Malaria is a life-threatening disease, therefore there is an urgent need to discover and develop new antimalarial drugs to overcome emerging drug resistance. Recently it was established that serotonin (5-HT) receptor ligands may provide new lead candidates for the treatment of malaria by their affinity to a 5HT1A-like receptor present in Plasmodium falciparum. The aim of the study was the evaluation of antimalarial activity of a series of derivatives of purine-2,4-diones and purine-2,4,8-triones as 5-HT1A receptor ligands, as well as the determination of their cytotoxic effects against a normal human fibroblast (NHDF) cell line. The in vitro antimalarial activity was investigated against D10 (chloroquine-sensitive) and W2 (chloroquine-resistant) strains of P. falciparum. The IC50 values for active agents were in the range 677.0-1623.7 ng/ml and 400.6–7288.3 ng/ml for the D10 and W2 strains, respectively. Moreover, tested compounds were more active against the W2 strain, with resistance indexes (RI) 0.6-0.7 and acceptable cytotoxicity on NHDF cells, as determined by the MTT assay. Considering the obtained activities, we have selected 8-(4-(-(3-chlorophenyl)piperazin-1-yl)butyl)-7-(3-fluorophenyl)-1,3-dimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as the most promising molecule for further studies in antimalarial chemotherapy and to determine its therapeutic efficacy in a number of in vitro and in vivo models.
The project is co-financed by the Polish National Agency for Academic Exchange, the Italian Ministry of Foreign Affairs and International Cooperation "Executive Programme for Scientific and Technological Cooperation between the Italian Republic and the Republic of Poland” and supported by JUMC grant no N42/DBS/000178.
