7-O-[4-methyl piperazine-1-(2-acetyl)]-2H-1-benzopyran-2-one: a novel antifilarial lead compound

In preliminary studies we found that benzopyrones (coumarins), which are known to exert many biological activities including anti-inflammatory effect, possess promising macrofilaricidal action as well. In order to explore the possibility of combining such a macrofilaricidal activity with the microfilaricidal potential of the known piperazine pharmacophore, we synthesized a series of compounds and evaluated their antifilarial effect. In the present study, one of these compounds, 7-O-[4-methyl piperazine-1-(2-acetyl)]-2H-1-benzopyran-2-one (2), which has shown promising macrofilaricidal action against rodent filariid Litomosoides carinii in cotton rats, was evaluated against infection with Brugia malayi in Mastomys coucha and jird (Meriones unguiculatus). In the B. malayi-M. coucha system, the compound at a dose of 300 mg/kg, oral (p.o.) x 5 days showed 53.6% adulticidal and 46.0% microfilaricidal activity along with 46.3% sterilization effect on the female worms. In addition, the compound interfered with the establishment of infective larvae (L-3)-induced infection to an extent of 50% at the same dose level. At 1 muM concentration it inhibited protease activity of R malayi to 82%. The compound thus provides a novel lead for further synthesis and development of antifilarial agents with macrofilaricidal, microfilaricidal, female-sterilizing and possible larvicidal efficacy. (C) 2003 Elsevier Science B.V. All rights reserved.