RESUMO
HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication. Recently, HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Herein, we report the discovery of azaindole carboxylic acids and azaindole hydroxamic acids as potent inhibitors of the HIV-1 IN enzyme and their structure-activity relationships. Several 4-fluorobenzyl substituted azaindole hydroxamic acids showed potent antiviral activities in cell-based assays and offered a structurally simple scaffold for the development of novel HIV-1 IN inhibitors.
Assuntos
Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/enzimologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Ácidos Hidroxâmicos/síntese química , Concentração Inibidora 50 , Ligantes , Magnésio/metabolismo , Picolinas/químicaRESUMO
From a perspective of process knowledge and enhancement, the analysis of the results of biological screening should not be limited to the outcome of specific projects, but additionally encompass a process centric view. Summarising outcomes across multiple projects is a powerful tool to gain a greater understanding of biological screening that will also enable optimisation of the strategy for specific projects or target classes. We have analysed a set of 73,651 compounds with reproducible (confirmed) results from 63 high-throughput screening (HTS) campaigns to reveal the underlying trends in the population of active compounds. We have focused on the overall physico-chemical profile of compound populations derived from biological screening since the in vivo activity of drug molecules is the result of physico-chemical and structural properties of the compound.