RESUMO
Pneumonia caused by bacterium S. pneumoniae is a severe acute respiratory infectious disease with high morbidity and mortality, especially for children and immunity-compromised patients. The emergence of multidrug-resistant S. pneumoniae also presents a challenge to human health. Leucyl-tRNA synthetase (LeuRS) catalyzes the attachment of l-leucine to tRNALeu, which plays an essential role in protein translation and is considered an attractive antimicrobial drug target. In the present work, benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. Exploration of the phenyl ring near Lysine 389 eventually yielded compounds 46 and 54 with submicromolar inhibitory potency. The co-crystal of compound 54 in the editing domain pocket of SpLeuRS was obtained and confirmed the formation of an additional hydrogen bond between the carbonyl of 54 and Lysine 389. It also showed anti-pneumococcal activity in vitro. The structure-activity relationship was discussed. This work will provide an essential foundation for the further development of anti-pneumococcal agents by targeting LeuRS.
Assuntos
Antibacterianos/farmacologia , Compostos Benzidrílicos/farmacologia , Compostos de Boro/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Compostos Benzidrílicos/química , Compostos de Boro/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Leucina-tRNA Ligase , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Streptococcus pneumoniae/enzimologia , Relação Estrutura-AtividadeRESUMO
Benzoxaboroles, as a novel class of bioactive molecules with unique physicochemical properties, have been shown to possess excellent antimicrobial activities with tavaborole approved in 2014 as an antifungal drug. Although urgently needed, the investigation of benzoxaboroles as anticancer agents has been lacking so far. In this study, we report the design, synthesis, and anticancer structure-activity relationship of a series of 7-propanamide benzoxaboroles. Compounds 103 and 115 showed potent activity against ovarian cancer cells with IC50 values of 33 and 21 nM, respectively. Apoptosis was induced by these compounds and colony formation was effectively inhibited. Furthermore, they also showed excellent efficacy in ovarian tumor xenograft mouse model.
