Vol. 27, No. 10 (2015)
Synthesis and Biological Evaluation of 1,2,3,4-Tetrahydroisoquinolines Derivatives 3653
(C=O),1273.42 (C-N).1H NMR (CDCl3, 400 MHz): 1.44-1.68
( m, 20H, CH2), 2.38 (d, 2H, COCH), 2.81 (t,2H, CH2N), 3.53-
3.74 (t, 2H, CH2N), 3.75 ( t, 2H, CH2N), 5.5 (t, 1H, CHN),
7.03-7.07 ( m, 4H, ArH), 8.0 (t, 1H, NH).
The inhibitory monoamine oxidase activity of compounds
6a-h was evaluated in vitro by the measurement of their
inhibitions of MAO-A and MAO-B.
Then, the IC50 values and MAO-B selectivity ratios [IC50
(MAO-B)]/ [IC50 (MAO-A)] for inhibitory effects of both,
new compounds and reference inhibitor, were calculated
(Table-1).
Compound 6e: m.p.: 112-113 °C. IR (KBr, νmax, cm–1):
3372.89, 3216.96 (N-H); 3054.19 (ArH ),2917.64 (CH2)
1672.57 (C=O). 1H NMR (CDCl3, 400 MHz): 1.16-1.84 (m,
10H, CH2), 2.73-2.83 (d, 2H, COCH), 3.23-3.63 (t, 2H, CH2N),
3.75 (t, 2H, CH2N), 5.5 (t, 1H, CHN), 7.03-7.07 (m, 4H,ArH),
8.0 (t, 1H, NH).
The prepared series of compounds proved to be selective
as inhibitor of the MAO-A and MAO-B. Acetyl analog 6a-b
neither improved MAO-B inhibitory potency nor enhanced
selectivity against MAO-A. Substitution with methylsulfonyl
or cyclohexaneformyl (6c-e) gave less active compounds.
Compound 6f, none substituted in the R2-positions, is by itself
very active and selective against MAO-B. Compound 6g, with
propynyl and allyl groups, is more active than 6f (none
substituted in the R2-positions) but it also selective against
MAO-B. The most potent molecule of this family is compound
6h, This one with two propynyl groups is the most active and
selective inhibitor of MAO-B than others.
This inhibitor of MAO-B selectivity is an important factor
to discriminate the potential therapeutic application of this kind
of molecules. Comparing the inhibit MAO-B activities of 6f
and 6g, the introduction of propynyl group increases the
inhibitory activity. Substitution with two propynyl groups in
the R1- and R2-positions, compound 6h, improves the inhibit
MAO-B activity. The presence of propynyl substituent in the
R1- and R2-positions seems to be important to modulate and
improve the inhibitory enzymatic activity of the 1-amino-
methyl-1,2,3,4-tetrahydroisoquinoline.
Compound 6f: m.p.: 152-156 °C. IR (KBr, νmax, cm–1):
3291.28 (N-H); 3014.19 (ArH), 2918.64 (CH2).1H NMR
(CDCl3, 400 MHz): 1.82-1.84 ( s, 1H, CH), 2.54-3.23 (d, 8H,
CH2), 5.2 (t, 1H, CHN),7.03-7.07 (m, 4H, ArH).
Compound 6g: m.p.: 173-176 °C. IR (KBr, νmax, cm–1):
3285.46, (N-H); 3028.23 (ArH), 2922.53 (CH2). 1H NMR
(CDCl3, 400 MHz): 1.85-1.88 ( s,1H, CH), 2.53-3.43 (d,10H,
CH2), 5.2 (t, 1H, CHN), 5.5-5.8 (m, 3H, CH),7.05-7.13 ( m,4H,
ArH).
Compound 6h: m.p.: 144-146 °C. IR (KBr, νmax, cm–1):
3291.28, (N-H); 3031.15 (ArH), 2917.76 (CH2).1H NMR
(CDCl3, 400 MHz): 1.82-1.92 ( m, 2H, CH), 2.51-3.29 (d,10H,
CH2), 5.3 (t, 1H, CHN),7.05-7.08 (m,4H, ArH).
RESULTS AND DISCUSSION
With the aim of finding out new structural features for
the monoamine oxidase inhibitory activity and selectivity, we
decided in this work to explore the importance of the number
and position of different groups under the 1,2,3,4-tetrahydro-
isoquinoline in 1-aminomethyl-position, to establish a relation
between them and with the substituted analogue.
Conclusion
In conclusion, a series of 1-aminomethyl-1,2,3,4-tetra-
hydroisoquinoline derivatives was synthesized and found to
have inhibitory activities against MAO-A and MAO-B.
Compound 6h showed good in vitro activities and moderate
selectivity. Further studies are underway to optimize this class
of compounds for the treatment of the Parkinson’s disease.
The preparation of these 1-aminomethyl-1,2,3,4-tetra-
hydroisoquinoline was performed via the classical Gabriel
reaction and Bischler-Napieralski reaction. First of all,
phenylethylamine (1) reacted with chloroacetyl chloride and
potassium phthalimide to give compound 3, then dehydration
cyclization and followed by reduction of the compound 4
afforded the key intermediates 5. The key intermediate 5 was
acylated to the derivatives 6a-h. This cyclization reaction was
carried out by P2O5 as dehydrating agent, under acetonitrile reflux,
during 5 h. The reaction to obtain compound 4 is very simple
and the yields are 85 %. The synthesis of the key intermediates 5
was accomplished in one-pot and the yields are 70 %.
ACKNOWLEDGEMENTS
This work was supported by Natural Science Foundation
(81172097). Thanks are also due toChongqing Medical University
for partial financial support.
TABLE-1
MAO-A AND MAO-B INHIBITORY ACTIVITY RESULTS FOR COMPOUNDS 6a-h AND REFERENCE COMPOUNDS
IC50a (µM)
Compound
R1
R2
Ratiob
MAO-A
76.670
59.541
103.739
50.866
*
MAO-B
257.447
*
291.037
424.237
1167.665
394.088
167.545
92.399
0.566
6a
6b
6c
6d
6e
6f
6g
CH3CO
ClCH2CO
CH3O2S
C6H11CO
H
CH3CO
ClCH2CO
CH3O2S
C6H11CO
C6H11CO
H
3.36
–
2.81
8.34
–
*
–
HC≡CCH2
HC≡CCH2
HC≡CCH2
*
–
H2C=CHCH2
HC≡CCH2
6h
39.773
1.296
2.32
0.44
Rasagiline
*Inactive at highest concentration tested; aAverage values (at least two experiments); bRatio = MAO-B IC50/MAO-A IC50