Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides Scientific paper

Main Article Content

Deana Andric
https://orcid.org/0000-0002-0753-6516
Sladjana Dukić-Stefanovic
Mihajlo Krunić
https://orcid.org/0000-0001-5779-6618
Ivana Jevtić
https://orcid.org/0000-0002-7653-2420
Jelena Penjisevic
https://orcid.org/0000-0002-3374-1193
Vladimir Sukalovic
Sladjana Kostic-Rajacic
https://orcid.org/0000-0003-0777-3076

Abstract

Serotonin, or 5-hydroxytryptamine (5-HT), is a biogenic amine most noted as a neurotransmitter, an activator of the utmost subtype family of G-pro-tein-coupled receptors (GPCR). Drugs targeting 5-HT1A and other 5-HT rec­eptors treat central nervous system diseases such as schizophrenia and depress­ion. Recent advances in serotonin receptor structure research gave us several crystal 5-HT1A receptor structures, most notably 5-HT1A bound to the anti­psychotic drug aripiprazole (Abilify®). This discovery prompted us to evaluate a series of newly synthesized ligands for serotonergic activity since those aryl­piperazine derivatives share minimal general structure with aripiprazole. The results of molecular docking analysis of unsubstituted starting substances encouraged us to propound further modifications of the tail and head parts of the parent molecules to maximize receptor binding affinity. Intrigued by the results of molecular analysis, all foreseen derivatives were synthesized. The pharmacological activity of all nine (5a and 6a are synthesized previously) compounds was assessed by the in vitro tests and in silico pharmacokinetics predictions for the most promising candidates. All tested ligands have imp­roved affinity compering to parent compounds (10a and 11a), 8b and 9b exp­ressed the best pharmacological profile with an improved binding affinity toward serotonin 5-HT1A receptors (Ki 12.1 and 4.8 nM, respectively).

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Article Details

How to Cite
[1]
D. Andric, “Synthesis, computational and pharmacological evaluation of novel N-{4-[2-(4-aryl-piperazin-1-yl)ethyl]phenyl}-arylamides: Scientific paper”, J. Serb. Chem. Soc., vol. 89, no. 3, pp. 291–303, Apr. 2024.
Section
Organic Chemistry

Funding data

References

D. Hoyer, J. P. Hannon, G. R. Martin, Pharmacol. Biochem. Behav. 71 (2002) 533 (https://doi.org/10.1016/s0091-3057(01)00746-8)

P. M. Whitaker-Azmitia, Neuropsychopharmacology 21 (1999) 2S (https://doi.org/10.1016/S0893-133X(99)00031-7)

E. Lacivita, P. Di Pilato, P. De Giorgio, N. A. Colabufo, F. Berardi, R. Perrone, M. Leopoldo, Expert Opin. Ther. Pat. 22 (2012) 887 (https://doi.org/10.1517/13543776.2012.703654)

I. Malík, J. Csöllei, J. Jampílek, L. Stanzel, I. Zadražilová, J. Hošek, Š. Pospíšilová, A. Čížek, A. Coffey, Molecules 21 (2016) 1274 (https://doi.org/10.3390/molecules21101274)

Y. Chu, B. Raja Sekhara Reddy, V. Pratap Reddy Gajulapalli, K. Sudhakar Babu, E. Kim, S. Lee, Bioorg. Med. Chem. Lett. 30 (2020) 127613 (https://doi.org/10.1016/j.bmcl.2020.127613)

C. Wang, Z. Wang, M. Gao, Y. Li, Y. Zhang, K. Bao, Y. Wu, Q. Guan, D. Zuo, W. Zhang, Bioorg. Chem. 106 (2021) 104199 (https://doi.org/10.1016/j.bioorg.2020.104199)

R. O. Silva, A. S. de Oliveira, L. F. Nunes Lemesde, L. Camargo Nascente, P. Coelho do Nascimento Nogueira, E. R. Silveira, G. D. Brand, G. Vistoli, A. Cilia, E. Poggesi, M. Buccioni, G. Marucci, M. L. Bolognesi, L. A. S. Romeiro, Eur. J. Med. Chem. 122 (2016) 601 (https://doi.org/10.1016/j.ejmech.2016.06.052)

