S. K. Tipparaju et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3565–3569
R1
3567
O
O
R1
N
a
N
O
R2
14, R1 = Cl, R2 = H
R1
c
R3
O
R2
O
NC
18, R1 = Cl, R2 = H, R3 = carbazolyl
19, R1 = H, R2 = OMe, R3 = carbazolyl
20, R1 = R2 = H, R3 = carbazolyl
O
R1
N
b
e
N
Br
O
R2
O
R1
17a, R1 = H, R2 = H or OMe
17b, R1 = Cl or H, R2 = H
HO
R2
N
O
R1
d
R3
O
R2
N
21, R1 = Cl, R2 = H, R3 = indolyl
22, R1 = Cl, R2 = H, R3 = bezotriazolyl
23, R1 = Cl, R2 = H, R3 = imidazolyl
R3
O
R2
15, R1 = Cl, R2 = H, R3 = 1-naphthyl
16, R1 = Cl, R2 = H, R3 = 2-naphthyl
Scheme 2. Reagents and conditions: (a) NaH, DMF/THF, 4-CN-PhCH2Br, 0–25 °C, 12 h; (b) NaH, DMF, 1,3-dibromopropane, 0–25 °C, 6 h; (c) NaH, DMF, carbazole, 0–25 °C,
12 h; (d) For 21: NaH, DMF, indole, rt, 16 h; for 22: benzotriazole, DMF, K2CO3, rt, 12 h; for 23: imidazole, KOH, THF, 85 °C, 16 h; (e) NaH, DMF/THF, 1- or 2-bromomethyl
naphthalene, 0–25 °C, 12 h.
O
N
Cl
Cl
Cl
O
O
Br
N
O
N
Br
O
b
f
d
N
N
MeO
X1
Cl
Cl
Cl
Y
27, X1 = H
28, X1 = Cl
d
36
Cl
37
Cl
24,Y= OMe
25,Y= F
26,Y= OBn
c
a
X1
X2
Z
O
Y
Z
d
e
HN
N
N
X2
X1
Y
BnO
33, Y = OMe, X1 = H, X2 = Cl, Z = O
34, Y = OMe, X1 = X2 = Cl, Z = O
35, Y = OBn, X1 = X2 = H, Z = CH2
30, Y = OMe, X1 = H, X2 = Cl, Z = O
31, Y = OMe, X1 = X2 = Cl, Z = O
32, Y = OBn, X1 = X2 = H, Z = CH2
29
Scheme 3. Reagents and conditions: (a) benzyl alcohol, NaH, THF, rt, 12 h; (b) for 27: KOH-CuCO3, 2-chlorophenol, 180 °C, 15 h; For 28: 2,4-dichlorophenol, KOtBu, DMF, rt,
3 h, then at 45 °C under vacuum, Cu(OTf)2ꢁPhCH3, DMF, reflux, 16 h; (c) trimethylbenzylstannane, Pd(PPh3)4, DMF, 80 °C, 12 h; (d) m-chloroperbenzoic acid, CHCl3, rt, 12 h; (e)
Ac2O, reflux, 5 h, 1 N HCl, 100 °C, 12 h; (f) KOH–CuCO3, 2,4-dichlorophenol, 180 °C, 15 h.
zyme inhibitory activity was observed when a chlorine atom is
present at the 20-position on the aromatic ring B (cf. 1 vs 2). A sim-
ilar improvement in the binding affinity of triclosan derivatives to
the BaENR active site was recently observed by us.8 Attachment of
an electron withdrawing cyano group to the aromatic ring of the
benzyloxy moiety resulted in 14, which showed an ENR inhibitory
activity lower than the lead compound. Thus, we explored the
activities of compounds with other hydrophobic substitutents at
the 3-position of the pyridone ring. Introduction of 1- and 2-naph-
thyl groups resulted in compounds 15 and 16 whose enzymatic
activity was comparable to the lead compound. Introduction of a
bulkier carbazole unit, tethered with a three-carbon chain on the
other hand, decreased the BaENR inhibitory activity (Table 1, com-
pounds 18–20). Again, the importance of having a chlorine atom at
the 20-position on ring B to improve the inhibitory activity of these
compounds is evident by comparing the activities of 18 and 20.
Replacing the carbazole unit with a smaller indole moiety resulted
in twofold improvement in the ENR inhibitory activity (compound
21), while a benzotriazolyl substitution resulted in the compound
(22) with an ENR inhibitory activity comparable to that of the lead
compound. Introduction of an imidazolyl unit did not improve the
activity.
compounds 3–8 with various functional groups at the 40-position of
the ring B. Compound 4, bearing an amino group at the 40-position
turned out to be the best compound with an IC50 of 0.8 lM. Conver-
sion of the amino functionality into an acetamide (compound 8) re-
duced the BaENR inhibitory activity by half. Thus, it appears that the
presence of an electron-donating group at the 40-position is able to
enhance the interaction of ligands with the enzyme active site. At-
tempts to replace the aromatic ring B of these 2-pyridones with an
acetylene (compound 9) or an isoxazole (compound 10) were not
successful in improving the activity (Table 2).
We briefly explored the activities of C-substituted 2-pyridones
that are structurally similar to the N-substituted 2-pyridones dis-
cussed above (compounds 33–35). These C-substituted pyridones
are capable of existing in their enol form as hydroxypyridines, and
thus closely mimic triclosan in structure. The activities of these com-
pounds are shown in Table 2. It is gratifying to note that the novel C-
substituted 2-pyridone, 35 showed a 10-fold improvement in ENR
inhibitory activity over its N-substituted analog 1. The GOLD-dock-
ing conformation of 35 inFigure 2C suggests a nearly identical orien-
tation of the C-substituted 2-pyridones compared to the N-
substituted pyridones. Although the origin of improved activity of
compound 35 is not completely clear at this stage, the pyridone
NH and the nicotinamide ring are about 3.6 Å apart and thus ligand
binding stabilization from an N–Hꢁ ꢁ ꢁp interaction cannot be ruled
out.16 Moderate ENR inhibition was observed by the 3-phenoxy-2-
pyridones 33 and 34. Among the pyridine N-oxides, compound 37
exhibited modest ENR inhibition, while compound 30 was inactive.
We explored the SAR of the 2-pyridones by functionalizing ring B.
From the docking conformations of the lead compound into the
BaENR X-ray crystal structure (Fig. 2B), we anticipated that hydro-
gen bond donors/acceptors at the 40-position would be ideally posi-
tionedto interactwith eitherAla97orArg99. Hence, wesynthesized