Synthesis and biological evaluation of first N-alkyl syn dimeric 4-aryl-1,4-dihydropyridines as competitive HIV-1 protease inhibitors

A first series of novel N-alkyl substituted syn dimeric 4-aryl-1,4-dihydropyridines 12-17 have been synthesised and evaluated as HIV-I protease inhibitors in in vitro assays. While the N-methyl derivatives 12 and 13 were almost inactive, with IC50-values of about 225 muM, the N-benzyl compounds with varied ester groups all exhibited stronger activities, with IC50-values of 11-12 muM for the presently best compounds 16 and 17 with ethyl ester functions. The type of HIV-1 protease inhibition of the novel inhibitors was characterised as competitive. With the increase of observed activity from N-methyl derivatives to N-benzyl compounds the binding mode may correspond to that of cyclic ureas with hydrophobic interactions of the four aromatic residues to the S1/S1' and S2/S2' regions of HIV-I protease. (C) 2001 Editions scientifiques et medicales Elsevier SAS.