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![CETP inhibitor pharmacophore model with (A) 8f and (B) 8g. Aro stands for aromatic rings; Acc for H-bond acceptor; Don for H-bond donor; Cat for cationic group; PiN for p-ring; and Hyd for hydrophobic groups. Picture made by MOE [29].](profile/Reema-Abu-Khalaf/publication/320596425/figure/fig4/AS:620695872622593@1524996836377/CETP-inhibitor-pharmacophore-model-with-A-8f-and-B-8g-Aro-stands-for-aromatic-rings.png)
CETP inhibitor pharmacophore model with (A) 8f and (B) 8g. Aro stands for aromatic rings; Acc for H-bond acceptor; Don for H-bond donor; Cat for cationic group; PiN for p-ring; and Hyd for hydrophobic groups. Picture made by MOE [29].
Source publication
Cardiovascular disease is the most common cause for mortality and morbidity in the
developed world, which risk is inversely related to the HDL cholesterol levels.
Therefore, there is a great interest in developing new CETP inhibitors capable of
raising HDL as a novel approach for prevention of cardiovascular disease.
Herein, synthesis and character...
Citations
... There are four inhibitors of CETP that have been in clinical development: torcetrapib, dalcetrapib, anacetrapib, and evacetrapib [10]. Previously, the Sheikha et al prepared various CETP inhibitors, such as benzylamino-methanones [11], substituted benzamides [12,13], and fluorinated benzamides [14]. In a former study for our group, potential aromatic sulfonamide CETP inhibitors were revealed [15,16]. ...
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.
Objective
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.
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.
... Earlier, our team designed and synthesized diverse CETP inhibitors such as: benzylidene-amino methanones [10], benzylamino-methanones [11], N-(4-benzyloxyphenyl)-4-methylbenzenesulfonamides [12], N-(4-benzylamino-phenyl)-toluene-4-sulfonic acid esters [12], chlorobenzyl benzamides [13], fluorinated benzamides [14] (Fig. 1), substituted benzyl benzamides [15][16][17], and aromatic sulfonamides [18,19]. In an effort to optimize our previously prepared fluorinated benzamides (1a-1c, Fig. 1), and to better understand the structure activity relationship of this novel series of inhibitors, new derivatives were synthesized and explored by replacing the fluorine substituent (X) in 1a-1c with the bulkier trifluoromethyl group at ortho-, meta-, and para-positions. ...
... Additionally, some analogues form Hbond with C13, I215, and S230 ( Table 2). The importance of such residues was described by our previous computational studies [14,15,17]. ...
Background:
Hyperlipidemia is considered a major risk factor for the progress of atherosclerosis.
Objective:
Cholesteryl ester transfer protein (CETP) facilitates the relocation of cholesterol esters from HDL to LDL. CETP inhibition produces higher HDL and lower LDL levels.
Methods:
Synthesis of nine benzylamino benzamides 8a-8f and 9a-9c was performed.
Results:
In vitro biological study displayed potential CETP inhibitory activity, where compound 9c had the best activity with an IC50 of 1.03 µM. Induced-fit docking demonstrated that 8a-8f and 9a-9c accommodated the CETP active site and hydrophobic interaction predominated ligand/ CETP complex formation.
Conclusion:
Pharmacophore mapping showed that this scaffold endorsed CETP inhibitors features and consequently elaborated the high CETP binding affinity.
... Besides, evacetrapib study was terminated due to its low efficacy, while anacetrapib is still under further investigation [12]. Earlier our group design and synthesize different potential CETP inhibitors ( Figure 2) such as: benzylideneamino methanones [13], benzyl-amino-methanones [14], N-(4-benzyloxyphenyl)-4-methyl-benzenesulfonamides, N-(4-benzylamino-phenyl)-toluene-4-sulfonic acid esters [15], chlorobenzyl benzamides [16], fluorinated benzamides [17,18], substituted benzyl benzamides [19,20] and aryl sulfonamides [21,22]. ...
... The methyl benzoate intermediates 5a-d were synthesized as previously described [16][17][18][19][20] and purified by column chromatography using different concentrations of cyclohexane and ethyl acetate. The preparation of the acyl intermediates 7a-d from methyl esters 5a-d was carried out as formerly stated [16][17][18][19][20]. ...
... The methyl benzoate intermediates 5a-d were synthesized as previously described [16][17][18][19][20] and purified by column chromatography using different concentrations of cyclohexane and ethyl acetate. The preparation of the acyl intermediates 7a-d from methyl esters 5a-d was carried out as formerly stated [16][17][18][19][20]. ...
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.
... Formerly, our group synthesized a series of CETP inhibitors with various scaffolds, including benzylidene-aminomethanones [14], benzylamino-methanones [15], N-(4benzyloxyphenyl)-4-methylbenzene-sulfonamides, N-(4benzylamino-phenyl)-toluene-4-sulfonic acid esters [16], chlorobenzyl benzamides [17], substituted benzyl benzamides [18,19], and fluorinated benzamides [20,21]. Formerly, potential inhibitors of CETP have been discovered by our group, which are hit compounds A, B and C, as shown in Fig. (1). ...
Background
Cardiovascular disease is one of the leading causes of death. Atherosclerosis causes arterial constriction or obstruction resulting in acute cardiovascular illness. Cholesteryl ester transfer protein (CETP) facilitates reverse cholesterol transport. It supports transfer of cholesteryl ester from HDL to LDL and VLDL. Inhibition of CETP by drugs limits cardiovascular disease, by decreasing LDL and increasing HDL.
Objectives
In this study, fourteen trifluoromethyl substituted benzene sulfonamides 6a-6g and 7a-7g were prepared.
Methods
The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR and HR-MS. They were in vitro tested to estimate their CETP inhibitory activity.
Results
In vitro biological evaluation showed that compounds 7d-7f had the highest inhibitory activity with 100% inhibition, while the inhibition observed by compounds 6a-6g, 7a-7c and 7g ranged from 2%-72% at 10 µM concentration. It was found that the addition of a fourth aromatic ring significantly improved the activity, which may be due to the hydrophobic nature of CETP. Also, presence of ortho-chloro, meta-chloro and para-methyl substituents result in high inhibitory activity.
Conclusion
The induced fit docking studies revealed that hydrophobic interaction guided ligand/CETP binding interaction in addition to H-bond formation with Q199, R201, and H232. Furthermore, pharmacophore mapping demonstrated that this series satisfies the functionalities of the current CETP inhibitors.
... 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). ...
... 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). New oxoacetamido-benzamide analogs 9a-g were designed and synthesized by varying the aromatic ring meta substitution (H, Cl, OCH 3 , CH 3 ) for the F-atom, in addition to varying the aromatic ring para substitution with either trifluoromethoxy or trifluoromethyl groups. ...
... Preparation of 3-aminobenzoic acid methyl ester (3) and the next methyl 3-(4-(trifluoromethoxy)benzylamino) benzoate intermediate (5a) were carried out as previously described (Abu Khalaf et al., 2017a;Abu Khalaf et al., 2017b;Abu Khalaf et al., 2017c). Purification was achieved by column chromatography using cyclohexane:ethyl acetate (8.5:1.5) as the eluent. ...
... Formerly, our group synthesized a series of CETP inhibitors with various scaffolds including benzylideneamino-methanones [23], benzylamino-methanones [24], N-(4-benzyloxyphenyl)-4methylbenzene-sulfonamides, N-(4-benzylamino-phenyl)-toluene-4-sulfonic acid esters [25], chlorobenzyl benzamides [26], substituted benzyl benzamides [27,28], and fluorinated benzamides [29,30]. In continuation of our earlier work, structural modifications were carried out on our previously discovered potential CETP inhibitor, hit 1, which had an IC 50 of 1.9 µM (Fig. 1). ...
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 benzeneulfonamides 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.
... In our previous studies, a series of potential CETP inhibitors were designed and synthesized, including benzylideneamino-methanones [25], benzylamino-methanones [26], N-(4-benzyloxyphenyl)-4-methylbenzene-sulfonamides, N-(4benzylamino-phenyl)-toluene-4-sulfonic acid esters [27], chlorobenzyl benzamides [28], substituted benzyl benzamides [29,30], and fluorinated benzamides [31]. In the current research, and as a continuation of the previous work, synthesis, characterization, and molecular modeling of a variety of 3,5-bis(trifluoromethyl)benzylamino benzamides and biological testing against CETP were carried out in order to investigate the structure-activity relationship for benzamide derivatives. ...
Background
There is an alarming spread of cases of lipid-disorders in the world that occur due to harmful lifestyle habits, hereditary risk influences, or as a result of other illnesses or medicines. Cholesteryl ester transfer protein (CETP) is a 476-residue lipophilic glycoprotein that helps in the transport of cholesteryl ester and phospholipids from the atheroprotective HDL to the proatherogenic LDL and VLDL. Inhibition of CETP leads to elevation of HDL cholesterol and reduction of LDL cholesterol and triglycerides, so it's considered a good target for the treatment of hyperlipidemia and its comorbidities.
Objectives
In this research synthesis, characterization, molecular modeling and biological evaluation of eight 3,5-bis(trifluoromethyl)benzylamino benzamides 9a-d and 10a-d were carried out.
Methods
The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR and HR-MS. They were in vitro biologically tested to estimate their CETP inhibitory activity.
