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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

Synthesis, Molecular Modeling and Biological Evaluation of Novel Trifluoromethyl Benzamides as Promising CETP Inhibitors

Author(s): Reema Abu Khalaf*, Amani Abusaad, Bara'a Al-Nawaiseh, Dima Sabbah and Ghadeer Albadawi

Volume 20, Issue 5, 2024

Published on: 18 May, 2023

Page: [564 - 574] Pages: 11

DOI: 10.2174/1573409919666230509123852

Price: $65

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Abstract

Background: Hyperlipidemia is considered a major risk factor for the progress of atherosclerosis.

Objective: Cholesteryl ester transfer protein (CETP) facilitates the relocation of cholesterol esters from HDL to LDL. CETP inhibition produces higher HDL and lower LDL levels.

Methods: Synthesis of nine benzylamino benzamides 8a-8f and 9a-9c was performed.

Results: In vitro biological study displayed potential CETP inhibitory activity, where compound 9c had the best activity with an IC50 of 1.03 μM. Induced-fit docking demonstrated that 8a-8f and 9a-9c accommodated the CETP active site and hydrophobic interaction predominated ligand/ CETP complex formation.

Conclusion: Pharmacophore mapping showed that this scaffold endorsed CETP inhibitors features and consequently elaborated the high CETP binding affinity.

Keywords: CETP inhibitors, hyperlipidemia, induced-fit docking, pharmacophore mapping, trifluoromethyl benzamides, molecular docking.

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[1]
Beheshti, S.; Madsen, C.M.; Varbo, A.; Benn, M.; Nordestgaard, B.G. Relationship of familial hypercholesterolemia and high LDL cholesterol to ischemic stroke: The copenhagen general population study. Circulation, 2018, 138(6), 578-589.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033470] [PMID: 29593013]
[2]
Blauw, L.L.; Noordam, R.; Soidinsalo, S.; Blauw, C.A.; Li-Gao, R.; de Mutsert, R.; Berbée, J.F.P.; Wang, Y.; van Heemst, D.; Rosendaal, F.R.; Jukema, J.W.; Mook-Kanamori, D.O.; Würtz, P.; Willems van Dijk, K.; Rensen, P.C.N. Mendelian randomization reveals unexpected effects of CETP on the lipoprotein profile. Eur. J. Hum. Genet., 2019, 27(3), 422-431.
[http://dx.doi.org/10.1038/s41431-018-0301-5] [PMID: 30420679]
[3]
Kobayashi, J. Which is the best predictor for the development of atherosclerosis among circulating lipoprotein lipase, Hepatic lipase, and endothelial lipase? J. Atheroscler. Thromb., 2019, 26(9), 758-759.
[http://dx.doi.org/10.5551/jat.ED108] [PMID: 30814386]
[4]
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]
[5]
Gou, L.; Jin, T.; Chen, S.; Li, N.; Hao, D.; Zhang, S.; Zhang, L. Bio-macromolecular dynamic structures and functions, illustrated with DNA, antibody, and lipoprotein. Chin. Phys. B, 2018, 27(2), 028708.
[http://dx.doi.org/10.1088/1674-1056/27/2/028708]
[6]
Maugeais, C.; Perez, A.; von der Mark, E.; Magg, C.; Pflieger, P.; Niesor, E.J. Evidence for a role of CETP in HDL remodeling and cholesterol efflux: Role of cysteine 13 of CETP. Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 2013, 1831(11), 1644-1650.
[http://dx.doi.org/10.1016/j.bbalip.2013.07.007] [PMID: 23872476]
[7]
Dergunov, A.D.; Shabrova, E.V.; Dobretsov, G.E. Cholesteryl ester diffusion, location and self-association constraints determine CETP activity with discoidal HDL: Excimer probe study. Arch. Biochem. Biophys., 2014, 564, 211-218.
[http://dx.doi.org/10.1016/j.abb.2014.09.019] [PMID: 25449063]
[8]
Suhy, A.; Hartmann, K.; Newman, L.; Papp, A.; Toneff, T.; Hook, V.; Sadee, W. Genetic variants affecting alternative splicing of human cholesteryl ester transfer protein. Biochem. Biophys. Res. Commun., 2014, 443(4), 1270-1274.
[http://dx.doi.org/10.1016/j.bbrc.2013.12.127] [PMID: 24393849]
[9]
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]
[10]
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]
[11]
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]
[12]
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]
[13]
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]
[14]
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]
[15]
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., 2017, 350(12), 1700204.
[http://dx.doi.org/10.1002/ardp.201700204]
[16]
Abu Khalaf, R.; NasrAllah, A.; Jarrar, W.; Sabbah, D. Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis. Braz. J. Pharm. Sci., 2022, 58, 1-13.
[17]
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]
[18]
Khalaf, R.A.; Asa’ad, M.; Habash, M. Thiomethylphenyl benzenesulfonamides as potential cholesteryl ester transfer protein inhibitors: Synthesis, molecular modeling and biological evaluation. Curr. Org. Chem., 2022, 26(8), 807-815.
[http://dx.doi.org/10.2174/1385272826666220601150913]
[19]
Khalaf, R.A.; Shaiah, H.A.; Sabbah, D. Trifluoromethylated aryl sulfonamides as novel CETP inhibitors: Synthesis, induced fit docking, pharmacophore mapping and subsequent in vitro validation. Med. Chem., 2023, 19(4), 393-404.
[http://dx.doi.org/10.2174/1573406418666220908164014]
[20]
Schrödinger. Protein Preparation Wizard, Maestro, Macromodel, QPLD-dock, and Pymol; Schrödinger, LLC: Portland, OR, U.S.A., 2021, p. 97204.
[21]
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]
[22]
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]
[23]
The Molecular Operating Environment, Chemical Computing Group. Inc Montreal; Quebec, Canada, 2016.

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