Login Register Cart 0
Generic placeholder image

Current Organic Chemistry

Editor-in-Chief

ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

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

Thiomethylphenyl Benzenesulfonamides as Potential Cholesteryl Ester Transfer Protein Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation

Author(s): Reema Abu Khalaf*, Manal Asa'ad and Maha Habash

Volume 26, Issue 8, 2022

Published on: 30 June, 2022

Page: [807 - 815] Pages: 9

DOI: 10.2174/1385272826666220601150913

Price: $65

Abstract

Background: The number of lipid disorders cases has risen dramatically around the world as a result of poor dietary habits, hereditary risk factors, or other diseases or medicines. Cholesteryl ester transfer protein (CETP) is a 476 amino acid lipophilic glycoprotein that helps transport cholesteryl esters and phospholipids from proatherogenic LDL and VLDL to atheroprotective HDL. CETP inhibition increases HDL cholesterol, lowers LDL cholesterol and triglycerides, rendering it a promising therapy option for hyperlipidemia and its comorbidities.

Methods: In this research, fourteen benzenesulfonamides 7a-7g and 8a-8g were synthesized and identified using 1H-NMR, 13C-NMR, IR and MS. The in vitro biological evaluation of 7a- 7g and 8a-8g revealed CETP inhibitory activities ranging from 15.6 to 100% at 10 μM concentration.

Results: Four aromatic rings compounds bearing either m-CH3 (8c) or p-Cl (8g) were the most potent compounds with 100% CETP inhibition, while the most active compound was 7c bearing three aromatic rings and m-CH3 with an IC50 of 0.12 μM. LibDock displayed that benzenesulfonamides can form hydrophobic interactions with the side chains of Leu129, Cys13, Ala202, Val198, Leu217 and Ile215 and participate in п-п stacking with Phe441, Phe197 and Arg201 in the binding pocket of CETP.

Conclusion: Pharmacophore mapping showed significant matching with the pharmacophoric features of Hypo4/8 and shape-complemented Hypo4/8 of CETP inhibitors for potent compounds.

Keywords: CETP, HDL, hyperlipidemia, LibDock, pharmacophore, sulfonamides.