R. R. Kumar, B. Sahu, S. Pathania, P. K. Singh, M. J. Akhtar, B. Kumar, ChemMedChem 16 (2021) 1878 (https://doi.org/10.1002/cmdc.202100045)

J. Staroń, R. Bugno, A. S. Hogendorf, A. J. Bojarski, Expert Opin. Ther. Pat. 28 (2018) 679 (https://doi.org/10.1080/13543776.2018.1514011)

P. Zaręba, P. Śliwa, G. Satała, P. Zajdel, G. Latacz, J. Jaśkowska, Eur. J. Med. Chem. 235 (2022) 114319 (https://doi.org/10.1016/j.ejmech.2022.114319)

K. Ostrowska, K. Młodzikowska, M. Głuch-Lutwin, A. Gryboś, A., Siwek, Eur. J. Med. Chem. 137 (2017) 108 (https://doi.org/10.1016/j.ejmech.2017.05.047)

E. Pindelska, M. A. Mogilnicki, J. Jaśkowska, I. D. Madura, Cryst. Growth Des. (2023) (https://doi.org/10.1021/acs.cgd.3c00438)

P. Kowalski, J. Jaśkowska, A. J. Bojarski, B. Duszyńska, A. Bucki, M. Kołaczkowski, J. Heterocyclic Chem. 48 (2011) 192 (https://doi.org/10.1002/jhet.526)

V. Sukalovic, A. E. Bogdan, G. Tovilovic, D. Ignjatovic, D. Andric, S. Kostic-Rajacic, V. Soskic, Arch. Pharm. Chem. Life Sci. 346 (2013) 708 (https://doi.org/10.1002/ardp.201300189)

J. Z. Penjišević, V. B. Šukalović, S. Dukic-Stefanovic, W. Deuther-Conrad, D. B. Andrić, S. V. Kostić -Rajačić, Arab. J. Chem. 16 (2023) 104636 (https://doi.org/10.1016/j.arabjc.2023.104636)

G. Tovilovic, N. Zogovic, L. Harhaji-Trajkovic, M. Misirkic-Marjanovic, K. Janjetovic, L. Vucicevic, S. Kostic-Rajacic, A. Schrattenholz, A. Isakovic, V. Soskic, V. Trajkovic, ChemMedChem 7 (2012) 495 (https://doi.org/10.1002/cmdc.201100537)

A. Daina, O. Michielin, V. Zoete, Sci. Rep. 7 (2017) 42717 (https://doi.org/10.1038/srep42717)

M. N. Drwal, P. Banerjee, M. Dunkel, M. R. Wettig, R. Preissner, Nucleic Acids Res. 42 (2014) W53 (https://doi.org/10.1093/nar/gku401)

Schrödinger Release 2018-4, Maestro, Schrödinger, LLC, New York, NY, 2018

P. Xu, S. Huang, H. Zhang, C. Mao, X. E. Zhou, X. Cheng, I. A. Simon, D-D. Shen, H-Y. Yen, C. V. Robinson, K. Harpsøe, B. Svensson, J. Guo, H. Jiang, D. E. Gloriam, K. Melcher, Y. Jiang, Y. Zhang, H. E. Xu, Nature 592 (2021) 469 (https://doi.org/10.1038/s41586-021-03376-8)

W. Sherman, H. S. Beard, R. Farid, Chem. Biol. Drug Des. 67 (2006) 83 (https://doi.org/10.1111/j.1747-0285.2005.00327.x)

D. A. Shapiro, S. Renock, E. Arrington, L. A. Chiodo, L-X. Liu, D. R. Sibley, B. L. Roth, R. Mailman, Neuropsychopharmacology 28 (2003) 1400 (https://doi.org/10.1038/sj.npp.1300203)

M. Sencanski, V. Sukalovic, K. Shakib, V. Soskic, L. Dosen-Micovic, S. Kostic-Rajacic, Chem. Biol. Drug. Des. 83 (2014) 462 (https://doi.org/10.1111/cbdd.12261).