Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Aug 6;29(16):3723.
doi: 10.3390/molecules29163723.

Chain Extension of Piperazine in Ethanol: Synthesis of 2-(4-(2-(Phenylthio)ethyl)piperazinyl)acetonitriles and ACAT-1 Inhibitors

Ying Huang  1   2   3 , Tingyu Zhu  1   2   3 , Yinghua Li  1 , Deguang Huang  1
Affiliations

Chain Extension of Piperazine in Ethanol: Synthesis of 2-(4-(2-(Phenylthio)ethyl)piperazinyl)acetonitriles and ACAT-1 Inhibitors

Ying Huang et al. Molecules. .

Abstract

A base-induced synthesis of 2-(4-(2-(phenylthio)ethyl)piperazinyl) acetonitriles by reaction of disulfides, 1-(chloromethyl)-4-aza-1-azonia bicyclo[2.2.2]octane chloride and trimethylsilyl cyanide is reported. The scope of the method is demonstrated with 30 examples. The reaction mechanism research indicates that the three-component reaction would be a SN2 reaction. The products exhibit good activities towards advanced synthesis of aqueous soluble acyl-CoA: cholesterol O-acyltransferase-1 (ACAT-1) inhibitors. Our work is superior as it uses less-odor disulfides as carbon sources and EtOH as solvent in a water and dioxygen insensitive reaction system, followed by a simple purification process.

Keywords: ACAT-1 inhibitors; catalyst-free reaction; green solvent; medicinal chemistry; sulfur-containing ethyl piperazine.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Representative bioactive sulfur-containing ethyl piperazine compounds (a) [23], (b) [6], (c) [1], and (d) [8,20].
Scheme 1
Scheme 1
Different strategies (a) [8,19,20,21,22], (b) [23,24,25], and (c) [26,27,28,29] to synthesize sulfur-containing ethyl piperazine compounds.
Scheme 2
Scheme 2
Different strategies (route 1 [8]; route 2 [20,30,31,32]) to synthesize the ACAT-1 inhibitor [K-604].
Figure 2
Figure 2
Scope of disulfides with respect to compounds 2 a,b; a Reaction conditions: 1 (0.1 mmol), CAABC (0.2 mmol), TMSCN (0.22 mmol), Cs2CO3 (0.6 mmol), EtOH (1 mL), air, 100 °C, 3 h, isolated yields. b Reactions were conducted using 2-mercaptobenzoxazole (0.2 mmol) and 2-mercapto benzimidazole (0.2 mmol) as substrates.
Scheme 3
Scheme 3
Control experiments: (a) Study the influence of O2 on the yield; (b) Examine the reaction using thiophene as the thiolate source; (c) Examine the reaction in the absence of TMSCN; (d) Examine the reaction by the replacement of CAABC with CYAABC; (e) Examine the reaction by the replacement of CAABC with DABCO; (f) Examine the reaction by the replacement of CAABC with EAABB; (g) Check the standard reaction without the presence of PhSSPh.
Scheme 4
Scheme 4
Proposed reaction mechanism.
Scheme 5
Scheme 5
Exploration of the synthesis of ACAT-1 inhibitors 5a and 5b: (a) Our method 1 to prepare [K-604]; (b) Our method 2 to prepare [K-604].
Figure 3
Figure 3
Crystal structures of compounds 2b (CCDC 2328305), 2ab (CCDC 2328309), 3b (CCDC 2328313), 4b (CCDC 2328311) and 5a showing thermal ellipsoids of 50% probability surfaces. The structure of 5a was solved by fast-data collection with the crystallographic data shown in Supplementary Materials.
See this image and copyright information in PMC

References

    1. Tomass S.I., Pfahler J., Mautone N., Rovere A., Esposito C., Passeri D., Pellicciari R., Novellino E., Pannek M., Steegborn C., et al. Synthesis and Evaluation of Cyclic Secondary Amine Substituted Phenyl and Benzyl Ni-trofuranyl Amides as Novel Antituberculosis Agents. ACS Med. Chem. Lett. 2020;11:862–868. - PMC - PubMed
    1. Geng F., Cheng X., Wu X., Yoo J.Y., Cheng C., Guo J.Y., Mo X., Ru P., Hurwitz B., Kim S.-H., et al. Inhibition of SOAT1 Suppresses Glioblastoma Growth via Blocking SREBP-1-Mediated Lipogenesis. Clin. Cancer Res. 2016;22:5337–5348. doi: 10.1158/1078-0432.CCR-15-2973. - DOI - PMC - PubMed
    1. Ohmoto T., Nishitsuji K., Yoshitani N., Mizuguchi M., Yanagisawa Y., Saito H., Sakashita N. K604, a Specific Acyl-CoA: Cholesterol Acyltrans-ferase 1 Inhibitor, Suppresses Proliferation of U251-MG Glio-blastoma Cells. Mol. Med. Rep. 2015;12:6037–6042. doi: 10.3892/mmr.2015.4200. - DOI - PubMed
    1. Yang W., Bai Y., Xiong Y., Zhang J., Chen S., Zheng X., Meng X., Li L., Wang J., Xu C., et al. Potentiating the Antitumour Response of CD8+T Cells by Modulating Cholesterol Metabolism. Nature. 2016;531:651–655. doi: 10.1038/nature17412. - DOI - PMC - PubMed
    1. Ballet S., Mauborgne A., Bourgoin S., Caussade F., Cloarec A., Hamon M., Cesselin F., Collin E. Effects of the Analgesic Drug up 26-91 on the in vivo Release of Substance P and Cal-citonin Gene-Related Peptide from the Rat Spinal Cord. Fundam. Clin. Pharmacol. 1997;11:151–199.

LinkOut - more resources