« Previous
Graphical Abstract

[1]
Organization, W.H. Global diffusion of eHealth: making universal health coverage achievable: report of the third global survey on eHealth; World Health Organiza-tion, 2017.
[2]
Karr, S. Epidemiology and management of hyperlipidemia. Am. J. Manag. Care, 2017, 23(9)(Suppl.), S139-S148.
[PMID: 28978219]
[3]
Purva, A.; Sharma, K. A review on dyslipidemia: Types, risk factors and management. Asian Journal of Pharmaceutical Research and Development, 2020, 8(2), 96-98.
[http://dx.doi.org/10.22270/ajprd.v8i2.682]
[4]
Shim, J-S.; Heo, J.E.; Kim, H.C. Factors associated with dietary adherence to the guidelines for prevention and treatment of hypertension among Korean adults with and without hypertension. Clin. Hypertens., 2020, 26(1), 5.
[http://dx.doi.org/10.1186/s40885-020-00138-y] [PMID: 32190348]
[5]
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]
[6]
Chen, T.; Sun, M.; Wang, J-Q.; Cui, J-J.; Liu, Z-H.; Yu, B. A novel swine model for evaluation of dyslipidemia and atherosclerosis induced by human CETP overexpres-sion. Lipids Health Dis., 2017, 16(1), 169.
[http://dx.doi.org/10.1186/s12944-017-0563-x] [PMID: 28893253]
[7]
Raposo, H.F.; Forsythe, P.; Chausse, B.; Castelli, J.Z.; Moraes-Vieira, P.M.; Nunes, V.S.; Oliveira, H.C.F. Novel role of cholesteryl ester transfer protein (CETP): Attenua-tion of adiposity by enhancing lipolysis and brown adipose tissue activity. Metabolism, 2021, 114, 154429.
[http://dx.doi.org/10.1016/j.metabol.2020.154429] [PMID: 33166579]
[8]
Shrestha, S.; Wu, B.J.; Guiney, L.; Barter, P.J.; Rye, K.A. Cholesteryl ester transfer protein and its inhibitors. J. Lipid Res., 2018, 59(5), 772-783.
[http://dx.doi.org/10.1194/jlr.R082735] [PMID: 29487091]
[9]
Dixit, S.M.; Ahsan, M.; Senapati, S. Steering the lipid transfer to unravel the mechanism of cholesteryl ester transfer protein inhibition. Biochemistry, 2019, 58(36), 3789-3801.
[http://dx.doi.org/10.1021/acs.biochem.9b00301] [PMID: 31418269]
[10]
Morehouse, L.A.; Sugarman, E.D.; Bourassa, P-A.; Sand, T.M.; Zimetti, F.; Gao, F.; Rothblat, G.H.; Milici, A.J. Inhibition of CETP activity by torcetrapib reduces suscep-tibility to diet-induced atherosclerosis in New Zealand White rabbits. J. Lipid Res., 2007, 48(6), 1263-1272.
[http://dx.doi.org/10.1194/jlr.M600332-JLR200] [PMID: 17325387]
[11]
Ranalletta, M.; Bierilo, K.K.; Chen, Y.; Milot, D.; Chen, Q.; Tung, E.; Houde, C.; Elowe, N.H.; Garcia-Calvo, M.; Porter, G.; Eveland, S.; Frantz-Wattley, B.; Kavana, M.; Addona, G.; Sinclair, P.; Sparrow, C.; O’Neill, E.A.; Koblan, K.S.; Sitlani, A.; Hubbard, B.; Fisher, T.S. Biochemical characterization of cholesteryl ester transfer protein inhibitors. J. Lipid Res., 2010, 51(9), 2739-2752.
[http://dx.doi.org/10.1194/jlr.M007468] [PMID: 20458119]
[12]
Krauss, R.M.; Wojnooski, K.; Orr, J.; Geaney, J.C.; Pinto, C.A.; Liu, Y.; Wagner, J.A.; Luk, J.M.; Johnson-Levonas, A.O.; Anderson, M.S.; Dansky, H.M. Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib. J. Lipid Res., 2012, 53(3), 540-547.
[http://dx.doi.org/10.1194/jlr.M018010] [PMID: 22180633]
[13]
Clark, R.W.; Ruggeri, R.B.; Cunningham, D.; Bamberger, M.J. Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action. J. Lipid Res., 2006, 47(3), 537-552.
[http://dx.doi.org/10.1194/jlr.M500349-JLR200] [PMID: 16326978]
[14]
Gerasymenko, O.; Demchenko, A. Side effects of cholesteryl ester transfer protein inhibitors., 2019.
[15]
Niesor, E.J.; Magg, C.; Ogawa, N.; Okamoto, H.; von der Mark, E.; Matile, H.; Schmid, G.; Clerc, R.G.; Chaput, E.; Blum-Kaelin, D.; Huber, W.; Thoma, R.; Pflieger, P.; Kakutani, M.; Takahashi, D.; Dernick, G.; Maugeais, C. Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases re-verse cholesterol transport. J. Lipid Res., 2010, 51(12), 3443-3454.
[http://dx.doi.org/10.1194/jlr.M008706] [PMID: 20861162]
[16]
Schwartz, G.G.; Olsson, A.G.; Abt, M.; Ballantyne, C.M.; Barter, P.J.; Brumm, J.; Chaitman, B.R.; Holme, I.M.; Kallend, D.; Leiter, L.A.; Leitersdorf, E.; McMurray, J.J.; Mundl, H.; Nicholls, S.J.; Shah, P.K.; Tardif, J.C.; Wright, R.S. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med., 2012, 367(22), 2089-2099.
[http://dx.doi.org/10.1056/NEJMoa1206797] [PMID: 23126252]
[17]
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]
[18]
Castro-Perez, J.; Briand, F.; Gagen, K.; Wang, S-P.; Chen, Y.; McLaren, D.G.; Shah, V.; Vreeken, R.J.; Hankemeier, T.; Sulpice, T.; Roddy, T.P.; Hubbard, B.K.; Johns, D.G. Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters. J. Lipid Res., 2011, 52(11), 1965-1973.
[http://dx.doi.org/10.1194/jlr.M016410] [PMID: 21841206]
[19]
Rohman, A.; Arifah, F.; Irnawati, A.G.; Muchtaridi, R.M. A review on phytochemical constituents, role on metabolic diseases, and toxicological assessments of underuti-lized part of Garcinia mangostana L. fruit. J. Appl. Pharm. Sci., 2020, 10(07), 127-146.
[20]
Wang, Y.; Zhang, L.; Wang, F.; Li, Z-H.; Dong, Z-J.; Liu, J-K. New diterpenes from cultures of the fungus Engleromyces goetzii and their CETP inhibitory activity. Nat. Prod. Bioprospect., 2015, 5(2), 69-75.
[http://dx.doi.org/10.1007/s13659-015-0055-5] [PMID: 25850378]
[21]
Javandoost, A.; Afshari, A.; Nikbakht-Jam, I.; Khademi, M.; Eslami, S.; Nosrati, M.; Foroutan-Tanha, M.; Sahebkar, A.; Tavalaie, S.; Ghayour-Mobarhan, M.; Ferns, G.; Hadizadeh, F.; Tabassi, A.; Mohajeri, A. Effect of crocin, a carotenoid from saffron, on plasma cholesteryl ester transfer protein and lipid profile in subjects with meta-bolic syndrome: A double blind randomized clinical trial. ARYA Atheroscler., 2017, 13(5), 245-252.
[PMID: 29371871]
[22]
Ghaffari, S.; Roshanravan, N. Saffron; An updated review on biological properties with special focus on cardiovascular effects. Biomed. Pharmacother., 2019, 109, 21-27.
[http://dx.doi.org/10.1016/j.biopha.2018.10.031] [PMID: 30391705]
[23]
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]
[24]
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]
[25]
Abu Khalaf, R.; Sheikha, G.A.; Al-Sha’er, M.; Albadawi, G.; Taha, M. Design, synthesis, and biological evaluation of sulfonic acid ester and benzenesulfonamide deriva-tives as potential CETP inhibitors. Med. Chem. Res., 2012, 21(11), 3669-3680.
[http://dx.doi.org/10.1007/s00044-011-9917-5]
[26]
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]
[27]
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]
[28]
Abu Khalaf, R. NasrAllah, A.; Jarrar, W.; Sabbah, D. CETP inhibitory oxoacetamideo-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis. Braz. J. Pharm. Sci., 2021.
[29]
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]
[30]
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]
[31]
Gasteiger, J.; Marsili, M. Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron, 1980, 36(22), 3219-3228.
[http://dx.doi.org/10.1016/0040-4020(80)80168-2]
[32]
Diller, D.J.; Merz, K.M., Jr High throughput docking for library design and library prioritization. Proteins, 2001, 43(2), 113-124.
[http://dx.doi.org/10.1002/1097-0134(20010501)43:2<113:AID-PROT1023>3.0.CO;2-T] [PMID: 11276081]

Rights & Permissions Print Cite
Article Metrics
36
1
© 2024 Bentham Science Publishers | Privacy Policy