Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Trifluoromethylated Aryl Sulfonamides as Novel CETP Inhibitors: Synthesis, Induced Fit Docking, Pharmacophore Mapping and Subsequent In vitro Validation

Author(s): Reema Abu Khalaf*, Hamza Al Shaiah and Dima Sabbah

Volume 19, Issue 4, 2023

Published on: 03 October, 2022

Page: [393 - 404] Pages: 12

DOI: 10.2174/1573406418666220908164014

Price: $65

Abstract

Background: Cardiovascular disease is one of the leading causes of death. Atherosclerosis causes arterial constriction or obstruction, resulting in acute cardiovascular illness. Cholesteryl ester transfer protein (CETP) facilitates reverse cholesterol transport. It supports the transfer of cholesteryl ester from HDL to LDL and VLDL. Inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL.

Objectives: In this study, fourteen trifluoromethyl substituted benzene sulfonamides 6a-6g and 7a-7g were prepared.

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

Results: In vitro biological evaluation showed that compounds 7d-7f had the highest inhibitory activity with 100% inhibition, while the inhibition observed by compounds 6a-6g, 7a-7c and 7g ranged from 2%-72% at 10 μM concentration. It was found that the addition of a fourth aromatic ring significantly improved the activity, which may be due to the hydrophobic nature of CETP. Also, the presence of ortho-chloro, meta-chloro and para-methyl substituents results in high inhibitory activity.

Conclusion: The induced fit docking studies revealed that hydrophobic interaction guided ligand/ CETP binding interaction in addition to H-bond formation with Q199, R201, and H232. Furthermore, pharmacophore mapping demonstrated that this series satisfies the functionalities of the current CETP inhibitors.

Keywords: Atherosclerosis, cardiovascular disease, cholesteryl ester transfer protein, induced fit docking, pharmacophore mapping, sulfonamides, trifluoromethyl.

« Previous
Graphical Abstract

[1]
Zão, A.; Magalhães, S.; Santos, M. Frailty in cardiovascular disease: Screening tools. Rev. Port. Cardiol., 2019, 38(2), 143-148.
[2]
Zhu, Y.; Xian, X.; Wang, Z.; Bi, Y.; Chen, Q.; Han, X.; Tang, D.; Chen, R. Research progress on the relationship between atherosclerosis and inflammation. Biomolecules, 2018, 8(3), 80.
[http://dx.doi.org/10.3390/biom8030080] [PMID: 30142970]
[3]
Taghizadeh, E.; Esfehani, R.J.; Sahebkar, A.; Parizadeh, S.M.; Rostami, D.; Mirinezhad, M.; Poursheikhani, A.; Mobarhan, M.G.; Pasdar, A. Familial combined hyperlipidemia: An overview of the underlying molecular mechanisms and therapeutic strategies. IUBMB Life, 2019, 71(9), 1221-1229.
[http://dx.doi.org/10.1002/iub.2073] [PMID: 31271707]
[4]
Ogura, M. PCSK9 inhibition in the management of familial hypercholesterolemia. J. Cardiol., 2018, 71(1), 1-7.
[http://dx.doi.org/10.1016/j.jjcc.2017.07.002] [PMID: 28784313]
[5]
Paththinige, C.S.; Sirisena, N.D.; Dissanayake, V.H.W. Genetic determinants of inherited susceptibility to hypercholesterolemia - a comprehensive literature review. Lipids Health Dis., 2017, 16(1), 103.
[http://dx.doi.org/10.1186/s12944-017-0488-4] [PMID: 28577571]
[6]
Jarab, A.S.; Alefishat, E.A.; Al-Qerem, W.; Mukattash, T.L.; Al-Hajjeh, D.M. Lipid control and its associated factors among patients with dyslipidaemia in Jordan. Int. J. Clin. Pract., 2021, 75(5)e14000
[http://dx.doi.org/10.1111/ijcp.14000] [PMID: 33400313]
[7]
Busatto, S.; Walker, S.A.; Grayson, W.; Pham, A.; Tian, M.; Nesto, N.; Barklund, J.; Wolfram, J. Lipoprotein-based drug delivery. Adv. Drug Deliv. Rev., 2020, 159, 377-390.
[http://dx.doi.org/10.1016/j.addr.2020.08.003] [PMID: 32791075]
[8]
Ahotupa, M. Oxidized lipoprotein lipids and atherosclerosis. Free Radic. Res., 2017, 51(4), 439-447.
[http://dx.doi.org/10.1080/10715762.2017.1319944] [PMID: 28412863]
[9]
Tonouchi, R.; Okada, T.; Abe, Y.; Kazama, M.; Kuromori, Y.; Yoshino, Y.; Iwata, F.; Hara, M.; Saito, E.; Morioka, I. Subclass distribution of low‐density lipoprotein triglyceride and the clustering of metabolic syndrome components in Japanese children. Pediatr. Int., 2021, 63(6), 664-670.
[http://dx.doi.org/10.1111/ped.14490] [PMID: 33020997]
[10]
Stadler, J.T.; Marsche, G. Obesity-related changes in high-density lipoprotein metabolism and function. Int. J. Mol. Sci., 2020, 21(23), 8985.
[http://dx.doi.org/10.3390/ijms21238985] [PMID: 33256096]
[11]
Chang, Y.; Robidoux, J. Dyslipidemia management update. Curr. Opin. Pharmacol., 2017, 33, 47-55.
[http://dx.doi.org/10.1016/j.coph.2017.04.005] [PMID: 28527325]
[12]
Qiu, X.; Mistry, A.; Ammirati, M.J.; Chrunyk, B.A.; Clark, R.W.; Cong, Y.; Culp, J.S.; Danley, D.E.; Freeman, T.B.; Geoghegan, K.F.; Griffor, M.C.; Hawrylik, S.J.; Hayward, C.M.; Hensley, P.; Hoth, L.R.; Karam, G.A.; Lira, M.E.; Lloyd, D.B.; McGrath, K.M.; Stutzman-Engwall, K.J.; Subashi, A.K.; Subashi, T.A.; Thompson, J.F.; Wang, I.K.; Zhao, H.; Seddon, A.P. Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules. Nat. Struct. Mol. Biol., 2007, 14(2), 106-113.
[http://dx.doi.org/10.1038/nsmb1197] [PMID: 17237796]
[13]
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]
[14]
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]
[15]
Sheikha, G.A.; 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]
[16]
Khalaf, R.A.; Sheikha, G.A.; Al-Sha’er, M.; Taha, M. Design, synthesis and biological evaluation of N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives as potential DPP IV inhibitors. Open Med. Chem. J., 2013, 7(1), 39-48.
[http://dx.doi.org/10.2174/1874104501307010039] [PMID: 24358058]
[17]
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]
[18]
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]
[19]
Abu Khalaf, R. NasrAllah, A.; Jarrar, W.; Sabbah, D. CETP inhibitory oxoacetamideo-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis. Braz. J. Pharm. Sci., 2020.
[20]
Abu Khalaf, R.; 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]
[21]
Khalaf, R.A.; Awad, M.; Al-Qirim, T.; Sabbah, D. Synthesis and molecular modeling of novel 3,5-bis(trifluoromethyl) benzylamino benzamides as potential CETP inhibitors. Med. Chem., 2022, 18(4), 417-426.
[http://dx.doi.org/10.2174/1573406417666210830125431] [PMID: 34463228]
[22]
Abu Khalaf, R.; Asa’ad, M. Synthesis and biological evaluation of aromatic sulfonamides as novel cholesteryl ester transfer protein inhibitors. Master Thesis, Al-Zaytoonah University of Jordan, Amman, Jordan, 2021.
[23]
Abu Khalaf, R.; Shalluf, A. Diaryl sulfonamides: synthesis, characterization and in vitro biological evaluation as CETP inhibitors. Master Thesis, Al-Zaytoonah University of Jordan, Amman, Jordan, 2021.
[24]
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]
[25]
Schrödinger In: Protein Preparation Wizard, Maestro, Macromodel, QPLD-dock, and Pymol; Schrödinger, LLC: Portland, OR, U.S.A., 2021; p. 97204.
[26]
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]
[27]
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]
[28]
MOE In: The Molecular Operating Environment; Chemical Computing Group, Inc Montreal: Quebec, Canada, 2020.

Rights & Permissions Print Cite
Article Metrics
1
© 2025 Bentham Science Publishers | Privacy Policy