Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Apr 15;21(8):2400-2.
doi: 10.1016/j.bmcl.2011.02.069. Epub 2011 Feb 18.

6-Benzoyl-3-hydroxypyrimidine-2,4-diones as Dual Inhibitors of HIV Reverse Transcriptase and Integrase

Affiliations
Free PMC article

6-Benzoyl-3-hydroxypyrimidine-2,4-diones as Dual Inhibitors of HIV Reverse Transcriptase and Integrase

Jing Tang et al. Bioorg Med Chem Lett. .
Free PMC article

Abstract

N-3-hydroxylation of pyrimidine-2,4-diones was recently found to yield inhibitors of both HIV-1 reverse transcriptase (RT) and integrase (IN). An extended series of analogues featuring a benzoyl group at the C-6 position of the pyrimidine ring was synthesized. Through biochemical studies it was found that these new analogues are dually active against both RT and IN in low micromolar range. Antiviral assays confirmed that these new inhibitors are active against HIV-1 in cell culture at nanomolar to low micromolar range, further validating 3-hydroxypyrimidine-2,4-diones as a viable scaffold for antiviral development.

Figures

Figure 1
Figure 1
Design of the new series of N-3-hydroxypyrimidine-2,4-diones featuring a C-6 benzoyl group.
Figure 2
Figure 2
Inhibitory modes of binding for compound 20 within A) the NNRTI binding pocket and B) the active site of IN CCD in complex with Mg2+ and DNA. The electrostatic potential surface of the binding pocket is shown to highlight the hydrophobic regions (white) in both enzymes.
Scheme 1
Scheme 1
Synthesis of compounds 1724a aReagents and conditions: a) urea, NaOMe, MeOH, reflux, 75%; b) POCl3, dimethylaniline, 89%; c) MeONa, MeOH, 81%; d) (i) substituted phenyl acetonitrile, NaH, DMF, rt; (ii) NaH, DMF, air, 84–87%; e) HCl, MeOH, reflux, 85–93%; f) CH3C(OTMS)=NTMS (BSA), benzyl alcohol substrate, (HCHO)n, TMSCl, TBAI (cat.), CH2Cl2, rt; or (for 1516) BSA, chloromethyl ethyl ether, TBAI (cat.), CH2Cl2, rt, 74–94%; g) NaH, m-CPBA, THF, rt, 38–68%.

Similar articles

See all similar articles

Cited by 8 articles

See all "Cited by" articles

Publication types

MeSH terms

LinkOut - more resources

Feedback