyclohexyloxy moiety had potent antiviral activity against wild-type HIV-1. Subsequent stereoselective synthesis of a stereoisomer displaying both methyl groups in equatorial position was found to have the best EC(50). Further modulations focused on position 3 of the pyridinone ring improved the antiviral activity against mutant viral strains. Compounds bearing a 3-ethyl (22) or 3-isopropyl group (23) had the highest activity against wild-type HIV-1 and displayed low-nanomolar potency against several clinically relevant mutant strains.
