Structural optimization of 3-hydroxy-N'-arylidenepropanehydrazonamides provided new analogs with nanomolar to subnanomolar antiplasmodial activity against asexual blood stages of Plasmodium falciparum, excellent parasite selectivity, and nanomolar activity against the earliest forms of gametocyte development. Particularly, derivatives with a 1,3-dihalo-6-trifluoromethylphenanthrene moiety showed outstanding in vivo properties and demonstrated in part curative activity in the Plasmodium berghei mouse model when administered perorally.

Desmopressin acetate (DDAVP) is an oligopeptide indicated for the treatment of primary nocturnal enuresis, for example. The poor oral bioavailability of DDAVP accelerated a shift to alternative routes of administration like nasal and oromucosal, whereby nasal administration results in high fluctuations increasing the risk of undesirable side effects. Aim of the study was to use a new composite dosage form (solid matrix attached to a bilayer mucoadhesive film) to make DDAVP available via oromucosal route, reducing the risk of undesirable side effects through precise dosing. DDAVP was incorporated into a solid matrix in the form of a minitablet, and both direct tableting (AV > 30) and granulation followed by tableting (AV = 17.86) were compared. Minitablets with content uniformity could only be obtained by granulation and loss supplementation (AV = 11.27) with immediate drug release (>80% after 7–8 min) and rapid disintegration (<49 s). Permeation studies were performed with a clinically relevant dose (200 μg) in a time interval of up to one hour, resulting in apparent permeation coefficients of 4.90 × 10 −6 cm/s (minitablet) and 2.04 × 10 −6 cm/s (composite). Comparable fluctuations showed no inferiority of composite and minitablet regarding dosing accuracy. Thus, a step towards controlled and dose-accurate transmucosal delivery of systemically active DDAVP could be achieved.

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3-Hydroxypropanamidines are a new promising class of highly active antiplasmodial agents. The most active compound 22 exhibited excellent antiplasmodial in vitro activity with nanomolar inhibition of chloroquine-sensitive and multidrug-resistant parasite strains ofPlasmodium falciparum (with IC50 values of 5 and 12 nM against 3D7 and Dd2 strains, respectively) as well as low cytotoxicity in human cells. In addition, 22 showed strong in vivo activity in thePlasmodium berghei mouse model with a cure rate of 66% at 50 mg/kg and a cure rate of 33% at 30 mg/kg in the Peters test after once daily oral administration for 4 consecutive days. A quick onset of action was indicated by the fast drug absorption shown in mice. The new lead compound was also characterized by a high barrier to resistance and inhibited the heme detoxification machinery in P. falciparum.