Anthelmintic activity of 3,6-dibenzyl-2,5-dioxopiperazine, cyclo(L-Phe-L-Phe)

Abstract

After oral administration, dipeptide Phe-Phe-OMe1 exhibits anthelmintic activity againstEchinococcus multilocularis larvae, cestoda, in mongolian gerbils (intraperitoneal localization), but not againstHymenolepis nana, cestoda, in fasted mice (gastro-intestinal localization). This compound rapidly provides its cyclization product dioxopiperazine2 in pH 7.4 buffer at 37°C, but was stable at pH 2.4 during 16h at 30°C. It was postulated that dipeptide1 could act as a prodrug of2. Initial pharmacokinetics studies were carried out in mice and dogs. After oral administration, biotransformation of1 into2 occurred to some extent in mice but not in fasted dogs. Results of these studies did not allow to ascertain that1 is a prodrug of2. Compound2 has been tested in mice againstH. nana andSchistosoma mansoni, a gastrointestinal trematoda. Albeit less active than the reference compound praziquantel,2 has shown a good activity against both worms. 2,5dioxopiperazines represent therefore a new class of anthelmintics.