Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thiourea isosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites.

摘要: A new series of potent aryl/alkylated (bis)urea- and (bis)thiourea polyamine analogues were synthesized evaluated in vitro for their antiplasmodial activity. Altering the carbon backbone terminal substituents increased potency compound library 3-fold, with most active compounds, 15 16, showing half-maximal inhibitory concentrations (IC50 values) 28 30 nM, respectively, against various Plasmodium falciparum parasite strains without any cross-resistance. In evaluation cytotoxicity these revealed marked selectivity towards targeting malaria parasites compared to mammalian HepG2 cells (>5000-fold lower IC50 parasite). Preliminary biological analogue phenotype that (bis)urea compounds target asexual proliferation, whereas same have unique ability block transmissible gametocyte forms parasite, indicating pluripharmacology proliferative non-proliferative parasite. this manuscript, we describe results postulate a refined structure-activity relationship (SAR) model analogues. The terminally (bis)thiourea-polyamine featuring 3-5-3 or 3-6-3 represent structurally novel distinct class potential antiplasmodials activities low nanomolar range, high lifecycle P. parasites.