TY - JOUR
T1 - Synthesis and antiviral evaluation of 4′-(1,2,3-triazol-1-yl) thymidines
AU - Vernekar, Sanjeev Kumar V.
AU - Qiu, Li
AU - Zacharias, Jeana
AU - Geraghty, Robert J.
AU - Wang, Zhengqiang
PY - 2014/5
Y1 - 2014/5
N2 - Non-obligate chain terminating nucleosides with a linear substituent (azido or ethynyl group) at the 4′ position represent an important class of compounds in antiviral discovery, particularly against hepatitis C virus (HCV) and human immunodeficiency virus (HIV). We have previously shown that 3′-azidothymidine (AZT)-derived 1,2,3-triazoles can be potent inhibitors of HIV-1. To gauge the medicinal chemistry impact of functionalizing the 4′-linear substituent and possibly generate novel antiviral nucleoside scaffolds, we have explored azide-alkyne cycloaddition reactions with 4′-azidothymidine (ADRT). The Ru-mediated reaction failed and the Cu-catalyzed variant generated 1,2,3-triazoles (9a-y) with only modest yields and efficiencies, indicating a substantial steric barrier around the 4′-azido group. Antiviral screening identified a few triazole analogues moderately active against HIV-1 (18-62% inhibition at 10 μM) and/or influenza A virus (15-50% inhibition at 10 μM), and none active against West Nile virus (WNV) or HCV. These results suggest that the linear 4′ azido group of ADRT may be essential for target binding and that its chemical manipulation could largely compromise antiviral potency. This journal is
AB - Non-obligate chain terminating nucleosides with a linear substituent (azido or ethynyl group) at the 4′ position represent an important class of compounds in antiviral discovery, particularly against hepatitis C virus (HCV) and human immunodeficiency virus (HIV). We have previously shown that 3′-azidothymidine (AZT)-derived 1,2,3-triazoles can be potent inhibitors of HIV-1. To gauge the medicinal chemistry impact of functionalizing the 4′-linear substituent and possibly generate novel antiviral nucleoside scaffolds, we have explored azide-alkyne cycloaddition reactions with 4′-azidothymidine (ADRT). The Ru-mediated reaction failed and the Cu-catalyzed variant generated 1,2,3-triazoles (9a-y) with only modest yields and efficiencies, indicating a substantial steric barrier around the 4′-azido group. Antiviral screening identified a few triazole analogues moderately active against HIV-1 (18-62% inhibition at 10 μM) and/or influenza A virus (15-50% inhibition at 10 μM), and none active against West Nile virus (WNV) or HCV. These results suggest that the linear 4′ azido group of ADRT may be essential for target binding and that its chemical manipulation could largely compromise antiviral potency. This journal is
UR - http://www.scopus.com/inward/record.url?scp=84899445051&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899445051&partnerID=8YFLogxK
U2 - 10.1039/c4md00039k
DO - 10.1039/c4md00039k
M3 - Article
AN - SCOPUS:84899445051
SN - 2040-2503
VL - 5
SP - 603
EP - 608
JO - MedChemComm
JF - MedChemComm
IS - 5
ER -