AZT and related compounds - a theoretical study

Human immunodeficiency virus (HIV), a retrovirus, is the putative etiologic agent of acquired immunodeficiency syndrome (AIDS). We performed a full theoretical study of structurally related compounds: AZT (3'-azido-2', 3' dideoxythymidine), ddC (2',3'-dideoxycytidine), c-AZT (C-nucleoside isostere analogue of AZT) and 3'-N-3-C-FMAU (2'-'up' F derivative of c-AZT) in the search for a structure-activity relationship. For all the compounds under study, the global minimum is conformation 1, which presents the thymine (pyrimidine ring) at the anti configuration, the sugar ring on the 3'-endo configuration and the C-5'-OH on the outside orientation. MEPs generated for this conformation showed differences on the contour distribution for c-AZT and 3'-N-3-C-FMAU, showing a higher curve concentration. All the molecules presented another minimum conformation 13, which showed a typical orientation for an intramolecular H-bond between the C-5'...OH and the C2O groups. This conformation has a special feature for 3'-N-3-C-FMAU, where the F2'up substituent participates in a three-point H-bond. The difference above mentioned might explain the different activity, since AZT and ddC are both active compounds, while c-AZT and 3'-N-3-C-FMAU are inactive. (C) 1998 Elsevier Science B.V.