Design and synthesis of sustain-acting melatonin prodrugs

Abstract

Twelve melatonin amide prodrugs aiming at prolonging the action of melatonin in vivo by improving its half-life were designed and synthesized. Using an 80% human plasma model, it was found that the aliphatic amide derivatives were relatively stable and melatonin release from these compounds was not sufficient with melatonin release percentage. After 4-hour incubation with 80% human plasma, the melatonin release percentage achieved only approximately less than 20%. In contrast, the N 1 -succinyl and N 1 -glutaroylmelatonin derivatives (compounds 11 and 12, resp.) were found to release melatonin in much higher rates. After 3-hour incubation in 80% human plasma, the melatonin release rates from 11 and 12 were found to be 67.3 and 75.6%, respectively. From these results, the N 1 -succinyl and N 1 -glutaroylmelatonin derivatives (compounds 11 and 12) could be promising as sustained release prodrugs of melatonin. © 2013 Phm Vǎn Thoi and Nguyen Hai Nam.