Results
These compounds offered inhibitory effectiveness ranging from 42.2% to 100% at a concentration of 10 µM. Compounds bearing unsubstituted three aromatic rings (9a) or ortho-CF3 substituted (9b) were the most effective compounds among their analogs and showed IC50 values of 1.36 and 0.69 μM, respectively. The high docking scores of 9a-d and 10a-d against 4EWS imply that they might be possible CETP inhibitors. Pharmacophore mapping results demonstrate that the series approves the fingerprint of CETP active inhibitors and therefore explains their high binding affinity against CETP binding site.
Conclusion
This work concludes that 3,5-bis(trifluoromethyl)benzylamino benzamides can serve as a promising CETP inhibitors lead compounds.
... The resulted pharmacophore model was adopted in the design and synthesis of acridines [21], N 4sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives [22] and sulfamoyl-phenyl acid esters [23] DPP-IV inhibitors. The use of such methodology was reported earlier in the discovery of new lead compounds for the inhibition of cholesteryl ester transfer protein [24][25][26][27][28][29], β-D-glycosidases [30][31][32], N-myristoyl transferase [33], and phosphoinostide 3-kinase [34][35][36]. ...
Background:
Lately, diabetes has become the main health concern for millions of people around the world. Dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged as a new class of oral antidiabetic agents. Formerly, acridines, N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives, and sulfamoyl-phenyl acid esters were designed and developed as new DPP-IV inhibitors.
Objective:
This study aims to develop a pharmacophore model of DPP-IV inhibitors and to evaluate phenanthridines as a novel scaffold for inhibiting DPP-IV enzyme. In addition, to assess their binding interactions with the enzyme through docking in the binding site of 4A5S (PDB).
Methods:
Herein, Quantum-Polarized Ligand Docking (QPLD) and ligand-based pharmacophore modeling investigations were performed. Three novel 3,8-disubstituted-6-phenyl phenanthridine derivatives 3-5 have been designed, synthesized and characterized. In vitro biological testing against DPP-IV was carried out using fluorometric assay kit.
Results:
QPLD study demonstrates that compounds 3-5 forms H-bond with Lys554, Trp629, and Tyr631, besides charge transfer interaction between their aromatic rings and the aromatic rings of Tyr547 and Tyr666. Moreover, they fit the three pharmacophoric point features of DPP-IV inhibitors and were proven to have in vitro DPP-IV inhibitory activity where compound 5 displayed a % inhibition of 45.4 at 100 μM concentration.
Conclusion:
Phenanthridines may serve as a potential lead compound for developing new DPP-IV inhibitors as a promising antidiabetic agent. Computational results suggest future structural simplification.
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.
Background
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.
Method
and their structure was fully determined using 1H-NMR, 13C-NMR, HR-MS, and IR.
Conclusion
Ligandfit docking experiment revealed the difference in the binding mode among the synthesized compounds which is reflected on their CETP inhibitory activity.
BACKGROUND: There is a strong negative relationship between high-density lipoprotein cholesterol (HDL-C) and the risk of cardiovascular disease (CVD). Cholesterol ester transfer protein (CETP) is a glycoprotein transporter that transfers cholesterol esters to very low-density lipoprotein and low-density lipoprotein cholesterol (LDL-C). The CETP inhibitor is a new strategy against CVD because of its ability to increase HDL-C. Various Indonesian plants have not been optimally used, and in silico phytochemical screening of these plants showing potential as CETP inhibitors is still limited. AIM: This study for exploring Indonesian phytochemicals as CETP inhibitors for new CVD treatments. METHODS: We screened 457 phytochemicals registered in the herbal database and met Lipinski’s rule of five. Their molecular structures were downloaded from the PubChem database. The three-dimensional structures of CETP and dalcetrapib (the CETP inhibitor standard) were obtained from a protein data bank (http://www.rcsb.org/pdb/) with the 4EWS code and ZINC database with the ZINC03976476 code, respectively. CETP–dalcetrapib binding complexes were validated 5 times using AutoDock Vina 1.1.2 software. Interactions between CETP and phytochemicals were molecularly docked with the same software and visualized using Pymol 1.8× software. RESULTS: Dalcetrapib had a docking score of −9.22 kcal/mol and bound to CETP at Ser230 and His232 residues. The 11 phytochemicals had lower binding scores than dalcetrapib, but only L-(+)-tartaric acid, chitranone, and oxoxylopine could interact with CETP at the Ser230 residue. These are commonly found in Tamarindus indica, Plumbago zeylanica, and Annona reticulata, respectively. CONCLUSION: L-(+)-Tartaric acid, chitranone, and oxoxylopine show potential as CETP inhibitors in silico.
