RESUMEN
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.
Asunto(s)
Antituberculosos/química , Hidrazonas/química , Animales , Antituberculosos/síntesis química , Antituberculosos/farmacología , Línea Celular , Chlorocebus aethiops , Hidrazonas/síntesis química , Hidrazonas/farmacología , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Relación Estructura-Actividad , Células VeroRESUMEN
Malaria is a major health problem in poverty-stricken regions where new antiparasitic drugs are urgently required at an affordable price. We report herein the design, synthesis, and biological investigation of novel antimalarial agents with low potential to develop resistance and structurally based on a highly conjugated scaffold. Starting from a new hit, the designed modifications were performed hypothesizing a specific interaction with free heme and generation of radical intermediates. This approach provided antimalarials with improved potency against chloroquine-resistant plasmodia over known drugs. A number of structure-activity relationship (SAR) trends were identified and among the analogues synthesized, the pyrrolidinylmethylarylidene and the imidazole derivatives 5r, 5t, and 8b were found as the most potent antimalarial agents of the new series. The mechanism of action of the novel compounds was investigated and their in vivo activity was assessed.
Asunto(s)
Acridinas/síntesis química , Antimaláricos/síntesis química , Hidrazonas/síntesis química , Quinolinas/síntesis química , Acridinas/química , Acridinas/farmacología , Animales , Antimaláricos/química , Antimaláricos/farmacología , Cloroquina/farmacología , Diseño de Fármacos , Resistencia a Medicamentos , Hemoproteínas/antagonistas & inhibidores , Humanos , Hidrazonas/química , Hidrazonas/farmacología , Células KB , Malaria/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Conformación Molecular , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei , Plasmodium falciparum/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
A series of N1-arylidene-N2-quinolyl- and N2-acrydinylhydrazones were synthesized and tested for their antimalarial properties. These compounds showed remarkable anti-plasmodial activity in vitro especially against chloroquine-resistant strains. Their potent biological activity makes them promising lead structures for the development of new antimalarial drugs.