title: Synthesis and structure-activity relationships of cassiarin A as potential antimalarials with vasorelaxant activity.
abstract: Cassiarin A 1, a tricyclic alkaloid, isolated from the leaves of Cassia siamea (Leguminosae), shows powerful antimalarial activity against Plasmodium falciparum in vitro as well as P. berghei in vivo, which may be valuable leads for novel antimalarials. Interactions of parasitized red blood cells (pRBCs) with endothelium in aorta are especially important in the processes contribute to the pathogenesis of severe malaria. Nitric oxide (NO) reduces endothelial expression of receptors/adhesion molecules used by pRBC to adhere to vascular endothelium, and reduces cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 showed vasorelaxation activity against rat aortic ring, which may be related with NO production. A series of a hydroxyl and a nitrogen-substituted derivatives and a dehydroxy derivative of 1 have been synthesized as having potent antimalarials against P. falciparum with vasodilator activity, which may reduce cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 exhibited a potent antimalarial activity and a high selectivity index in vitro, suggesting that the presence of a hydroxyl and a nitrogen atom without any substituents may be important to show antimalarial activity. Relative to cassiarin A, a methoxy derivative showed more potent vasorelaxant activity, although it did not show improvement for inhibition of P. falciparum in vitro. These cassiarin derivatives may be promising candidates as antimalarials with different mode of actions.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo 142-8501, Japan. moritah@hoshi.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morita
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tomizawa
authors.forename: Jun
authors.initials: J
authors.lastname: Deguchi
authors.forename: Tokio
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Arai
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Zaima
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hosoya
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hirasawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Katsuo
authors.initials: K
authors.lastname: Kamata
authors.forename: Wiwied
authors.initials: W
authors.lastname: Ekasari
authors.forename: Aty
authors.initials: A
authors.lastname: Widyawaruyanti
authors.forename: Tutik Sri
authors.initials: TS
authors.lastname: Wahyuni
authors.forename: Noor Cholies
authors.initials: NC
authors.lastname: Zaini
authors.forename: Toshio
authors.initials: T
authors.lastname: Honda
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001667:Binding, Competitive / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000502:physiology; D002469:Cell Separation; D042783:Endothelial Cells; D004727:Endothelium / Q000469:parasitology / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry*; D016778:Malaria, Falciparum / Q000188:drug therapy; D008833:Microcirculation / Q000187:drug effects; D015394:Molecular Structure; D009569:Nitric Oxide / Q000009:adverse effects; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D015815:Cell Adhesion Molecules; D006575:Heterocyclic Compounds, 3-Ring; C524027:cassiarin A; D009569:Nitric Oxide