Design, Synthesis and Biological Evaluation of Novel N-Arylpiperazines Containing a 4,5-Dihydrothiazole Ring

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2023 Oct 28

PMID 37895954

Authors

Giorgia Andreozzi

Maria Rosaria Ambrosio

Elisa Magli

Giovanni Maneli

Beatrice Severino

Angela Corvino

Rosa Sparaco

Elisa Perissutti

Francesco Frecentese

Vincenzo Santagada

Anna Lesniak

Magdalena Bujalska-Zadrozny

Giuseppe Caliendo

Pietro Formisano

Ferdinando Fiorino

Affiliations

Soon will be listed here.

Abstract

Arylpiperazines represent one of the most important classes of 5-HTR ligands and have attracted considerable interests for their versatile properties in chemistry and pharmacology, leading to the research of new derivatives that has been focused on the modification of one or more portions of such pharmacophore. An efficient protocol for the synthesis of novel thiazolinylphenyl-piperazines (-) and the corresponding acetylated derivatives was used (-). The new compounds were tested for their functional activity and affinity at 5-HT receptors, showing an interesting affinity profile with a Ki value of 412 nM for compound . The cytotoxic activity of novel thiazolinylphenyl-piperazines (-) and corresponding N-acetyl derivatives (-) against human prostate and breast cancer cell lines (LNCAP, DU-145 and PC-3, MCF-7, SKBR-3 and MDA-MB231) was investigated according to the procedure described in the literature. The reported data showed a cytotoxic effect for - and - compounds (IC values ranging from 15 µM to 73 µM) on the investigated cancer cell lines, with no effect on noncancer cells. Future studies will be aimed to investigate the mechanism of action and therapeutic prospects of these new scaffolds.

Citing Articles

Arylpiperazine Derivatives and Cancer: A New Challenge in Medicinal Chemistry.

Andreozzi G, Corvino A, Severino B, Magli E, Perissutti E, Frecentese F Pharmaceuticals (Basel). 2024; 17(10).

PMID: 39458961 PMC: 11510360. DOI: 10.3390/ph17101320.

References

Fiorino F, Magli E, Perissutti E, Severino B, Frecentese F, Esposito A . Synthesis of 1-naphtylpiperazine derivatives as serotoninergic ligands and their evaluation as antiproliferative agents. Eur J Med Chem. 2011; 46(6):2206-16. DOI: 10.1016/j.ejmech.2011.03.001. View

Leon-Gonzalez A, Saez-Martinez P, Jimenez-Vacas J, Herrero-Aguayo V, Montero-Hidalgo A, Gomez-Gomez E . Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells. Antioxidants (Basel). 2021; 10(9). PMC: 8464900. DOI: 10.3390/antiox10091348. View

Fiorino F, Severino B, De Angelis F, Perissutti E, Frecentese F, Massarelli P . Synthesis and in-vitro pharmacological evaluation of new 5-HT1A receptor ligands containing a benzotriazinone nucleus. Arch Pharm (Weinheim). 2007; 341(1):20-7. DOI: 10.1002/ardp.200700151. View

Perez-Lloret S, Rascol O . Piribedil for the Treatment of Motor and Non-motor Symptoms of Parkinson Disease. CNS Drugs. 2016; 30(8):703-17. DOI: 10.1007/s40263-016-0360-5. View

Del Bello F, Bonifazi A, Giorgioni G, Quaglia W, Amantini C, Morelli M . Chemical manipulations on the 1,4-dioxane ring of 5-HT receptor agonists lead to antagonists endowed with antitumor activity in prostate cancer cells. Eur J Med Chem. 2019; 168:461-473. DOI: 10.1016/j.ejmech.2019.02.056. View

Fiorino F, Magli E, Severino B, Corvino A, Ciano A, Perissutti E . Synthesis and in vitro pharmacological evaluation of novel 2-hydroxypropyl-4-arylpiperazine derivatives as serotoninergic ligands. Arch Pharm (Weinheim). 2014; 347(10):698-706. DOI: 10.1002/ardp.201400174. View

Magli E, Kedzierska E, Kaczor A, Severino B, Corvino A, Perissutti E . Synthesis, docking studies, and pharmacological evaluation of 5HT ligands containing the N'-cyanoisonicotinamidine or N'-cyanopicolinamidine nucleus. Arch Pharm (Weinheim). 2019; 352(5):e1800373. DOI: 10.1002/ardp.201800373. View

