Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

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

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

Fluorinated Diaryl Sulfonamides: Molecular Modeling, Synthesis, and In Vitro Validation as New CETP Inhibitors

Author(s): Reema Abu Khalaf*, Azhar Shalluf and Maha Habash

Volume 20, Issue 6, 2024

Published on: 18 October, 2023

Page: [987 - 997] Pages: 11

DOI: 10.2174/0115734099268407230927113905

Price: $65

conference banner
Abstract

Background: Hyperlipidemia, a cardiovascular disease risk factor, is characterized by a rise in low-density lipoprotein (LDL), triglycerides and total cholesterol, and a decrease in high-density lipoprotein (HDL). Cholesteryl ester transfer protein (CETP) enables the transfer of cholesteryl ester from HDL to LDL and very low-density lipoprotein.

Objectives: CETP inhibition is a promising approach to prevent and treat cardiovascular diseases. By inhibiting lipid transport activity, it increases HDL levels and decreases LDL levels.

Materials and Method: Herein, diaryl sulfonamides 6a-6g and 7a-7g were prepared, and the structure of these compounds was fully determined using different spectroscopic techniques.

Results: These compounds underwent biological evaluation in vitro and showed different inhibitory activities against CETP; 100% inhibitory activity was observed for compounds 7a-7g, while activities of compounds 6a-6g ranged up to 42.6% at 10 μM concentration. Pharmacophore mapping agreed with the bioassay results where the four aromatic ring compounds 7a-7g possessed higher fit values against Hypo4/8 and the shape-complemented Hypo4/8 in comparison to compounds 6a-6g.

Conclusion: Docking of the synthesized compounds using libdock and ligandfit engines revealed that compounds 7a-7g formed п-п stacking and hydrophobic interactions with the binding pocket, while compounds 6a-6g missed these hydrophobic interactions with amino acids Leu206, Phe265, and Phe263.

« Previous
Graphical Abstract

[1]
Zhang, Y.; Kishi, H.; Kobayashi, S. Add-on therapy with traditional Chinese medicine: An efficacious approach for lipid metabolism disorders. Pharmacol. Res., 2018, 134, 200-211.
[http://dx.doi.org/10.1016/j.phrs.2018.06.004] [PMID: 29935947]
[2]
Yu, G.; Yang, Z.; Peng, T.; Lv, Y. Circular RNAs: Rising stars in lipid metabolism and lipid disorders. J. Cell. Physiol., 2021, 236(7), 4797-4806.
[http://dx.doi.org/10.1002/jcp.30200] [PMID: 33275299]
[3]
Miao, H.; Zhao, Y.H.; Vaziri, N.D. Lipidomics biomarkers of diet-induced hyperlipidemia and its treatment with poria cocos. J. Agric. Food Chem., 2016, 64(4), 969-979.
[http://dx.doi.org/10.1021/acs.jafc.5b05350] [PMID: 26758241]
[4]
Jeong, S.; Lee, J.; Kwon, O.; Kim, J.W.; Oh, B. A randomized, double-blind, placebo-controlled trial investigating cholesterol-lowering effects and safety of yellow yeast rice in adults with mild to moderate hypercholesterolemia. Medicine, 2018, 97(30), e11634.
[http://dx.doi.org/10.1097/MD.0000000000011634] [PMID: 30045307]
[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]
Maroufi, N.F.; Farzaneh, K.; Alibabrdel, M. Taq1B polymorphism of cholesteryl ester transfer protein (CETP) and its effects on the serum lipid levels in metabolic syndrome patients. Biochem. Genet., 2016, 54(6), 894-902.
[http://dx.doi.org/10.1007/s10528-016-9766-5] [PMID: 27496123]
[7]
Teramoto, T.; Kiyosue, A.; Iimura, T.; Takita, Y.; Riesmeyer, J.S.; Murakami, M. Efficacy and safety of the cholesteryl ester transfer protein inhibitor evacetrapib in combination with atorvastatin in japanese patients with primary hypercholesterolemia. Circ. J., 2018, 82(1), 183-191.
[http://dx.doi.org/10.1253/circj.CJ-16-1324] [PMID: 28768921]
[8]
Chen, C.; Sun, R.; Sun, Y. Synthesis, biological evaluation and SAR studies of ursolic acid 3β-ester derivatives as novel CETP inhibitors. Bioorg. Med. Chem. Lett., 2020, 30(2), 126824.
[http://dx.doi.org/10.1016/j.bmcl.2019.126824] [PMID: 31780304]
[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]
Chang, Y.; Zhou, S.; Li, E. Fragment-based discovery of novel pentacyclic triterpenoid derivatives as cholesteryl ester transfer protein inhibitors. Eur. J. Med. Chem., 2017, 126, 143-153.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.098] [PMID: 27750148]
[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.; 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]
[13]
Abu Khalaf, R. Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis. Braz. J. Pharm. Sci., 2022, 58, 1-13.
[14]
Abu Khalaf, R.; Abusaad, A.; Al-Nawaiseh, B.; Sabbah, D.; Albadawi, G. Synthesis, molecular modeling and biological evaluation of novel trifluoromethyl benzamides as promising CETP inhibitors; Curr Comput Aided Drug Des, 2023.
[15]
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]
[16]
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]
[17]
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]
[18]
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]
[19]
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]
[20]
Verdonk, M.L.; Berdini, V.; Hartshorn, M.J. 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]
[21]
Abu Hammad, 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