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  3. Design, synthesis and biological evaluation of novel aminopropylcarboxamide derivatives as sigma ligands

Design, synthesis and biological evaluation of novel aminopropylcarboxamide derivatives as sigma ligands

  • Bioorg Med Chem Lett. 2022 Sep 15:72:128860. doi: 10.1016/j.bmcl.2022.128860.
Daniele Zampieri 1,  Sara Fortuna 2,  Maurizio Romano 3,  Emanuele Amata 4,  Maria Dichiara 4,  Agostino Marrazzo 4,  Lorella Pasquinucci 4,  Rita Turnaturi 4,  Maria Grazia Mamolo 5
Affiliations

Affiliations

  • 1 Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Giorgieri 1, 34127 Trieste, Italy. Electronic address: dzampieri@units.it.
  • 2 Italian Institute of Technology (IIT), Via E. Melen 83, 16152 Genova, Italy.
  • 3 Department of Life Sciences, University of Trieste, Via Valerio 28/1, 34127 Trieste, Italy.
  • 4 Department of Drug and Health Sciences, University of Catania, Viale Doria 6, 95125 Catania, Italy.
  • 5 Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Giorgieri 1, 34127 Trieste, Italy.
PMID: 35724925 DOI: 10.1016/j.bmcl.2022.128860
Abstract

In our continuing effort to develop novel Sigma Receptor (SR) ligands, we present the design, synthesis and binding studies of a small library of aminopropylcarboxamide derivatives, obtained from a deconstruction of the piperidine ring of previously synthesized piperidine-based compounds. The best results were achieved with benzofuran (5c, 5g) and quinoline (5a, 5e) derivatives. These compounds revealed the highest affinity for both receptor subtypes. In particular, the 3,4-dimethoxyphenyl derivatives 5e and 5g showed the highest selectivity profile for S2R, especially the quinoline derivative 5e exhibited a 35-fold higher affinity for S2R subtype. The cytotoxic activity of aforementioned compounds was evaluated against SKBR3 and MCF7 cell lines, widely used for breast Cancer studies. Whereas the potency of 5g was similar that of Siramesine and Haloperidol in both cell lines, compounds 5a, 5c and 5e exhibited a potency at least comparable to that of Haloperidol in SKBR3 cells. A molecular modelling evaluation towards the S2R binding site, confirmed the strong interaction of compound 5e thus justifying its highest S2R affinity.

Keywords

Affinity; Aminopropylcarboxamide; Cytotoxicity; Molecular modelling; Selectivity; Sigma receptor.

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