Synthesis, structure-activity relationship and antiviral activity of 3'-N,N-dimethylamino-2',3'-dideoxythymidine and its prodrugs

Abstract

A probable NRTI molecule, viz. 3'-N,N-dimethylamino-2',3'-dideoxythymidine (4) and its 5'-O-carboxyl ester prodrugs - 5'-(N-alpha-BOC-L-phenylalanyl)-3'-N,N-dimethylamino-2',3'-dideoxythymidine (5), 5'-L-phenylalanyl-3'-N,N-dimethylamino-2',3'-dideoxythymidine (6) and 5'-decanoyl-3'-N,N-dimethylamino-2',3'-dideoxythymidine (7) have been synthesized and screened against HIV, HSV-1 and 2, parainfluenza-3, vesicular stomatitis and several other viruses. The compound 6 showed good antiviral activity with EC(50) value 0.03 microM (SI=8) against VSV in Hela and HEL cell lines. However, the lead compound 4 and its derivatives 5, 6 and 7 showed no remarkable activity against HIV-1 and other viruses. Molecular docking studies with HIV-1 RT using DS 2.5 and pymol softwares have shown marked differences in the interaction patterns between the lead compound 4 and AZT.

Graphical abstract

Fig. 1

Structures of AZT and 3′-N,N-dimethylamino-2′,3′-dideoxythymidine and their prodrugs.

Scheme 1

Synthesis of DMAT (4) and its prodrugs (5–7).

Fig. 2

Interaction of TTP with HIV-1 RT at dNTP-binding site.

Fig. 3

Interaction of AZTTP with HIV-1 RT at dNTP-binding site.

Fig. 4

Interaction of DMATTP with HIV-1 RT at dNTP-binding site.