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

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 IC50 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.

Synthesis, Molecular Modeling and Biological Evaluation of Novel Trifluoromethyl Benzamides as Promising CETP Inhibitors.

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.

Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation.

BACKGROUND: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein, and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduce the deterioration of gutderived endogenous incretin hormones secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of the pancreas. OBJECTIVE: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors were carried out. The target compounds were docked to study the molecular interactions and binding affinities against the DPP-IV enzyme. METHODS: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. RESULTS: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 µM concentration, where compound 3d harboring ortho- fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669, and Y752 backbones Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

Design and Synthesis of 4-O-Podophyllotoxin Sulfamate Derivatives as Potential Cytotoxic Agents.

4-O-Podophyllotoxin sulfamate derivatives were prepared using the natural lignan podophyllotoxin. The prepared compounds were afforded by reacting O-sulfonyl chloride podophyllotoxin with ammonia or aminoaryl/heteroaryl motif. Biological evaluation was performed in human breast cancer (MCF7), ovarian cancer (A2780), colon adenocarcinoma (HT29), and normal lung fibroblast (MRC5) cell lines. Compound 3 exhibited potent inhibitory activity and good selectivity margin. Compounds 2, 3, and 7 exerted apoptotic effect in MCF7 cells in a dose-dependent manner. The cytotoxicity of the verified compounds was inferior to that of podophyllotoxin.

Design, synthesis, and biological evaluation of benzylamino-methanone based cholesteryl ester transfer protein inhibitors.

Cholesteryl ester transfer protein (CETP) is a glycoprotein involved in transporting lipoprotein particles and neutral lipids between high-density lipoprotein (HDL) and low density lipoproteins (LDL) and therefore its a proper target for treating dyslipidemia and related disorders. Guided by our previously-reported pharmacophore and QSAR models for CETP inhibition, we synthesized and bioassayed a series of benzylamino-methanones. The most potent illustrated 30% CETP inhibition at 10 microM.

Synthesis, Structural Characterization and Docking Studies of Sulfamoyl- Phenyl Acid Esters as Dipeptidyl Peptidase-IV Inhibitors.

BACKGROUND: Diabetes mellitus is a major worldwide health concern that has several serious complications including retinopathy, neuropathy, nephropathy and macrovascular diseases. OBJECTIVE: Dipeptidyl peptidase-IV (DPP-IV) inhibitors, gliptins, are a new class of antidiabetic agents that potentiate the action of incretins in decreasing the blood glucose levels. METHODS: In the present study, synthesis and characterization of a series of ten N4-sulfonamido-acrylic and phthalamic acid methyl esters (3a-e and 5a-e) were achieved. RESULTS: In vitro anti-DPP-IV activity of the synthesized compounds was evaluated, where compound 3b demonstrated the best activity with a % inhibition of 41.7 at 10 µM concentration and an IC50 of 23.9 µM. Moreover, Glide docking experiments revealed that our targeted compounds accommodate the binding site of DPP-IV and tend to form H-bonding with the backbones of R125, E206, S209, D545, K554, W629, Y631, and G632. CONCLUSION: Modeling findings recommend the attachment of bulky hydrophobic group on the ester side of the structure in addition to harboring extra aromatic rings that might be beneficial for better binding interaction and biological activity.