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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Synthesis and Molecular Modeling of Novel 3,5-Bis(trifluoromethyl) benzylamino Benzamides as Potential CETP Inhibitors

Author(s): Reema Abu Khalaf*, Mohammad Awad, Tariq Al-Qirim and Dima Sabbah

Volume 18, Issue 4, 2022

Published on: 30 August, 2021

Page: [417 - 426] Pages: 10

DOI: 10.2174/1573406417666210830125431

Price: $65

Abstract

Background: There is an alarming spread of cases of lipid disorders in the world that occur due to harmful lifestyle habits, hereditary risk influences, or as a result of other illnesses or medicines. Cholesteryl Ester Transfer Protein (CETP) is a 476-residue lipophilic glycoprotein that helps in the transport of cholesteryl ester and phospholipids from the atheroprotective HDL to the proatherogenic LDL and VLDL. Inhibition of CETP leads to elevation of HDL cholesterol and reduction of LDL cholesterol and triglycerides; therefore, it is considered a good target for the treatment of hyperlipidemia and its comorbidities.

Objective: In this research, synthesis, characterization, molecular modeling, and biological evaluation of eight 3,5-bis(trifluoromethyl)benzylamino benzamides 9a-d and 10a-d were carried out.

Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. They were biologically tested in vitro to estimate their CETP inhibitory activity.

Results: These compounds offered inhibitory effectiveness ranging from 42.2% to 100% at a concentration of 10 μM. Compounds bearing unsubstituted three aromatic rings (9a) or ortho-CF3 substituted (9b) were the most effective compounds among their analogs and showed IC50 values of 1.36 and 0.69 μM, respectively. The high docking scores of 9a-d and 10a-d against 4EWS imply that they might be possible CETP inhibitors. Pharmacophore mapping results demonstrate that the series approves the fingerprint of CETP active inhibitors and therefore explains their high binding affinity against CETP binding site.

Conclusion: This work concludes that 3,5-bis(trifluoromethyl)benzylamino benzamides can serve as a promising CETP inhibitor lead compound.

Keywords: Benzamides, 3, 5-bis(trifluoromethyl)benzylamino, CETP inhibitors, induced-fit docking, pharmacophore, HDL.

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[1]
Dyrbuś, K.; Gąsior, M.; Penson, P.; Ray, K.K.; Banach, M. Inclisiran-New hope in the management of lipid disorders? J. Clin. Lipidol., 2020, 14(1), 16-27.
[http://dx.doi.org/10.1016/j.jacl.2019.11.001] [PMID: 31879073]
[2]
Tirronen, A.; Hokkanen, K.; Vuorio, T.; Ylä-Herttuala, S. Recent advances in novel therapies for lipid disorders. Hum. Mol. Genet., 2019, 28(R1), R49-R54.
[http://dx.doi.org/10.1093/hmg/ddz132] [PMID: 31227825]
[3]
Rader, D.J. New therapeutic approaches to the treatment of dyslipidemia. Cell Metab., 2016, 23(3), 405-412.
[http://dx.doi.org/10.1016/j.cmet.2016.01.005] [PMID: 26853751]
[4]
Martinez-Hervas, S.; Ascaso, J.F. Hypercholesterolemia. 2019.
[5]
Laufs, U.; Parhofer, K.G.; Ginsberg, H.N.; Hegele, R.A. Clinical review on triglycerides. Eur. Heart J., 2020, 41(1), 99-109c.
[http://dx.doi.org/10.1093/eurheartj/ehz785] [PMID: 31764986]
[6]
Kypreos, K.E.; Bitzur, R.; Karavia, E.A.; Xepapadaki, E.; Panayiotakopoulos, G.; Constantinou, C. Pharmacological management of dyslipidemia in atherosclerosis: Limitations, challenges, and new therapeutic opportunities. Angiology, 2019, 70(3), 197-209.
[http://dx.doi.org/10.1177/0003319718779533] [PMID: 29862840]
[7]
Karr, S. Epidemiology and management of hyperlipidemia. Am. J. Manag. Care, 2017, 23(9)(Suppl.), S139-S148.
[PMID: 28978219]
[8]
Semenkovich, C.F.; Goldberg, A.C.; Goldberg, I.J. Disorders of lipid metabolism. Williams textbook of endocrinology, 2016, 1660-1700.
[9]
Pérez-Méndez, Ó.; Pacheco, H.G.; Martínez-Sánchez, C.; Franco, M. HDL-cholesterol in coronary artery disease risk: Function or structure? Clin. Chim. Acta, 2014, 429, 111-122.
[http://dx.doi.org/10.1016/j.cca.2013.12.001] [PMID: 24333390]
[10]
Sirtori, C.R.; Ruscica, M.; Calabresi, L.; Chiesa, G.; Giovannoni, R.; Badimon, J.J. HDL therapy today: From atherosclerosis, to stent compatibility to heart failure. Ann. Med., 2019, 51(7-8), 345-359.
[http://dx.doi.org/10.1080/07853890.2019.1694695] [PMID: 31729238]
[11]
Xepapadaki, E.; Zvintzou, E.; Kalogeropoulou, C.; Filou, S.; Kypreos, K.E. The antioxidant function of HDL in atherosclerosis. Angiology, 2020, 71(2), 112-121.
[http://dx.doi.org/10.1177/0003319719854609] [PMID: 31185723]
[12]
Feingold, K.R.; Grunfeld, C. Introduction to lipids and lipoproteins. Endotext; MDText. com, Inc., 2018.
[13]
Rye, K-A.; Barter, P.J. Cardioprotective functions of HDLs. J. Lipid Res., 2014, 55(2), 168-179.
[http://dx.doi.org/10.1194/jlr.R039297] [PMID: 23812558]
[14]
Zhyvotovska, A.; Yusupov, D.; McFarlane, S.I. Introductory chapter: Overview of lipoprotein metabolism.Dyslipidemia; IntechOpen, 2019.
[15]
Kosmas, C.E.; Dejesus, E.; Rosario, D.; Vittorio, T.J. CETP inhibition: Past failures and future hopes. Clin. Med. Insights Cardiol., 2016, 10, S32667.
[http://dx.doi.org/10.4137/CMC.S32667]
[16]
Wang, X.; Li, W.; Hao, L.; Xie, H.; Hao, C.; Liu, C.; Li, W.; Xiong, X.; Zhao, D. The therapeutic potential of CETP inhibitors: A patent review. Expert Opin. Ther. Pat., 2018, 28(4), 331-340.
[http://dx.doi.org/10.1080/13543776.2018.1439476] [PMID: 29424255]
[17]
Chen, S-Y.; Li, N.; Jin, T-L.; Gou, L.; Hao, D-X.; Tian, Z-Q. Lipoprotein in cholesterol transport: Highlights and recent insights into its structural basis and functional mechanism. Chin. Phys. B, 2018, 27(2), 028702.
[http://dx.doi.org/10.1088/1674-1056/27/2/028702]
[18]
Lauer, M.E.; Graff-Meyer, A.; Rufer, A.C.; Maugeais, C.; von der Mark, E.; Matile, H.; D’Arcy, B.; Magg, C.; Ringler, P.; Müller, S.A.; Scherer, S.; Dernick, G.; Thoma, R.; Hennig, M.; Niesor, E.J.; Stahlberg, H. Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP. J. Struct. Biol., 2016, 194(2), 191-198.
[http://dx.doi.org/10.1016/j.jsb.2016.02.016] [PMID: 26876146]
[19]
Yamashita, S.; Ruscica, M.; Macchi, C.; Corsini, A.; Matsuzawa, Y.; Sirtori, C.R. Cholesteryl ester transfer protein: An enigmatic pharmacology - Antagonists and agonists. Atherosclerosis, 2018, 278, 286-298.
[http://dx.doi.org/10.1016/j.atherosclerosis.2018.09.035] [PMID: 30347344]
[20]
Nicholls, S.J. CETP-inhibition and hdl-cholesterol: A story of cv risk or cv benefit, or both. Clin. Pharmacol. Ther., 2018, 104(2), 297-300.
[http://dx.doi.org/10.1002/cpt.1118] [PMID: 29901215]
[21]
Bowman, L.; Hopewell, J.; Chen, F.; Wallendszus, K.; Stevens, W. Effects of anacetrapib in patients with atherosclerotic vascular disease. J. Vasc. Surg., 2018, 67(1), 356.
[http://dx.doi.org/10.1016/j.jvs.2017.11.029]
[22]
Bowman, L.; Hopewell, J.C.; Chen, F.; Wallendszus, K.; Stevens, W.; Collins, R.; Wiviott, S.D.; Cannon, C.P.; Braunwald, E.; Sammons, E.; Landray, M.J. Effects of anacetrapib in patients with atherosclerotic vascular disease. N. Engl. J. Med., 2017, 377(13), 1217-1227.
[http://dx.doi.org/10.1056/NEJMoa1706444] [PMID: 28847206]
[23]
Simic, B.; Mocharla, P.; Crucet, M.; Osto, E.; Kratzer, A.; Stivala, S.; Kühnast, S.; Speer, T.; Doycheva, P.; Princen, H.M.; van der Hoorn, J.W.; Jukema, J.W.; Giral, H.; Tailleux, A.; Landmesser, U.; Staels, B.; Lüscher, T.F. Anacetrapib, but not evacetrapib, impairs endothelial function in CETP-transgenic mice in spite of marked HDL-C increase. Atherosclerosis, 2017, 257, 186-194.
[http://dx.doi.org/10.1016/j.atherosclerosis.2017.01.011] [PMID: 28152406]
[24]
Dube, M-P.; Niesor, E.J.; Tardif, J-C.; Upmanyu, R. Dalcetrapib for therapeutic use; Google Patents, 2018.
[25]
Abu Khalaf, R.; Abu Sheikha, G.; Bustanji, Y.; Taha, M.O. Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration. Eur. J. Med. Chem., 2010, 45(4), 1598-1617.
[http://dx.doi.org/10.1016/j.ejmech.2009.12.070] [PMID: 20116902]
[26]
Abu Sheikha, G.; Abu Khalaf, R.; Melhem, A.; Albadawi, G. Design, synthesis, and biological evaluation of benzylamino-methanone based cholesteryl ester transfer protein inhibitors. Molecules, 2010, 15(8), 5721-5733.
[http://dx.doi.org/10.3390/molecules15085721] [PMID: 20724961]
[27]
Abu Khalaf, R.; Abu Sheikha, G.; Al-Sha’er, M.; Albadawi, G.; Taha, M. Design, synthesis, and biological evaluation of sulfonic acid ester and benzenesulfonamide derivatives as potential CETP inhibitors. Med. Chem. Res., 2012, 21(11), 3669-3680.
[http://dx.doi.org/10.1007/s00044-011-9917-5]
[28]
Abu Khalaf, R.; Abd El-Aziz, H.; Sabbah, D.; Albadawi, G.; Abu Sheikha, G. CETP inhibitory activity of chlorobenzyl benzamides: QPLD docking, pharmacophore mapping and synthesis. Lett. Drug Des. Discov., 2017, 14(12), 1391-1400.
[http://dx.doi.org/10.2174/1570180814666170412122304]
[29]
Abu Khalaf, R.; Sabbah, D.; Al-Shalabi, E.; Bishtawi, S.; Albadawi, G.; Abu Sheikha, G. Synthesis, biological evaluation, and molecular modeling study of substituted benzyl benzamides as CETP inhibitors. Arch. Pharm. (Weinheim), 2017, 350(12), 1700204.
[http://dx.doi.org/10.1002/ardp.201700204] [PMID: 29112287]
[30]
Abu Khalaf, R. NasrAllah, A.; Jarrar, W.; Sabbah, D. CETP inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis. Braz. J. Pharm. Sci., 2020.
[31]
Khalaf, R.A.; Al-Rawashdeh, S.; Sabbah, D.; Abu Sheikha, G. Molecular docking and pharmacophore modeling studies of fluorinated benzamides as potential CETP inhibitors. Med. Chem., 2017, 13(3), 239-253.
[http://dx.doi.org/10.2174/1573406412666161104121042] [PMID: 27823564]
[32]
Liu, S.; Mistry, A.; Reynolds, J.M.; Lloyd, D.B.; Griffor, M.C.; Perry, D.A.; Ruggeri, R.B.; Clark, R.W.; Qiu, X. Crystal structures of cholesteryl ester transfer protein in complex with inhibitors. J. Biol. Chem., 2012, 287(44), 37321-37329.
[http://dx.doi.org/10.1074/jbc.M112.380063] [PMID: 22961980]
[33]
Schrödinger Protein Preparation Wizard, Maestro, Macromodel, QPLD-dock, and Pymol; Schrödinger, LLC: Portland, OR, U.S.A., 2016, p. 97204.
[34]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID: 15027865]
[35]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID: 17034125]
[36]
The Molecular operating, Environment Chemical Computing Group; Inc Montreal: Quebec, Canada, 2016.

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