S. Rajamaki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3615–3618
3617
R1
5
S
R1
6
1
4
O
R1
4
O
HN
NH
6
2
5
3
a)
O
5
2
O
4
6
1
3
H2N
a)
O
O
O
1
R1
4
2
5
2
3
6
1
O
1
2a - 2g
3a - 3g
O
R2
3
Scheme 1. Meerwein arylation procedure used for the assembly of aryl aldehydes
3a–g. Reagents and conditions: (a) (i) 2a–g, NaNO2, HBF4, H2O, 0 °C; (ii) CuCl2,
acetone, rt. 3a: R1 = 4-CO2H, 5-OH. 3b: R1 = 4-OH, 5-CO2H. 3c: R1 = 2-CO2H, 4-F. 3d:
R1 = 4-Cl, 5-CO2H. 3e: R1 = 2-Cl, 4-CO2H, 5-OMe. 3f: R1 = 2-OH, 3-CO2H. 3g: R1 = 2-
OH, 3-OH, 5-CO2H.
12b - 12l
3a - 3i
or
R1
4
5
6
1
O
S
O
R1
4
HN
3
O
5
6
R3
2
O
R1
5
O
R2
R2 = H
2 = Me 11a
R2 = OMe 11b
b)
1
3
R1
2
6
1
4
8
O
O
6
2
5
3
a)
O
O
R
R2
R3 = S
R3 = NH 14a,b,l
B(OH)2
4
3
Y
1
2
13a,d,e,g,l,p
4
5a, 5b
3h, 3i
Scheme 4. Knoevenagel condensation for the assembly of final compounds 12, 13
and 14. Reagents and conditions: (a) 2-thiobarbituric acid, concd HCl, EtOH, rt; (b)
for R3 = S: rhodanine, b-alanine, AcOH, 20 °C; for R3 = NH: thiohydantoin, b-alanine,
AcOH, 120 °C.
Scheme 2. Suzuki coupling strategy for the assembly of aryl aldehydes 3h–j.
Reagents and conditions: (a) 5a or 5b, Pd(PPh3)2Cl2, Na2CO3, EtOH, DME, 50 °C. 3h:
R
1 = 2-Me, 5-CO2H. 3i: R1 = 2,6-OMe, 4-CO2H.
inferior yields or no coupling product at all. Better results were ob-
tained when employing a Heck reaction between the protected fur-
fural derivatives and a suitable functionalized phenyl halide. The
reaction conditions reported by McClure et al.13 using Cy3P as li-
gand in DMF at 110 °C were found to be most suitable for this
transformation. The obtained coupling products were then further
functionalized to furnish the desired compounds necessary for the
following condensation step (Scheme 3).
The condensation reactions with thiobarbituric acid, rhodanine
and thiohydantoin were carried out as described in literature.14,15
When reacted in ethanol with acid catalyst, thiobarbituric acid
and the substituted phenyl furfural derivatives readily gave the de-
sired condensation products, which could be easily isolated by
simple filtration. Condensation reactions with rhodanine and thi-
ohydantoin were carried out in acetic acid in the presence of b-ala-
nine (Scheme 4).
In summary a new hit compound exhibiting anti IN activity and
moderate inhibition of HIV-1 cell replication was identified by the
use of an improved virtual screening protocol. Subsequently syn-
thesis of a small family of structurally related compounds was
accomplished establishing SAR of these inhibitors. Further studies
including the elucidation of the mechanism of action on this novel
family of potential IN inhibitors are ongoing in our laboratories and
will be reported in due course.
In order to gain insight into the mechanism of action, some
compounds were also submitted to 30-processing assays (Table
1). However, it seems from the obtained data, that classical
in vitro testing is not sufficient for the classification of these novel
IN inhibitors.10
Synthesis of the desired compounds was accomplished by a
straight forward strategy. This involved first the synthesis of differ-
ently substituted biaryl aldehydes and subsequent Knoevenagel
condensation with thiobarbituric acid, rhodanine or thiohydantoin.
The furaldehydes necessary for the condensation reactions with
thiobarbituric acid and rhodanine were either purchased or syn-
thesised by three different methods.
The majority of the biaryl aldehydes could be obtained by a
Meerwein arylation.11 This involved the formation of a diazonium
salt from suitable substituted aniline (2a–g) and subsequent Cu(II)
mediated coupling reaction with furfural to give the desired aro-
matic aldehydes in good yields (Scheme 1).
Alternatively, the desired products were obtained by a Suzuki
coupling reaction12 between an appropriate substituted phenyl ha-
lide and 5-formyl-2-furanboronic acid using Pd(PPh3)2Cl2 as the
catalyst and an aqueous solution of Na2CO3 as the base (Scheme 2).
Attempts to use the Meerwein protocol or a Suzuki reaction for
the synthesis of the biaryl aldehydes 8, 11a and 11b led either to
CO2H
CHO
Acknowledgments
O
a)
O
Br
O
O
This work was supported by the European Union (TRIoH Con-
sortium, LSHB-2003-503480 and THINC, HEALTH-2007-2.3.2-1).
ASINEX is acknowledged for partial support of this work and
Molecular Discovery for access to the GRID code.
O
O
O
O
O
O
6
7
8
OH
References and notes
OH
O
CO2H
O
b)
O
O
I
CO2Me
O
1. (a) Meadows, D. C.; Gervay-Hague, J. Chem. Med. Chem. 2006, 1, 16; (b) De Clerq,
E. J. Med. Chem. 2005, 48, 1297.
O
R2
R2 = Me 9a
2 = OMe 9b
2. (a) Yin, P. D.; Das, D.; Mitsuya, H. Cell. Mol. Life Sci. 2006, 63, 1706; (b) Imamichi,
T. Curr. Chem. Pharm. Des. 2004, 10, 4039.
3. Reviews: (a) Esposito, D.; Craigie, R. Adv. Virus Res. 1999, 52, 319; (b) Assante-
Appiah, E.; Skalka, A. M. Adv. Virus Res. 1999, 12, 2231.
R2
R2 = Me 11a
2 = OMe 11b
10
R
R
4. Selected reviews include: (a) Dayam, R.; Gundla, R.; Al-Mawsawi, L. Q.;
Neamati, N. Med. Res. Rev. 2008, 28, 118; (b) Pommier, Y.; Johnson, A. A.;
Marchand, C. Nat. Rev. Drug Discovery 2005, 4, 236; (c) Hazuda, D. J.; Felock, P.;
Witmer, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.; Espeset, A.; Gabryelski, L.;
Schleif, W.; Blau, C.; Miller, M. D. Science 2000, 287, 646.
Scheme 3. Heck coupling strategy for the assembly of aryl aldehydes 8 and 11.
Reagents and conditions: (a) (i) PdCl2, Cy3P, Bu4NBr, KOAc, DMF, 110 °C; (ii) NaClO2,
KH2PO4, 2,3-dimethyl-2-butene, t-BuOH, H2O, rt; (b) (i) PdCl2, Cy3P, Bu4NBr, KOAc,
DMF, 110 °C; (ii) NaOH, THF, MeOH, reflux.