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 N1‐succinyl and N1‐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 N1‐succinyl and N1‐glutaroylmelatonin derivatives (compounds 11 and 12) could be promising as sustained release prodrugs of melatonin.