Palestinian Medical and Pharmaceutical Journal (Pal. Med. Pharm. J.)

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Keywords

• Benzamides
• Inhibitors
• Induced-fit docking
• Trifluoro-oxoacetamido
• CETP
• Pharmacophore

Abstract

Cardiovascular diseases are the first leading cause for death in the United States and the third globally. Cholesteryl ester transfer protein (CETP) is a glycoprotein excreted mainly from the liver and transfers cholesteryl esters from high-density lipoproteins to low-density lipoproteins. Inhibition of CETP activity decreases lipid transfers, which raises high-density lipoprotein cholesterol and lowers that of low-density lipoproteins. Cardiovascular risk is decreased when CETP activity is inhibited. There is a growing need for new CETP inhibitors which encourages us to conduct this research. In this work, synthesis of eighteen new trifluoro-oxoacetamido benzamides 9a-r was carried out by nucleophilic acyl substitution reaction to form the amide followed by characterization of the prepared derivatives using 1H-NMR, 13C-NMR and IR spectroscopy. In vitro study showed that the synthesized compounds 9a-r exhibited distinguished activity against CETP with IC50 values ranging from 1.24 µM to 7.16 × 10-8 µM, where compound 9l had the best activity. Induced-fit docking results illustrated that torcetrapib, anacetrapib, and 9a-r accommodated CETP binding cleft and that hydrophobic force predominated the inhibitor/CETP complex formation. Additionally, they bonded to C13, Q199, R201, and H232 residues through H-bond. ΔG of the verified analogues surpassed that of co-crystallized ligand (0RP) and anacetrapib anticipating the matching of analogues’ core structures to CETP key binding residues. Moreover, inhibitors 9a-r mapped the pharmacophore model’s fingerprint of CETP active inhibitors and subsequently elaborated the binding score values against CETP binding domain.

معلومات المقال

قيد النشر

الكلمات الإفتتاحية

• Benzamides
• Inhibitors
• Induced-fit docking
• Trifluoro-oxoacetamido
• CETP
• Pharmacophore

الملخص

Cardiovascular diseases are the first leading cause for death in the United States and the third globally. Cholesteryl ester transfer protein (CETP) is a glycoprotein excreted mainly from the liver and transfers cholesteryl esters from high-density lipoproteins to low-density lipoproteins. Inhibition of CETP activity decreases lipid transfers, which raises high-density lipoprotein cholesterol and lowers that of low-density lipoproteins. Cardiovascular risk is decreased when CETP activity is inhibited. There is a growing need for new CETP inhibitors which encourages us to conduct this research. In this work, synthesis of eighteen new trifluoro-oxoacetamido benzamides 9a-r was carried out by nucleophilic acyl substitution reaction to form the amide followed by characterization of the prepared derivatives using 1H-NMR, 13C-NMR and IR spectroscopy. In vitro study showed that the synthesized compounds 9a-r exhibited distinguished activity against CETP with IC50 values ranging from 1.24 µM to 7.16 × 10-8 µM, where compound 9l had the best activity. Induced-fit docking results illustrated that torcetrapib, anacetrapib, and 9a-r accommodated CETP binding cleft and that hydrophobic force predominated the inhibitor/CETP complex formation. Additionally, they bonded to C13, Q199, R201, and H232 residues through H-bond. ΔG of the verified analogues surpassed that of co-crystallized ligand (0RP) and anacetrapib anticipating the matching of analogues’ core structures to CETP key binding residues. Moreover, inhibitors 9a-r mapped the pharmacophore model’s fingerprint of CETP active inhibitors and subsequently elaborated the binding score values against CETP binding domain.