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-α-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 EC50 value 0.03 μM (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 abstractSynthesis, molecular modeling and antiviral/anti-HIV activity of 3′-N,N-dimethylamino-2′,3′-dideoxythymidine and its prodrugs have been described. Figure optionsDownload full-size imageDownload as PowerPoint slide