708
A. Gaspar et al. / Bioorg. Med. Chem. Lett. 21 (2011) 707–709
Table 1
O
O
COOH
O
CONHR
hMAO-A and hMAO-B inhibitory activity results for compounds 2–6, 8–12 and
reference compounds
a)
Compound
hMAO-A IC50
(
lM)
hMAO-B IC50
(
lM)
SI
O
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
2 R = Ph
—
—
—
—
3 R = (40-I-Ph)
4 R = (40-OCH3-Ph)
5 R = (40-SCH3-Ph)
6 R = (40-CH3-Ph)
8 R = Ph
(1)
2
3
4
5
6
R= Ph
R=(4'-I-Ph)
R=(4'-OCH3-Ph)
R=(4'-SCH3-Ph)
R=(4'-CH3-Ph)
—
0.40 0.022
0.069 0.003
0.45 0.029
0.12 0.0080
0.068 0.003
0.017 0.002
7.54 0.36
>250c
>1449c
>222c
>833c
>1471c
4043
0.87
9 R = (40-I-Ph)
10 R = (40OCH3-Ph)
11 R = (40SCH3-Ph)
12 R = (40-CH3-Ph)
Deprenyl
O
O
68.73 4.21b
6.56 0.76
a)
Iproniazide
CONHR
COOH
a
Inactive at 100 lM (highest concentration tested). At higher concentrations the
O
O
compounds precipitate.
b
P <0.01 versus the corresponding IC50 values obtained against hMAO-B, as
(7)
8
9
R= Ph
R (4'-I-Ph)
determined by ANOVA/Dunnett’s.
=
c
Values obtained under the assumption that the corresponding IC50 against
10 R=(4'-OCH3-Ph)
11 R=(4'-SCH3-Ph)
12 R=(4'-CH3-Ph)
hMAO-A is the highest concentration tested (100 lM).
to compounds 8 and 10. From the overall data it was concluded that
the positive hydrophobicity (+ ) of the substituent, besides induc-
tive and mesomeric effects, located on the phenyl exocyclic moiety
markedly influence the potency and selectivity of the chromone
carboxamides.
Noteworthy to mark out that the chromones bearing the same
type of substituents in position 2 of c-pyrone nucleus (chromones
Scheme 1. Structure of the chromones understudy. Reagents and conditions: (a) BOP
or PyBOP, R-C6H4–NH2, CH2Cl2, DMF, DIPEA.
p
type of substituents in para-position of the exocyclic aromatic
nucleus (Scheme 1) were obtained by an expedite synthetic strat-
egy and screened towards human MAO isoforms (hMAO) to evalu-
ate their potency/selectivity ratio.
2–6) present a total loss of MAO activity.
Preliminary studies on the type of hMAO inhibition were per-
formed revealing that chromone 3-phenylcarboxamides behave
as quasi-reversible MAO-B inhibitors (data not shown).
The chromone derivatives 2–6 and 8–12 were efficiently syn-
thesized according to the synthetic protocol outlined in Scheme
1.9 Chromone carboxamide derivatives were synthesized straight-
forward by a one-pot condensation reaction that occurs, in equi-
molar amounts, between the corresponding chromone carboxylic
acid (compound 1 or 7) and aniline or its ring-substituted deriva-
tives. The reaction was clean and the compounds were obtained
with moderate/high yields (50%–80%). After the reaction, the crude
products were purified by flash column chromatography and
crystallization.
The MAO inhibitory activity of compounds 2–6 and 8–12 was
evaluated in vitro by the measurement of the enzymatic activity
of human recombinant MAO isoforms in BTI insect cells infected
with baculovirus.10 Then, the IC50 values and MAO-B selectivity ra-
tios (SI) [IC50 (MAO-A)]/[IC50 (MAO-B)] for inhibitory effects of
both new compounds and reference compounds (R-(ꢀ)-deprenyl
and iproniazide) were calculated.
In the present Letter, the effect of the introduction of a methyl or
iodo substituent in para-position of the exocyclic aromatic ring of
chromone 3-phenylcarboxamides was outlined. In fact, the intro-
duction of this type of groups improves the pharmacologic potential
of chromone 3-phenylcarboxamides confirming that this lead could
be effectively optimized in a candidate for the treatment of neurode-
generative diseases. These findings have encouraged us to continue
the efforts towards the optimization of the lead compound.
In conclusion chromone appears to be an interesting scaffold for
the design of selective IMAO. The easy synthetic accessibility and
especially the versatile binding properties of chromones make
them as ‘privileged’ scaffolds. These discoveries open a new avenue
to obtain highly potent and selective MAO-B inhibitors structurally
based on chromone scaffold.
The results of the inhibitory potencies and selectivities of the
chromones under study towards MAO isoforms, and reference com-
pounds, are depicted in Table 1. From the data one can conclude that
Acknowledgements
The authors acknowledge Portuguese Fundação para a Ciência e
a Tecnologia (FCT) for financial support (project PTDC/QUI/70359/
2006) and AG doctoral grant (SFRH/BD/43531/2008).
‘chromones bearing carboxamide substituents in position 3 of the c-
pyrone nucleus’ act preferably as MAO-B inhibitors (IMAO-B) with
IC50 values in micro to nanomolar range (8–12). The same tendency
was found with the chromone carboxylic acids.8 In addition, one can
conclude that the type of substituents in the para-position of the
exocyclic aromatic ring can modulate the affinity and selectivity of
the chromones-3-carboxamides as IMAO-B. The introduction of a
methoxyl group (10) seems to have no effect in IMAO-B potency
whencomparedwith theactivityfound forcompound(8). Neverthe-
less it is important to point out that the introduction of a thiomethyl
group (11), a bioisostere of the methoxyl function, has improved the
potency of the compound 3–4-fold relatively to the compounds 8
and 10. The most promissory compounds as IMAO-B, with an IC50
<75 nm and a SI of >1440, are the compounds 9 and 12, which are
substituted in para-position by iodo and methyl groups, respec-
tively, representing an improvement of potency of six fold relatively
References and notes
1. Foley, P.; Gerlach, M.; Youdim, M. B. H.; Riederer, P. Parkinsonism Relat. Disord.
2000, 6, 25.
2. Rezak, M. Dis. Mon. 2007, 53, 214.
3. Riederer, P.; Lachenmayer, L.; Laux, G. Curr. Med. Chem. 2004, 11, 2033.
4. The Chemistry of Heterocyclic Compounds, Chromenes, Chromanones and
Chromones; Ellis, G. P., Ed.; J. Wiley and Sons: New York, 2007; Vol. 31,.
5. Shaw, A. Y.; Chang, C. Y.; Liau, H. H.; Lu, P. J.; Chen, H. L.; Yang, C. N.; Li, H. Y. Eur.
J. Med. Chem. 2009, 44, 2552.
6. (a) Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem.
2005, 12, 887; (b) Matos, M. J.; Viña, D.; Janeiro, P.; Borges, F.; Santana, L.;
Uriarte, E. Bioorg. Med. Chem. Lett. 2010, 20, 5157.
7. Brühlmann, C.; Ooms, F.; Carrupt, P. A.; Testa, B.; Catto, M.; Leonetti, F.;
Altomare, C.; Carotti, A. J. Med. Chem. 2001, 44, 3195.