Synthesis and structure-activity relationships of cassiarin A as potential antimalarials with vasorelaxant activity

Hiroshi Morita, Yuichiro Tomizawa, Jun Deguchi, Tokio Ishikawa, Hiroko Arai, Kazumasa Zaima, Takahiro Hosoya, Yusuke Hirasawa, Takayuki Matsumoto, Katsuo Kamata, Wiwied Ekasari, Aty Widyawaruyanti, Tutik Sri Wahyuni, Noor Cholies Zaini, Toshio Honda

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)8234-8240
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number24
DOIs
Publication statusPublished - 15 Dec 2009

Keywords

  • Antimalarial activity
  • Cassia siamea
  • Cassiarin A
  • Nitric oxide
  • Plasmodium falciparum
  • SAR
  • Vasorelaxant activity

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