TY - JOUR
T1 - 6-Arylthio-3-hydroxypyrimidine-2,4-diones potently inhibited HIV reverse transcriptase-associated RNase H with antiviral activity
AU - Wang, Lei
AU - Tang, Jing
AU - Huber, Andrew D.
AU - Casey, Mary C.
AU - Kirby, Karen A.
AU - Wilson, Daniel J.
AU - Kankanala, Jayakanth
AU - Xie, Jiashu
AU - Parniak, Michael A.
AU - Sarafianos, Stefan G.
AU - Wang, Zhengqiang
N1 - Publisher Copyright:
© 2018 Elsevier Masson SAS
PY - 2018/8/5
Y1 - 2018/8/5
N2 - Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not targeted by current drugs. Although a few chemotypes have been reported to inhibit HIV RNase H in biochemical assays, their general lack of significant antiviral activity in cell culture necessitates continued efforts in identifying highly potent RNase H inhibitors to confer antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-arylthio subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays these new analogues inhibited RT RNase H in single-digit nanomolar range without inhibiting RT polymerase (pol) at concentrations up to 10 μM, amounting to exceptional biochemical inhibitory selectivity. Many analogues also inhibited integrase strand transfer (INST) activity in low to sub micromolar range. More importantly, most analogues inhibited HIV in low micromolar range without cytotoxicity. In the end, compound 13j (RNase H IC50 = 0.005 μM; RT pol IC50 = 10 μM; INST IC50 = 4.0 μM; antiviral EC50 = 7.7 μM; CC50 > 100 μM) represents the best analogues within this series. These results characterize the new 6-arylthio-HPD subtype as a promising scaffold for HIV RNase H inhibitor discovery.
AB - Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not targeted by current drugs. Although a few chemotypes have been reported to inhibit HIV RNase H in biochemical assays, their general lack of significant antiviral activity in cell culture necessitates continued efforts in identifying highly potent RNase H inhibitors to confer antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-arylthio subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays these new analogues inhibited RT RNase H in single-digit nanomolar range without inhibiting RT polymerase (pol) at concentrations up to 10 μM, amounting to exceptional biochemical inhibitory selectivity. Many analogues also inhibited integrase strand transfer (INST) activity in low to sub micromolar range. More importantly, most analogues inhibited HIV in low micromolar range without cytotoxicity. In the end, compound 13j (RNase H IC50 = 0.005 μM; RT pol IC50 = 10 μM; INST IC50 = 4.0 μM; antiviral EC50 = 7.7 μM; CC50 > 100 μM) represents the best analogues within this series. These results characterize the new 6-arylthio-HPD subtype as a promising scaffold for HIV RNase H inhibitor discovery.
KW - 3-Hydroxypyrimidine-2,4-dione (HPD)
KW - Human immunodeficiency virus (HIV)
KW - Inhibitors
KW - Integrase strand transfer
KW - RNase H
KW - Structure-activity-relationship (SAR)
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U2 - 10.1016/j.ejmech.2018.07.039
DO - 10.1016/j.ejmech.2018.07.039
M3 - Article
C2 - 30031976
AN - SCOPUS:85050076267
SN - 0223-5234
VL - 156
SP - 652
EP - 665
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -