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

Synthesis and In-Silico Studies of Ortho-Fluorinated Benzenesulfonamides as Putative Anti-CETP Agents

Author(s): Reema Abu Khalaf*, Lama Jaradat and Maha Habash

Volume 28, Issue 9, 2024

Published on: 05 April, 2024

Page: [716 - 724] Pages: 9

DOI: 10.2174/0113852728295939240315040152

Price: $65

Abstract

Cardiovascular disease is one of the primary causes of death. Atherosclerosis produces artery constriction or obstruction, which can lead to a heart attack or stroke. Cholesteryl Ester Transfer Protein (CETP) is a protein that aids in reverse cholesterol transport. It promotes cholesteryl ester transfer from HDL to LDL and VLDL. So, inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL cholesterol. In this study, ten ortho-fluoro substituted benzenesulfonamides 6a-6j were prepared, and their structure was fully determined using 1H NMR, 13C NMR, HR-MS, and IR. In vitro biological evaluation showed that compound 6d has the highest inhibitory activity with 100% inhibition, while compounds 6a-6c and 6e-6j had activities ranged from 29% - 83% at 10 μM concentration. Interestingly, para-substituted derivatives (6d, 6g, and 6j) were observed to have greater CETP inhibitory activities than their ortho- and meta- analogues irrespective to the nature of substituent, i.e., CH3, Cl, or NO2. Ligandfit docking experiment revealed the difference in the binding mode among the synthesized compounds, which is reflected in their CETP inhibitory activity.

