Structures of three (2R,3S)-4-(arylmethyl)-1-(4-phenyl-3-amino-2-hydroxy-butyl)-piperazine derivatives, potential anti-malarial agents

Abstract

Selected (2R,3S)-4-(arylmethyl)-1-(4-phenyl-3-substituted-amino-2-hydroxybutyl)piperazine derivatives have anti-malarial activity. The crystal structures of active tert-butyl (2S,3R)-4-(4-benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-3-hydroxy-1-phenylbutan-2-ylcarbamate, (1), nonactive (2S,3R)-4-(4-nitrobenzyl)piperazin-1-yl)-3-hydroxy-1-phenyl-2-(4-toluenesulfonamido)butane, (2), and the active dihydrated salt, (2S,3R)-4-(4-(benzo[d]-[1,3]dioxol-5-ylmeäthyl)piperazin-1-yl)-3-hydroxy-1-phenyl-2-(4-toluenesulfonamido)butane.dihydrogen chloride, (3) are reported. Biological studies indicated the importance of the OH, the benzyl group and the methylene substituents, at the piperazinyl nitrogens, for generating activity. The bond distances in 1 and 2 and the two independent dications of 3, involving these units, do not correlate with activities. However, the molecular conformation adopted by 2, was different from that in 1 and the dications of 3. Both 1 and 2 possess O(1)—H(1)—O(1) and N—HN—O intermolecular H-bonds: in both cases, the O—H—O hydrogen bonds involve the hydroxyl oxygen atom, while the N—H—O interaction for 1 involves the carbonyl oxygen and that for 2, a sulfonyl oxygen. The dications of 3 are not directly connected by H-bonds, but each independent dication is linked via chloride anions and water molecules into chains. Three-dimensional networks are obtained for 1–3 from intermolecular C—H-π and or intermolecular C—H—O and C—H-π interactions.