RESUMO
Plasmodium falciparum subtilisin-like protease 1 (PfSUB1) is a serine protease that plays key roles in the egress of the parasite from red blood cells and in preparing the released merozoites for the subsequent invasion of new erythrocytes. The development of potent and selective PfSUB1 inhibitors could pave the way to the discovery of potential antimalarial drugs endowed with an innovative mode of action and consequently able to overcome the current problems of resistance to established chemotherapies. Through the screening of a proprietary library of compounds against PfSUB1, we identified hydrazone 2 as a hit compound. Here we report a preliminary investigation of the structure-activity relationships for a class of PfSUB1 inhibitors related to our identified hit.
Assuntos
Antimaláricos/química , Hidrazonas/química , Plasmodium falciparum/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Quinolinas/química , Inibidores de Serina Proteinase/química , Subtilisinas/antagonistas & inibidores , Antimaláricos/síntese química , Antimaláricos/farmacologia , Hidrazonas/síntese química , Hidrazonas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/metabolismo , Quinolinas/síntese química , Quinolinas/farmacologia , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Subtilisinas/metabolismoRESUMO
Here we describe the identification and preliminary characterization of a new class of pyrrolo(imidazo)quinoxaline hydrazones as florescent probes for Aß(1-42) fibrils. All the newly developed compounds were able to bind amyloid fibrils formed in vitro and some of them displayed an increase of their fluorescence upon binding. When tested on brain tissue preparations presenting Aß deposits, the described hydrazones selectively stained amyloid structures and did not display aspecific binding. The hydrazones did not show antifibrillogenic activity and electron microscopy analysis revealed that they do not interfere with fibrils structure. The described pyrrolo(imidazo)quinoxalines could be useful for studying amyloid structures in vitro. Moreover, their experimentally proven ability to cross the blood-brain barrier in mouse opens the possibility of developing these compounds as potential amyloid imaging agents for in vivo applications.
Assuntos
Peptídeos beta-Amiloides/química , Corantes Fluorescentes/química , Hidrazonas/química , Fragmentos de Peptídeos/química , Quinoxalinas/química , Peptídeos beta-Amiloides/síntese química , Animais , Encéfalo/metabolismo , Cristalografia por Raios X , Corantes Fluorescentes/farmacocinética , Hidrazonas/sangue , Hidrazonas/farmacocinética , Masculino , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Estrutura Molecular , Fragmentos de Peptídeos/síntese química , Quinoxalinas/sangue , Quinoxalinas/farmacocinética , Espectrometria de Fluorescência , Estereoisomerismo , Distribuição TecidualRESUMO
Among the enzymes involved in the life cycle of HCV, the non-structural protein NS3, with its double function of protease and NTPase/helicase, is essential for the virus replication. Exploiting our previous knowledge in the development of nucleotide-mimicking NS3 helicase (NS3h) inhibitors endowed with key structural and electronic features necessary for an optimal ligand-enzyme interaction, we developed the tetrahydroacridinyl derivative 3a as the most potent NS3h competitive inhibitor reported to date (HCV NS3h K(i)=20 nM).
Assuntos
Descoberta de Drogas , Hepacivirus/enzimologia , Hidrazinas/química , Hidrazinas/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Ligação Competitiva/efeitos dos fármacos , Hidrazinas/síntese química , Ligação Proteica , Pirazinas/síntese química , Quinolinas/síntese químicaRESUMO
A series of 4-quinolylhydrazones was synthesized and tested in vitro against Mycobacterium tuberculosis. At a concentration of 6.25microg/mL, most of the newly synthesized compounds displayed 100% inhibitory activity against M. tuberculosis in cellular assays. Further screening allowed the identification of very potent antitubercular agents. Compound 4c was also tested in a time-course experiment and against mtb clinical isolates, displaying interesting results.