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. 2010 Sep;45(9):3787-93.
doi: 10.1016/j.ejmech.2010.05.028. Epub 2010 May 20.

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

Ramendra K Singh  1 , Dipti Yadav, Diwakar Rai, Garima Kumari, C Pannecouque, Erik De Clercq
Affiliations

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

Ramendra K Singh et al. Eur J Med Chem. 2010 Sep.

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.

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Figures

None
Graphical abstract
Fig. 1
Fig. 1
Structures of AZT and 3′-N,N-dimethylamino-2′,3′-dideoxythymidine and their prodrugs.
Scheme 1
Scheme 1
Synthesis of DMAT (4) and its prodrugs (5–7).
Fig. 2
Fig. 2
Interaction of TTP with HIV-1 RT at dNTP-binding site.
Fig. 3
Fig. 3
Interaction of AZTTP with HIV-1 RT at dNTP-binding site.
Fig. 4
Fig. 4
Interaction of DMATTP with HIV-1 RT at dNTP-binding site.
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