Molecular Docking and Pharmacophore Modeling Studies of Fluorinated Benzamides as Potential CETP Inhibitors

Khalaf, Reema Abu; Rawashdeh, Sara Al; Sabbah, Dima A.; Sheikha, Ghassan Abu

doi:10.2174/1573406412666161104121042

Cited by 17 publications

(18 citation statements)

References 23 publications

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“…In order to explore the backbones of 8a–j and their attachments, we screened them against CETP inhibitors pharmacophore model . We found that 8a–j match the CETP inhibitors fingerprint (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Utilizing a previously generated pharmacophore model by our group , and in order to get further details about the functionalities of the synthesized compounds responsible for activity, 8a–j were mapped against the adopted pharmacophore model of CETP inhibitors .…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, the structure of CETP revealed a 60‐Å long tunnel structure that demonstrated binding of two neutral lipids, hydrophobic cholesteryl esters in the tunnel, and two phospholipids, phosphatidylcholines, that plug the two distinct openings at each end .…”

Section: Introductionmentioning

confidence: 99%

“…Our research group identified different potential CETP inhibitors including benzenesulfonamides and toluene‐4‐sulfonic acid esters , benzylamino‐methanones , fluorinated benzamides , benzylideneamino‐methanones , and chlorobenzyl benzamides .…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors

Khalaf

Sabbah

Al‐Shalabi

et al. 2017

Archiv der Pharmazie

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Cardiovascular disease is the most common cause for mortality and morbidity in the developed world; its risk is inversely related to the high-density lipoprotein (HDL) cholesterol levels. Therefore, there is a great interest in developing new cholesteryl ester transfer protein (CETP) inhibitors capable of raising HDL as a novel approach for the prevention of cardiovascular disease. Herein, the synthesis and characterization of ten benzyl benzamides 8a-j that aim at CETP inhibition was performed. The in vitro CETP inhibition bioassay revealed that benzamide 8j had the best activity, with a percent inhibition of 82.2% at 10 μM concentration and an IC value of 1.3 μM. The docking study shows that the verified compounds accommodate the binding cleft of CETP and are enclosed by a hydrophobic lining. Furthermore, the scaffold of 8a-j matches the pharmacophoric points of CETP inhibitors, particularly in its hydrophobic and aromatic functionalities.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis, Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors

Khalaf

Sabbah

Al‐Shalabi

et al. 2017

Archiv der Pharmazie

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“…Previously, our group designed and synthesized a range of different CETP inhibitors, including benzylidene-amino methanones (Abu , benzylamino methanones (Abu , N-(4-benzyloxyphenyl)-4-methyl-benzenesulfonamides (Abu Khalaf et al, 2012), N-(4-benzylamino-phenyl)toluene-4-sulfonic acid esters (Abu Khalaf et al, 2012), chlorobenzyl benzamides (Abu Khalaf et al, 2017a), fluorinated benzamides (Abu Khalaf et al, 2017b), and substituted benzyl benzamides (Abu Khalaf et al, 2017c). In an attempt to optimize our previously synthesized CETP inhibitors, compound A (% inhibition = 50% at 10 µM, Figure 1) was chosen as a lead (Abu Khalaf et al, 2017c).…”

Section: Introductionmentioning

confidence: 99%

Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis

Khalaf

NasrAllah

Jarrar

et al. 2022

Braz. J. Pharm. Sci.

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Dyslipidemia is an abnormal lipid profile associated with many common diseases, including coronary heart disease and atherosclerosis. Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that is responsible for the transfer of cholesteryl ester from high-density lipoprotein athero-protective particles to pro-atherogenic very low-density lipoprotein and low-density lipoprotein particles. The requirement for new CETP inhibitors, which block this process has driven our current work. Here, the synthesis as well as the ligand-based and structure-based design of seven oxoacetamido-benzamides 9a-g with CETP inhibitory activity is described. An in vitro study demonstrated that most of these compounds have appreciable CETP inhibitory activity. Compound 9g showed the highest inhibitory activity against CETP with an IC 50 of 0.96 μM. Glide docking data for compounds 9a-g and torcetrapib provide evidence that they are accommodated in the CETP active site where hydrophobic interactions drive ligand/CETP complex formation. Furthermore, compounds 9a-g match the features of known CETP active inhibitors, providing a rationale for their high docking scores against the CETP binding domain. Therefore, these oxoacetamido-benzamides show potential for use as novel CETP inhibitors.

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Synthesis, Molecular Modeling, and Evaluation of Novel Methylated Benzene Sulfonamide Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors

Khalaf,

Abuarqoub,

Afaneh

et al. 2024

ChemistrySelect

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Cardiovascular disease (CVD) is a leading cause of global mortality, with dyslipidemia being a significant modifiable risk factor. Dyslipidemia refers to all abnormalities in blood lipid levels. It plays a fundamental role in the development and progression of atherosclerosis. The reduction of low‐density lipoprotein (LDL) cholesterol has been shown to decrease cardiovascular risk. Cholesteryl ester transfer protein (CETP) plays a role in LDL metabolism, and its inhibition results in lower LDL levels. This study synthesizes and evaluates novel benzene sulfonamide derivatives as CETP inhibitors. Twenty compounds were synthesized and tested for their inhibitory activity using an in vitro bioassay. The results revealed that para‐methylated derivatives exhibited higher inhibitory activity compared to meta‐methylated derivatives, where compound 6n has an IC50 of 24.4 µM. Furthermore, electron withdrawing groups such as chlorine and nitro substitutions on the sulfanamido‐phenyl rings demonstrated superior inhibitory effects compared to electron donating groups. Positional isomerism of the substitutions also influenced inhibitory activity, with para substitutions being more effective. Nitro‐substituted compounds showed greater inhibition than chlorine‐substituted compounds, where compound 6t has an IC50 of 18.3 µM. Overall, this study provides valuable insights into the SAR of CETP inhibitors and identifies promising compounds for further investigation as potential therapeutics for CVD.

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Molecular Docking and Pharmacophore Modeling Studies of Fluorinated Benzamides as Potential CETP Inhibitors

Abstract: Ligand-based and structure-based drug design strategies confirm that hydrophobic interaction mediates ligand/protein complex formation and explains the activity of our verified molecules.

Cited by 17 publications

References 23 publications

Synthesis, Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors

Synthesis, Biological Evaluation, and Molecular Modeling Study of Substituted Benzyl Benzamides as CETP Inhibitors

Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis

Synthesis, Molecular Modeling, and Evaluation of Novel Methylated Benzene Sulfonamide Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors

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