TY - JOUR
T1 - 6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an inhibitor scaffold of HIV reverase transcriptase
T2 - Impacts of the 3-OH on inhibiting RNase H and polymerase
AU - Tang, Jing
AU - Kirby, Karen A.
AU - Huber, Andrew D.
AU - Casey, Mary C.
AU - Ji, Juan
AU - Wilson, Daniel J.
AU - Sarafianos, Stefan G.
AU - Wang, Zhengqiang
N1 - Publisher Copyright:
© 2017 Elsevier Masson SAS
PY - 2017
Y1 - 2017
N2 - 3-Hydroxypyrimidine-2,4-dione (HPD) represents a versatile chemical core in the design of inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H and integrase strand transfer (INST). We report herein the design, synthesis and biological evaluation of an HPD subtype (4) featuring a cyclohexylmethyl group at the C-6 position. Antiviral testing showed that most analogues of 4 inhibited HIV-1 in the low nanomolar to submicromolar range, without cytotoxicity at concentrations up to 100 μM. Biochemically, these analogues dually inhibited both the polymerase (pol) and the RNase H functions of RT, but not INST. Co-crystal structure of 4a with RT revealed a nonnucleoside RT inhibitor (NNRTI) binding mode. Interestingly, chemotype 11, the synthetic precursor of 4 lacking the 3-OH group, did not inhibit RNase H while potently inhibiting pol. By virtue of the potent antiviral activity and biochemical RNase H inhibition, HPD subtype 4 could provide a viable platform for eventually achieving potent and selective RNase H inhibition through further medicinal chemistry.
AB - 3-Hydroxypyrimidine-2,4-dione (HPD) represents a versatile chemical core in the design of inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H and integrase strand transfer (INST). We report herein the design, synthesis and biological evaluation of an HPD subtype (4) featuring a cyclohexylmethyl group at the C-6 position. Antiviral testing showed that most analogues of 4 inhibited HIV-1 in the low nanomolar to submicromolar range, without cytotoxicity at concentrations up to 100 μM. Biochemically, these analogues dually inhibited both the polymerase (pol) and the RNase H functions of RT, but not INST. Co-crystal structure of 4a with RT revealed a nonnucleoside RT inhibitor (NNRTI) binding mode. Interestingly, chemotype 11, the synthetic precursor of 4 lacking the 3-OH group, did not inhibit RNase H while potently inhibiting pol. By virtue of the potent antiviral activity and biochemical RNase H inhibition, HPD subtype 4 could provide a viable platform for eventually achieving potent and selective RNase H inhibition through further medicinal chemistry.
KW - 3-Hydroxypyrimidine-2,4-dione (HPD)
KW - Human immunodeficiency virus (HIV)
KW - Inhibitors
KW - Polymerase
KW - RNase H
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UR - http://www.scopus.com/inward/citedby.url?scp=85011866732&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2017.01.041
DO - 10.1016/j.ejmech.2017.01.041
M3 - Article
C2 - 28182989
AN - SCOPUS:85011866732
SN - 0223-5234
VL - 128
SP - 168
EP - 179
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -