Chem. Pharm. Bull., 53(6),653-661, June 2005

Regular Articles

Synthesis and Evaluation of β-Carbolinium Cations as New Antimalarial Agents Based on π-Delocalized Lipophilic Cation (DLC) Hypothesis

Kiyosei TAKASU,^*,a Tsubasa SHIMOGAMA,^a Chalerm SAIIN,^a Hye-Sook KIM,^b Yusuke WATAYA,^b Reto BRUN,^c and Masataka IHARA^*,a

^a Graduate School of Pharmaceutical Sciences, Tohoku University; Aobayama, Sendai 980-8578, Japan: ^b Faculty of Pharmaceutical Sciences, Okayama University; 1-1-1 Tsushimanaka, Okayama 700-0082, Japan: and ^c Swiss Tropical Institute; Socinstrasse 57, CH-4002 Basel, Switzerland. * To whom correspondence should be addressed. e-mail: kay-t@mail.pharm.tohoku.ac.jp

Several β-carbolines including naturally occurring substances and their corresponding cationic derivatives were synthesized and evaluated for antimalarial (antiplasmodial) activity in vitro and in vivo. A tetracyclic carbolinium salt was elucidated for antileishmanial and antitrypanosomal activities in vitro as well as antiplasmodial activity. Quarternary carbolinium cations showed much higher potencies in vitro than electronically neutral β-carbolines and a good correlation was observed between π-delocalized lipophilic cationic (DLC) structure and antimalarial efficacy. β-Carbolinium compounds exhibit medium suppressive activity in vivo against rodent malaria.

Key words antimalarial agent; β-carbolinium salt; total synthesis; π-delocalized lipophilic cationic (DLC) hypothesis; tropical disease; structure-activity relationship