Conformational behaviour, intra-molecular hydrogen bonding, gas phase acidities and hydrolysisstudy of fibrate-type antihyperlipidemic drugs
Keywords:
fibrates, conformational analysis, hydrogen bondingAbstract
A theoretical study on fibrate-type drugs in gas phase is presented. All stable conformations of fibric acid (as common and active moiety of these drugs) were identified and optimized at B3LYP/6-31+g(d) level. The lowest energy is observed in the case of symmetric conformer with intramolecular hydrogen bond between carboxyllic hydrogen and phenoxy oxygen. Similar energy is possessed by asymmetric conformation without any hydrogen bond, existing in two mirrored stereoconfigurations. The fibric anion can exist in two conformations only, also symmetrical and asymmetrical. Substituents present at para- position in clofibric acid, fenofibric acid and ciprofibrate do not influence on the conformational behaviour of active fibric acid nor anion moiety. They have two rotational minima around benzene ring, one visibly deeper. However, the substituent influences geometry significantly in the case of bezafibrate, forming hydrogen bonds between amide hydrogen or second benzene ring hydrogens and carboxyllic oxygen. Bezafibrate anion possesses hydrogen bonds between carboxyllic oxygens and second benzene ring hydrogens. Although geometries of bezafibrate without any hydrogen bond can exist, they have much higher energy and they cannot be suspected in real life. Additionally, gas phase acidities (proton affinities) and hydrolysis enthalpies of clofibrate (to clofibric acid) and fenofibrate (to fenofibric acid) were calculated.
References
1. Ablise M. et al. Molecular pharmacophore determination of lipid lowering drugs with the receptor mapping method. Mini Rev. Med. Chem., 2, 97, 2002.
2. Chapman M.J., Fibrates: therapeutic review. Br. J. Diabetes Vasc. Dis. 6, 11, 2006.
3. Fazio S. et al. The role of fibrates in managing hyperlipidemia: mechanisms of action and clinical efficacy. Curr Atheroscler Rep, 6, 148, 2004.
4. Frisch et al. Gaussian 09, Gaussian, Inc., Wallingford CT, 2009.
5. Henry R.F. et al. Fenofibrate. Acta Cryst. E 59, 699, 2003.
6. Le Y. et al. Electronic structure and UV spectrum of fenofibrate in solutions. Int. J. Pharm. 358, 214, 2008.
7. Matin A. et al. 7-Hydroxy-benzopyran-4-one derivatives: a novel pharmacophore of peroxisome proliferator-activated receptor alpha and -gamma (PPARalpha and gamma) dual agonists. J. Med. Chem., 52, 6835, 2009.
8. Roy A.K. et al. Structures of the formic acid trimer. Chem. Phys. Lett. 386, 162, 2004.
9. Sashidhara K.V. et al. Synthesis and antihyperlipidemic activity of novel coumarin bisindole derivatives. Bioorg. Med. Chem. Lett. 20, 3065, 2010.
Downloads
Published
Issue
Section
License
Copyright (c) 2011 Authors
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 Unported License.
