Abstract:
The malaria parasite, Plasmodium falciparum, exhibits genetic plasticity such that it increasingly develops resistance to current antimalarial drugs, especially in Southeast Asia where multi-drug resistance (MDR) threatens the last line of antimalarial drugs (1, 2). This obstructs the effectiveness of most of the current antimalarial drugs including the quinolines, antifolates and artemisinins (3). Therefore, there is an urgent need for innovative strategies to develop novel antimalarial drugs to eradicate the disease. Recently, (bis)urea and (bis)thiourea symmetrical, terminally alkylated polyamine analogs were shown to have potent antimalarial activities against chloroquine sensitive (3D7), chloroquine resistant (W2) and antifolate resistant (HB3) strains of P. falciparum parasites with antiplasmodial activities (IC50) as low as 88 ± 7 nM (4) and high selectivity to malaria parasites (>7000 fold lower IC50 against P. falciparum). These polyamine analogs had either 3-4-3, 3-6-3 or 3-7-3 carbon backbones. In the study reported here, 3-5-3 backbone analogs were analyzed for their antiplasmodial activity. Within this series of analogs, IC50 values as low as 28 ± 4 nM were obtained against 3D7 P. falciparum parasites and these compounds were equally as active against drug resistant strains of the parasite (17 ± 2 nM against W2 P. falciparum and 40 ± 3 nM against HB3 P. falciparum). These compounds were also found to have selectivity of >5000 fold against the parasite. The combination of the lead compounds with the polyamine biosynthesis inhibitor, α-difluoromethylornithine (DFMO), both resulted in additive interactions against P. falciparum 3D7 parasites. The analogs arrested parasitic growth after 48 h of exposure by blocking nuclear division and DNA replication, confining the parasites to the 1N stage (rings and early trophozoites). Compound 6 also led to irreversible parasite cytotoxicity over a 48 h period after a 12 h treatment with IC90 drug concentrations. Therefore, terminally alkylated (bis)urea and (bis)thiourea polyamine analogs of the 3-5-3 carbon backbone, pose an enticing structurally novel and distinct class of potential antimalarials with potent activities in the low nanomolar range and high selectivity ranges against P. falciparum parasites. Further mechanistic studies and in vivo activity determinations are currently underway.
