Synthesis and pharmacological evaluation of N-{4-[2-

(4-arylpiperazin-1-yl) ethyl] phenyl}arylamides

J. Penjišević , D. Andrić , S. Dukić-Stefanović , T. Spalholz , P. Brust and S. Kostić-Rajačić
1 2 3 3 3 1

1
Department of Chemistry, ICTM, University of Belgrade, Njegoševa 12 11000 Belgrade, Serbia
2
Department of Organic chemistry, Faculty of chemistry, University of Belgrade, Studentski Trg 12-16 11000 Belgrade, Serbia
3
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum ,
Dresden-Rossendorf, Permoserstraße 15 04318 Leipzig, Germany

Introduction

Serotonin 5HT1a receptor belongs to a class of G-protein coupled receptors. It serves

as a potential target in the treatment of neurological disorders such as depression. It is
a well-known fact that N-arylpiperazine moiety is present in compounds with
pronounced 5HT1a activity. Based on our previous investigation, seven novel N-{4-[2-
(4-arylpiperazin-1-yl)ethyl]phenyl}arylamides (Table 1.) were designed and
synthesized.1 Performed modifications include: different position of hydroxyl group in
aryl amide part of molecule and addition of methoxy and chloro substituents to the
phenyl ring of parent compounds.

Result and discussion

Synthetic route and reaction conditions of newly synthesised N-{4-[2-(4-arylpiperazin-1-

Homology model of 5HT1a receptor
based on 5HT1b crystal structure.
yl)ethyl]phenyl}arylamides is sumarized in Scheme 1.
New compounds were synthesized by acylation of N-arylpiperazines using 4-nitrophenylacetic acid (1).
Obtained amides were converted in 1-(4-nitrophenethyl)-4-arylpiperazines (3a,b) using diborane in THF.
Reduction of nitro compounds by Ra/Ni provided 1-(4-aminophenethyl)-4-arylpiperazines (4a,b). Target
arylamides (5a-g) were obtained by condensation 1-(4-aminophenethyl)-4-arylpiperazines (4a,b) with
corresponding aryl acids in presence of propylphosphoric acid anhydride (PPAA) in DMF.
All newly synthesized compounds Table 1. were evaluated for their activity toward 5HT1a receptors by in
vitro competitive displacement assay with [3H] 8-OH-DPAT on h5-HT1a-HEK cell homogenate 5HT1a
receptors.1

No. Structure Ki ± S.E.M

NO2 NO2 (nM)
CO2H O O

17.8±1.4
N
N N N

5a
H

Cl Cl

N N
a b O

5b 44.9±2.8
N N N N

N
H

N
Ar
Cl Cl

O2N Ar O

1 2 a,b 3a,b 5c
N

N
N
H
N N
16.3±1.5
Cl Cl

H 5d
N
N
H
N N
12.7±1.9
NH2 N R N
Cl Cl

5e
HO N N

12.8±1.2
O
HN

d
Cl Cl

c N N HO

12.0±0.9
O

5f
N N

N N
HN

H3CO

Ar Ar O

4 a,b 5 a-g 5g
HO

HN
N N

H3CO
4.8±0.2

Scheme 1. Synthetic route and chemical structures of the arylpiperazine serotonergic ligands: a) Arylpiperazine, PPAA, DMF, rt; Table 1. Structure of N-{4-[2-(4-arylpiperazin-1-yl)ethyl]phenyl}arylamides
b) B2H6 THF, 0°C, for 6h, rt for 1h, then reflux for 2h; c) NH4CHO2, 10% Pd/C, MeOH; d) RCO2H, PPAA, DMF, rt. tested for their binding activity toward 5Ht1a receptors.

Conclusion

Introduction of 2-methoxy and 2,3-dichloro groups, as well as meta and para hydroxyl group in molecule resulted in increment of affinity toward 5HT1a
receptors comparing to the parent compounds .

Authors acknowledge the Ministry of Education, Science and Technological Development of the Republic of Serbia for financial support, grant No. 172032.
1. Vladimir Sukalovic, Anca Elena Bogdan, Gordana Tovilovic, Djurdjica Ignjatovic, Deana Andric, Sladjana Kostic-Rajacic, and Vukic Soskic, Arch. Pharm. Chem. Life Sci, 2013, 346, 708-717

Email address: jelena.penjisevic@ihtm.bg.ac.rs