« Previous Next »
Graphical Abstract

[1]
Wilkins, E.; Wilson, L.; Wickramasinghe, K.; Bhatnagar, P.; Leal, J.; Fernandez, L.R.; Burns, R.; Rayner, M.; Townsend, N. European Cardiovascular Disease Statistics 2017; European Heart Network: Brussels, 2017.
[2]
Umer, A.; Kelley, G.A.; Cottrell, L.E.; Giacobbi, P., Jr; Innes, K.E.; Lilly, C.L. Childhood obesity and adult cardiovascular disease risk factors: A systematic review with meta-analysis. BMC Public Health, 2017, 17(1), 683.
[http://dx.doi.org/10.1186/s12889-017-4691-z] [PMID: 28851330]
[3]
Stewart, J.; Manmathan, G.; Wilkinson, P. Primary prevention of cardiovascular disease: A review of contemporary guidance and literature. JRSM Cardiovasc. Dis., 2017, 6, 2048004016687211.
[http://dx.doi.org/10.1177/2048004016687211] [PMID: 28286646]
[4]
Leong, D.P.; Joseph, P.G.; McKee, M.; Anand, S.S.; Teo, K.K.; Schwalm, J.D.; Yusuf, S. Reducing the global burden of cardiovascular disease, part 2: prevention and treatment of cardiovascular disease. Circ. Res., 2017, 121(6), 695-710.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.311849] [PMID: 28860319]
[5]
Pappan, N.; Rehman, A. Dyslipidemia. In: StatPearls; StatPearls Publishing, 2021.
[6]
Jarab, A.S.; Alefishat, E.A.; Qerem, A.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]
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]
[8]
Zhang, L.; Yan, F.; Zhang, S.; Lei, D.; Charles, M.A.; Cavigiolio, G.; Oda, M.; Krauss, R.M.; Weisgraber, K.H.; Rye, K.A.; Pownall, H.J.; Qiu, X.; Ren, G. Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein. Nat. Chem. Biol., 2012, 8(4), 342-349.
[http://dx.doi.org/10.1038/nchembio.796] [PMID: 22344176]
[9]
Lei, D.; Zhang, X.; Jiang, S.; Cai, Z.; Rames, M.J.; Zhang, L.; Ren, G.; Zhang, S. Structural features of cholesteryl ester transfer protein: A molecular dynamics simulation study. Proteins, 2013, 81(3), 415-425.
[http://dx.doi.org/10.1002/prot.24200] [PMID: 23042613]
[10]
Shinkai, H. Cholesteryl ester transfer-protein modulator and inhibitors and their potential for the treatment of cardiovascular diseases. Vasc. Health Risk Manag., 2012, 8, 323-331.
[http://dx.doi.org/10.2147/VHRM.S25238] [PMID: 22661899]
[11]
Masson, W.; Lobo, M.; Siniawski, D.; Huerín, M.; Molinero, G.; Valéro, R.; Nogueira, J.P. Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk. Diabetes Metab., 2018, 44(6), 508-513.
[http://dx.doi.org/10.1016/j.diabet.2018.02.005] [PMID: 29523487]
[12]
Ghosh, K.R.; Ghosh, M.S. Current status of CETP inhibitors in the treatment of hyperlipidemia: An update. Curr. Clin. Pharmacol., 2012, 7(2), 102-110.
[http://dx.doi.org/10.2174/157488412800228884] [PMID: 22432840]
[13]
Tsuruya, K.; Yoshida, H.; Nagata, M.; Kitazono, T.; Hirakata, H.; Iseki, K.; Moriyama, T.; Yamagata, K.; Yoshida, H.; Fujimoto, S.; Asahi, K.; Kurahashi, I.; Ohashi, Y.; Watanabe, T. Association of the triglycerides to high-density lipoprotein cholesterol ratio with the risk of chronic kidney disease: Analysis in a large Japanese population. Atherosclerosis, 2014, 233(1), 260-267.
[http://dx.doi.org/10.1016/j.atherosclerosis.2013.12.037] [PMID: 24529154]
[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.; Khalaf, A.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, A.R.; Sheikha, A.G.; Sha’er, A.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]
[17]
Khalaf, A.R.; Aziz, A.E.H.; Sabbah, D.; Albadawi, G.; Sheikha, A.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]
Khalaf, A.R.; Sabbah, D.; Shalabi, A.E.; Bishtawi, S.; Albadawi, G.; Sheikha, A.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] [PMID: 29112287]
[19]
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(e20028), 1-13.
[20]
Khalaf, A.R.; Rawashdeh, A.S.; Sabbah, D.; Sheikha, A.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]
Khalaf, A.R.; Abusaad, A.; Nawaiseh, A.B.; Sabbah, D. Synthesis, molecular modeling and biological evaluation of novel trifluoromethyl benzamides as promising CETP inhibitors. Curr. Comput. Aided Drug Des, 2024, 20(5), 564-574.
[23]
Khalaf, A.R.; Sabbah, D.; Shalabi, A.E.; Ikhmais, B.; Naser, W.; Albadawi, G. Fluorinated benzyloxalamides: Glide docking, pharmacophore mapping, synthesis and in vitro evaluation as potential cholesteryl ester transfer protein inhibitors. Indian J. Pharm. Sci., 2022, 84(6), 1476-1487.
[24]
Abu Khalaf, R. NasrAllah, A.; AlBadawi, G. Cholesteryl ester transfer protein inhibitory activity of new 4-bromophenethyl benzamides. Jordan J. Pharm. Sci., 2023, 16(2), 381-390.
[http://dx.doi.org/10.35516/jjps.v16i2.1465]
[25]
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] [PMID: 36093822]
[26]
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]
[27]
Khalaf, R.A.; Shalluf, A.; Habash, M. Fluorinated diaryl sulfonamides: Molecular modeling, synthesis, and in vitro validation as new CETP inhibitors. Curr. Computeraided Drug Des., 2023, 20(6), 987-997.
[http://dx.doi.org/10.2174/0115734099268407230927113905]
[28]
Küçükbay, H.; Gönül, Z.; Küçükbay, F.Z.; Tekin, Z.; Angeli, A.; Bartolucci, G.; Supuran, C.T.; Tatlıcı, E.; Apohan, E.; Yeşilada, Ö. Synthesis of new 7‐amino‐3,4‐dihydroquinolin‐2(1H)‐one‐peptide derivatives and their carbonic anhydrase enzyme inhibition, antioxidant, and cytotoxic activities. Arch. Pharm., 2021, 354(11), 2100122.
[http://dx.doi.org/10.1002/ardp.202100122]
[29]
Gönül, Z.; Öztürk, D.A.; Küçükbay, F.; Tekin, S.; Tekin, Z.; Küçükbay, H. Antioxidant and cytotoxic properties of some new dipeptide‐indole conjugates. J. Heterocycl. Chem., 2023, 60(1), 86-95.
[http://dx.doi.org/10.1002/jhet.4564]
[30]
Küçükbay, H.; Parladı, F.M.; Küçükbay, F.; Angeli, A.; Bartolucci, G.; Supuran, C.T. Synthesis, antioxidant and carbonic anhydrase inhibitory properties of monopeptide-anthraquinone conjugates. Organic Communications, 2021, 14(3), 255-269.
[http://dx.doi.org/10.25135/acg.oc.108.2107.2126]
[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.
[33]
Venkatachalam, C.M.; Jiang, X.; Oldfield, T.; Waldman, M. LigandFit: A novel method for the shape-directed rapid docking of ligands to protein active sites. J. Mol. Graph. Model., 2003, 21(4), 289-307.
[http://dx.doi.org/10.1016/S1093-3263(02)00164-X] [PMID: 12479928]
[34]
Jaradat, N.J.; Khanfar, M.A.; Habash, M.; Taha, M.O. Combining docking-based comparative intermolecular contacts analysis and k-nearest neighbor correlation for the discovery of new check point kinase 1 inhibitors. J. Comput. Aided Mol. Des., 2015, 29(6), 561-581.
[http://dx.doi.org/10.1007/s10822-015-9848-1] [PMID: 25956379]
[35]
Verdonk, M.L.; Berdini, V.; Hartshorn, M.J.; Mooij, W.T.M.; Murray, C.W.; Taylor, R.D.; Watson, P. Virtual screening using protein-ligand docking: Avoiding artificial enrichment. J. Chem. Inf. Comput. Sci., 2004, 44(3), 793-806.
[http://dx.doi.org/10.1021/ci034289q] [PMID: 15154744]
[36]
Hammad, A.A.M.; Afifi, F.U.; Taha, M.O. Combining docking, scoring and molecular field analyses to probe influenza neuraminidase–ligand interactions. J. Mol. Graph. Model., 2007, 26(2), 443-456.
[http://dx.doi.org/10.1016/j.jmgm.2007.02.002] [PMID: 17360207]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy