3-Hydroxy-N′-arylidenepropanehydrazonamides with Halo-Substituted Phenanthrene Scaffolds Cure P. berghei Infected Mice When Administered Perorally

Abstract

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.

3-Hydroxy-propanamidines, a New Class of Orally Active Antimalarials Targeting Plasmodium falciparum

“…Based on the previously established structure–activity relationship (SAR) in the hydrazonamide series, 3-HPAs 6–23 were synthesized using two different linear synthetic routes (Scheme ). − Different aromatic aldehydes were used as starting materials ( 2a–h ). The aldehydes were either commercially available ( 2a , d , and e ) or synthesized according to previously published methods ( 2b , c , and f–h ), − followed by their conversion to 3-hydroxypropanenitriles according to Leven et al ( 3a–h ) .…”

“… − Different aromatic aldehydes were used as starting materials ( 2a–h ). The aldehydes were either commercially available ( 2a , d , and e ) or synthesized according to previously published methods ( 2b , c , and f–h ), − followed by their conversion to 3-hydroxypropanenitriles according to Leven et al ( 3a–h ) . 3-Hydroxypropanenitriles 3a–d were converted into imidoester hydrochlorides ( 4a–d ) by Pinner reactions and the resulting imidoesters 4a–d were reacted directly with the respective arylalkyl amines and substituted anilines to yield amidine hydrochlorides ( 6–13 , 22 , and 23 ) as final compounds (route A) …”

“… a Values show the mean ± standard deviation (SD) of at least three independent experiments conducted in duplicate (11-points, serial dilution). b Values show the mean plus single values ( n 1 ; n 2 ) of two independent experiments. c Selective Index (SI). d Chloroquine. e Lumefantrine. f Previously published by Leven et al. ; n.d., not determined. …”

“…Known compounds 2b , 2c , 2f–h , 3a–c , and 4a–c were synthesized according to the procedures of Leven, Totten, and Tagawa (Scheme ). − The synthesis of starting materials 3d–h , 4d , and 5 and biological evaluation, cellular heme fractionation assay, in vitro selection of resistance, 1 H NMR and 13 C NMR spectra, and HPLC profiles of the target compounds are reported in the Supporting Information.…”

“…6 Previously, we reported the development of 3-hydroxypropanehydrazonamide (1), a chemotype with potent antiplasmodial in vivo activity that has some structural resemblance to LUM and HF (Figure 1). 7 Due to the potential formation of toxic hydrazine upon hydrazonamide hydrolysis, we have focused mainly on the replacement of the hydrazonamide motif by different alkylaryl-and aryl-substituted amidine (6−23), Npiperidinoamidine (24), and N-(4-fluoro)benzyloxyamidine (25) moieties (Figure 1). Herein, we describe the discovery of 3-hydroxypropanamidines (…”