3400
L. D. Fader et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3396–3400
Table 5
dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of
Structure–activity relationships for analogs 33–38
HIV-1 capsid assembly. Replacement of the C3 carbon with a nitro-
gen atom yielded the 1,5-dihydro-benzo[f][1,3,5]triazepine-2,4-
dione analog 4. Cyclization from the C3-position to the ortho posi-
tion of the C3-phenyl group of compound 3 resulted in the spirocy-
clic 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione analog 5. Both of
the modifications were found to generate compounds that inhibit
capsid assembly in a potency range comparable to that of lead
O
N
N
CF3
Y
O
OH
compound 3, but lacked
a labile chiral center. Preliminary
–Y–
IC50 (lM)
right-hand side SAR in both series indicated that improvements
in potency are possible and a combination of molecular modeling
and X-ray crystallographic data indicate that SAR might be trans-
ferable between the scaffolds represented by compounds 3, 4
and 5.
33
34
35
36
37
38
–CO–
1.5
2.1
3.6
0.29
0.73
1.1
–CH(OH)–
–CH(NH2)–
–CH(Me)–
–CH(Et)–
–CH(i-Pr)–
Acknowledgments
The authors wish to acknowledge Jean-François Mercier and
Elizabeth Wardrop for IC50 and EC50 value determinations, respec-
tively. We are also grateful to Michael Bös, Richard Bethell and Mi-
chael Cordingley for leadership and guidance throughout the
course of this work.
References and notes
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Mason, S. W. J. Virol. 2012, 86, 6643. was based on the pioneering work of
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Figure 3. Superposed models of compounds 3 (orange), 4 (red) and 5 (yellow)
bound to CANTD, based on related X-ray structures (PDBID 4E91). The protein
surface is coloured by hydrophobicity (green = hydrophobic, white = neutral,
red = hydrophilic) and has been cut away to reveal the deeply bound compounds.
The backbone trace of the protein is shown as a grey coil.
7
8. The assay used for IC50 determinations reported here was a modification to the
assay described in Ref. 7 measures the ability of compounds to disassemble
CA–NC complexes pre-assembled on oligonucleotide templates.
9. IC50 and EC50 values are typically the mean of two determinations.
10. MMFF94x force field in Molecular Operating Environment (MOE); Chemical
Computing Group Inc., 1010 Sherbooke St. West, Suite #910, Montreal, QC,
Canada, H3A 2R7.
11. The software Jaguar, version 7.0 (Schrödinger, LLC., New York, NY, 2007) was
used for QM calculations (heteroatom pairs active; a Poisson Boltzmann model
was used for solution calculations).
12. Detailed experimental procedures for most of the compounds in the present
manuscript can be found in: Simoneau, B.; Deroy, P.; Fader, L.; Faucher, A.-M.;
Gagnon, A.; Grand-Maitre, C.; Kawai, S.; Landry, S.; Mercier, J.-F.; Rancourt, J.
PCT Int. Appl. WO 2011/100838.
13. Barton, D. H. R.; Finet, J. P.; Khamsi, J. Tetrahedron Lett. 1986, 27(31), 3615.
14. Fader, L. D.; Landry, S.; Goulet, S.; Morin, S.; Kawai, S. H.; Bousquet, Y.; Dion, I.;
Hucke, O.; Goudreau, N.; Lemke, C. T.; Rancourt, J.; Bonneau, P.; Titolo, S.;
Amad, M.; Garneau, M.; Duan, J.; Mason, S.; Simoneau, B. Bioorg. Med. Chem.
Lett. 2013. Insert reference details.
In order to further optimize the triazepine and spirobenzodiaze-
pine series, we sought a structure-based approach to exploit infor-
mation gleaned from SAR in the original 3-phenylbenzodiazepine
series. Based on X-ray structures of related compounds bound to
CANTD, molecular modeling of compounds 3, 4, and 5 confirms that
all three analogs display similar trajectories from the RHS phenyl
moiety (Fig. 3). The small, 10–15° variations among these trajecto-
ries may provide subtle but meaningful differences during optimi-
zation. In the following companion paper we disclose an extensive
RHS exploration of the 3-phenylbenzodiazepine series represented
by compound 3 and the transposition of this knowledge onto the
newly described triazepine and spirobenzodiazepine series repre-
sented by compounds 4 and 5, respectively.
In conclusion, we have designed replacements for the
configurationally labile stereocenter at C3 of our 1,5-