Structure-activity relationships in a series of melatonin analogues with the low-density lipoprotein oxidation model

Despite an increasing number of publications concerning the antioxidant act ivity of melatonin, little is known about the structural features responsib le for this kind of activity. To understand the role played by the differen t elements of melatonin structure in its antioxidant activity, we have desi gned and tested several compounds related to this molecule in the low-densi ty lipoprotein peroxidation model. We present here the results of this stud y in terms of structure-activity relationships focusing on the influence of the acetamidoethyl side chain, the methoxy group, and the indole heterocyc le. In this model, we found that changing the acyl residue generally result ed in more active products. We obtained particularly good results with the nonanoyl derivative which showed a level of activity comparable to that of phenols despite lacking a phenolic function. The presence of a methoxy grou p in position 5 generally had a beneficial influence on the activity, but w hen located in position 6, the effects were various. The substitution of a hydroxy for the methoxy group led to phenolic compounds endowed with very h igh antioxidant activity. Replacing the amide with a ketone function did no t affect the activity while replacement with an amine group in some cases r esulted in prooxidant compounds. Finally, we compared the efficacy of diffe rent aromatic rings. The indole heterocycle proved to be better than benzof urane and naphthalene rings. (C) 1999 Elsevier Science Inc.