TY - JOUR
T1 - 3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides Potently Inhibit HIV-1 Integrase and RNase H
AU - Wu, Bulan
AU - Tang, Jing
AU - Wilson, Daniel J.
AU - Huber, Andrew D.
AU - Casey, Mary C.
AU - Ji, Juan
AU - Kankanala, Jayakanth
AU - Xie, Jiashu
AU - Sarafianos, Stefan G.
AU - Wang, Zhengqiang
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/7/14
Y1 - 2016/7/14
N2 - Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On the basis of our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized a new integrase strand transfer (INST) inhibitor type featuring a 5-N-benzylcarboxamide moiety. Significantly, the 6-alkylamino variant of this new chemotype consistently conferred low nanomolar inhibitory activity against HIV-1. Extended antiviral testing against a few raltegravir-resistant HIV-1 clones revealed a resistance profile similar to that of the second generation INST inhibitor (INSTI) dolutegravir. Although biochemical testing and molecular modeling also strongly corroborate the inhibition of INST as the antiviral mechanism of action, selected antiviral analogues also potently inhibited reverse transcriptase (RT) associated RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochemical properties suitable for further development.
AB - Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On the basis of our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized a new integrase strand transfer (INST) inhibitor type featuring a 5-N-benzylcarboxamide moiety. Significantly, the 6-alkylamino variant of this new chemotype consistently conferred low nanomolar inhibitory activity against HIV-1. Extended antiviral testing against a few raltegravir-resistant HIV-1 clones revealed a resistance profile similar to that of the second generation INST inhibitor (INSTI) dolutegravir. Although biochemical testing and molecular modeling also strongly corroborate the inhibition of INST as the antiviral mechanism of action, selected antiviral analogues also potently inhibited reverse transcriptase (RT) associated RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochemical properties suitable for further development.
UR - http://www.scopus.com/inward/record.url?scp=84978676933&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978676933&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b00040
DO - 10.1021/acs.jmedchem.6b00040
M3 - Article
C2 - 27283261
AN - SCOPUS:84978676933
SN - 0022-2623
VL - 59
SP - 6136
EP - 6148
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 13
ER -