RESUMEN
Three new series of quinoline, quinolone, and benzimidazole derivatives were synthesized and evaluated in vitro against Trypanosoma brucei gambiense. In the quinoline series, the metallo antimalarial drug candidate (ferroquine, FQ) and its ruthenium analogue (ruthenoquine, RQ, compound 13) showed the highest in vitro activities with IC50 values around 0.1 µM. Unfortunately, both compounds failed to cure Trypanosoma brucei brucei infected mice in vivo. The other heterocyclic compounds were active in vitro with IC50 values varying from 0.8 to 34 µM. One of the most interesting results was a fluoroquinolone derivative (compound 2) that was able to offer a survival time of 8 days after a treatment at the single dose of 100 µmol/kg by intraperitoneal route. Although no clear-cut structure-activity relationships emerged, further pharmacomodulations are worth to be developed in this series.
Asunto(s)
Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/uso terapéutico , Tripanocidas/química , Tripanocidas/uso terapéutico , Trypanosoma brucei brucei/efectos de los fármacos , Tripanosomiasis Africana/tratamiento farmacológico , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Aminoquinolinas/farmacología , Aminoquinolinas/uso terapéutico , Animales , Bencimidazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Línea Celular , Compuestos Ferrosos/síntesis química , Compuestos Ferrosos/química , Compuestos Ferrosos/farmacología , Compuestos Ferrosos/uso terapéutico , Halogenación , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Humanos , Metalocenos , Ratones , Quinolinas/síntesis química , Quinolinas/química , Quinolinas/farmacología , Quinolinas/uso terapéutico , Quinolonas/síntesis química , Quinolonas/química , Quinolonas/farmacología , Quinolonas/uso terapéutico , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/farmacologíaRESUMEN
Despite progress in modern chemotherapy to combat tuberculosis, the causative pathogen Mycobacterium tuberculosis (M.tb.) is far from eradicated. Bacillary resistance to anti-mycobacterial agents, bacillary persistence and human immunodeficiency virus (HIV) co-infection hamper current drug treatment to completely cure the infection, generating a constant demand for novel drug candidates to tackle these problems. A small library of novel heterocyclic compounds was screened in a rapid luminometric in vitro assay against the laboratory M.tb. strain H37Rv. A group of amidines was found to have the highest potency and was further evaluated for acute toxicity against C3A hepatocytes. Next, the most promising compounds were evaluated for activity against a multi-drug resistant clinical isolate. The group of amidines was also tested for their ability to kill intracellular M.tb. residing in mouse J774A.1 macrophages. Finally, we report on a correlation between the structural differences of the compounds and their anti-mycobacterial activity.