Cholesteryl Ester Transfer Protein Inhibitory Activity of New 4-Bromophenethyl Benzamides
DOI:
https://doi.org/10.35516/jjps.v16i2.1465Keywords:
Benzamides, 4-Bromophenethyl, CETP, HypercholesterolemiaAbstract
Cardiovascular diseases, as coronary heart disease, heart failure, and hypertension are the first leading cause of death in the United States and the third globally. CETP is a glycoprotein excreted mainly from the liver and found in plasma. Normal plasma CETP concentration is 1-4 µg/ml, while the ratio increased 70-80% in dyslipidemic patients. There is a growing need for new CETP inhibitors which encourages us to conduct this research. In this work, synthesis and in vitro study for four new 4-bromophenethylbenzamides 9a-d were carried out. In vitro study showed that the targeted compounds 9a-d exhibit acceptable activity against CETP, where compound 9a has a % inhibition of 40.7 at 10 µM concentration. It was found that the presence of the oxy group in both 9a and 9c enhances their activity which could be attributed to Hydrogen-bond formation with the amino acid residues of the CETP binding site.
References
(1) Benjamin E.J., Muntner P., Alonso A. et al. Heart Disease and Stroke Statistics-2019 Update: A Report from the American Heart Association. Circulation. 2019; 139(10):e56-e528.
(2) Jansen M., Puetz G., Hoffmann M.M. et al. mathematical model to estimate cholesterylester transfer protein (CETP) triglycerides flux in human plasma. BMC Syst. Biol. 2019; 13(1):1-12.
(3) Yu Y., Kuang Y.L., Lei D. et al. Polyhedral 3D structure of human plasma very low-density lipoproteins by individual particle cryo-electron tomography1. J. Lipid Res. 2016; 57(10):1879-1888.
(4) Yuana Y., Levels J., Grootemaat A. et al. Nieuwland R. Co-isolation of extracellular vesicles and high-density lipoproteins using density gradient ultracentrifugation. J. Extracell. Vesicles. 2014; 3:1-5.
(5) Younis N., Abu-Mallouh S., Almasri I. et al. Pancreatic Lipase Inhibition by Edible Plants Used in Three Middle East Countries: A Mini-Review. Jordan J. Pharm. Sci. 2021; 14(2):179-188.
(6) Kosmas C.E., DeJesus E., Rosario D. et al.CETP Inhibition: Past Failures and Future Hopes. Clin. Med. Insights Cardiol. 2016; 10:37-42.
(7) Jarab A.S., Alefishat E.A., Al-Qerem W. et al. Lipid control and its associated factors among patients with dyslipidemia in Jordan. Int. J. Clin. Pract. 2021; 75(5):e14000.
(8) Shrestha S., Wu B.J., Guiney L. et al. Cholesteryl ester transfer protein and its inhibitors. J. Lipid Res. 2018; 59(5):772-783.
(9) Skoumas J., Liontou C., Chrysohoou C. et al. Statin therapy and risk of diabetes in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia. Atherosclerosis. 2014; 237 (1):140-145.
(10) Dong B., Singh A.B., Fung C. et al. CETP inhibitors downregulate hepatic LDL receptor and PCSK9 expression in vitro and in vivo through a SREBP2-dependent mechanism. Atherosclerosis. 2014; 235 (2):449-462.
(11) Taybeh E.O., Al-Alami Z.M., Albasha A. Statin Use in Jordan: Patients Experience and Attitude toward Adverse Drug Reactions. Jordan J. Pharm. Sci. 2020; 13(2):197-205.
(12) Alkhalil M., Chai J.T., Choudhury R.P. Plaque imaging to refine indications for emerging lipid-lowering drugs. Eur. Heart J. Cardiovasc. Pharmacother. 2017; 3(1):58-67.
(13) Abu Khalaf R., Abu Sheikha G., Bustanji Y. et al. 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.
(14) Abu Sheikha G., Abu Khalaf R., Melhem A. et al. Design, synthesis, and biological evaluation of benzylamino-methanone-based cholesteryl ester transfer protein inhibitors. Molecules. 2010; 15(8):5721-5733.
(15) Abu Khalaf R., Abu Sheikha G., Al-Sha’er M., et al. Design, synthesis, and biological evaluation of sulfonic acid ester and benzenesulfonamide derivatives as potential CETP inhibitors. Med. Chem. Res. 2012; 21(11):3669-3680.
(16) Abu Khalaf R., Abd El-Aziz H., Sabbah D., et al. CETP Inhibitory Activity of Chlorobenzyl Benzamides: QPLD Docking, Pharmacophore Mapping, and Synthesis. Lett. Drug Des. Discov. 2017; 14(12):1391-1400.
(17) Abu Khalaf R., Al-Rawashdeh S., Sabbah D.et al. Molecular Docking and Pharmacophore Modeling Studies of Fluorinated Benzamides as Potential CETP Inhibitors. Med. Chem. 2017; 13(3):239-253.
(18) Abu Khalaf R., Awad M., Al-Qirim T. et al. Synthesis and Molecular Modeling of Novel 3, 5-Bis (trifluoromethyl) benzylamino Benzamides as Potential CETP Inhibitors. Med. Chem. 2022; 18(4):417-426.
(19) Abu Khalaf R., Sabbah D., Al-Shalabi E. et al. Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors. Arch. Pharm. 2017; 350(12):e1700204.
(20) Abu Khalaf R., Nasrallah A., Jarrar W. et al. Cholesteryl ester transfer protein inhibitory oxoacetamideo-benzamide derivatives: glide docking, pharmacophore mapping. and synthesis, Braz. J. Pharm. Sci., 2022; 58: e20028.
(21) Abu Khalaf R., 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.
(22) Abu Khalaf R., Al Shaiah H., 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.
