Discovery of nitroheterocycles active against African trypanosomes. In vitro screening and preliminary SAR studies.
A selection of 76 nitroheterocycles and related compounds from our in-house compound library was screened in vitro against the parasite Trypanosoma brucei rhodesiense, causative agent of human African trypanosomiasis (HAT). The unspecific cytotoxicity of the compounds was also evaluated against rat myoblast L6-cells to measure the selectivity of the compounds towards the parasite. This screening revealed some preliminary structure-activity relationships (SAR) among the series, and six hit compounds showing interesting activity (IC(50)≤10μM) and fair selectivity (SI>17). The 7-nitroquinoxalin-2-one and 5-nitroindazole scaffold derivatives 58 and 35, respectively, are particularly interesting because of their established oral bioavailability in mice. These hits represent interesting starting points for a medicinal project aimed at identifying the SAR behind this class of compounds.
Instituto de Química Médica, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
Vicente J
VJ
Arán
Marcel
M
Kaiser
Christophe
C
Dardonville
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D017672:Nitrogen Compounds / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
D006571:Heterocyclic Compounds; D017672:Nitrogen Compounds