3-Hydroxy-N′-arylidenepropanehydrazonamides represent a newclass of antiplasmodial compounds. The two most active phenanthrene-basedderivatives showed potent in vitro antiplasmodial activity against the 3D7 (sensitive) and Dd2 (multidrug-resistant)strains of Plasmodium falciparumwith nanomolar IC50values in the range of 8–28 nM. Further studies revealedthat the most promising derivative, bearing a 4-fluorobenzylidenemoiety, demonstrated in vivo antiplasmodial activity after oral administrationin a P. bergheimalaria model, although no completeparasite elimination was achieved with a four-dose regimen. The invivo efficacy correlated well with the plasma concentration levels,and no acute toxicity symptoms (e.g., death or changes in generalbehavior or physiological activities) were observed, which is in agreementwith a >1000-fold lower activity against L6 cells, a primary cellline derived from mammalian (rat) skeletal myoblasts. This indicatesthat lead compound 29displays selective activity against P. falciparum. Moreover, both phenanthrene-based derivativeswere active against stage IV/V gametocytes of P. falciparumin vitro. [ABSTRACT FROM AUTHOR]