Ambrosio M, Magli E, Caliendo G, Sparaco R, Massarelli P, DEsposito V . Serotoninergic receptor ligands improve Tamoxifen effectiveness on breast cancer cells. BMC Cancer. 2022; 22(1):171. PMC: 8845285. DOI: 10.1186/s12885-021-09147-y. View

Kumar B, Kumar N, Thakur A, Kumar V, Kumar R, Kumar V . A Review on the Arylpiperazine Derivatives as Potential Therapeutics for the Treatment of Various Neurological Disorders. Curr Drug Targets. 2022; 23(7):729-751. DOI: 10.2174/1389450123666220117104038. View

10.

Fiorino F, Severino B, De Angelis F, Perissutti E, Magli E, Frecentese F . New 5-HT(1A) receptor ligands containing a N'-cyanoisonicotinamidine nucleus: synthesis and in vitro pharmacological evaluation. Bioorg Med Chem Lett. 2010; 20(9):2978-82. DOI: 10.1016/j.bmcl.2010.02.106. View

11.

Magli E, Kedzierska E, Kaczor A, Bielenica A, Severino B, Gibula-Tarlowska E . Synthesis, docking studies, and pharmacological evaluation of 2-hydroxypropyl-4-arylpiperazine derivatives as serotoninergic ligands. Arch Pharm (Weinheim). 2021; 354(5):e2000414. DOI: 10.1002/ardp.202000414. View

12.

Meltzer H, Massey B . The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol. 2011; 11(1):59-67. DOI: 10.1016/j.coph.2011.02.007. View

13.

Chen H, Xu F, Liang X, Xu B, Yang Z, He X . Design, synthesis and biological evaluation of novel arylpiperazine derivatives on human prostate cancer cell lines. Bioorg Med Chem Lett. 2014; 25(2):285-7. DOI: 10.1016/j.bmcl.2014.11.049. View

14.

Fiorino F, Ciano A, Magli E, Severino B, Corvino A, Perissutti E . Synthesis, in vitro and in vivo pharmacological evaluation of serotoninergic ligands containing an isonicotinic nucleus. Eur J Med Chem. 2016; 110:133-50. DOI: 10.1016/j.ejmech.2016.01.021. View

15.

Fiorino F, Perissutti E, Severino B, Santagada V, Cirillo D, Terracciano S . New 5-hydroxytryptamine(1A) receptor ligands containing a norbornene nucleus: synthesis and in vitro pharmacological evaluation. J Med Chem. 2005; 48(17):5495-503. DOI: 10.1021/jm050246k. View

16.

Fiorino F, Severino B, Magli E, Perissutti E, Frecentese F, Esposito A . New potent 5-HT(2A) receptor ligands containing an N'-cyanopicolinamidine nucleus: Synthesis and in vitro pharmacological evaluation. Eur J Med Chem. 2011; 47(1):520-9. DOI: 10.1016/j.ejmech.2011.11.023. View

17.

Ambrosio M, DEsposito V, Costa V, Liguoro D, Collina F, Cantile M . Glucose impairs tamoxifen responsiveness modulating connective tissue growth factor in breast cancer cells. Oncotarget. 2018; 8(65):109000-109017. PMC: 5752499. DOI: 10.18632/oncotarget.22552. View

18.

Corvino A, Fiorino F, Severino B, Saccone I, Frecentese F, Perissutti E . The Role of 5-HT1A Receptor in Cancer as a New Opportunity in Medicinal Chemistry. Curr Med Chem. 2018; 25(27):3214-3227. DOI: 10.2174/0929867325666180209141650. View

19.

Kumar R, Sahu B, Pathania S, Singh P, Akhtar M, Kumar B . Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure-Activity Relationships. ChemMedChem. 2021; 16(12):1878-1901. DOI: 10.1002/cmdc.202100045. View

20.

Caliendo G, Fiorino F, Grieco P, Perissutti E, Santagada V, Severino B . Synthesis of new 1,2,3-benzotriazin-4-one-arylpiperazine derivatives as 5-HT1A serotonin receptor ligands. Bioorg Med Chem. 2000; 8(3):533-8. DOI: 10.1016/s0968-0896(00)00004-3. View