Synthesis, structure-activity relationship and antiviral activity of 3'-N,N-dimethylamino-2',3'-dideoxythymidine and its prodrugs.
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.
Nucleic Acids Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India. singhramk@rediffmail.com
Ramendra K
RK
Singh
Dipti
D
Yadav
Diwakar
D
Rai
Garima
G
Kumari
C
C
Pannecouque
Erik
E
De Clercq
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D054306:Dideoxynucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011355:Prodrugs / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014780:Viruses / Q000187:drug effects
C541618:3'-N,N-dimethyl-2',3'-dideoxythymidine; D000998:Antiviral Agents; D054306:Dideoxynucleotides; D011355:Prodrugs; D054303:HIV Reverse Transcriptase