Abstract
A quantitative structure–activity relationship (QSAR) study was performed for a series of antihyperlipidemic morpholine derivatives, exhibiting squalene synthase (SQS) inhibitory as well as antioxidant activity (inhibition of lipid peroxidation). Physico/stereo-chemical descriptors of low energy conformations of the compounds were calculated and a number of QSAR models with statistical significance and predictability were produced. The final models include chemical descriptors such as E LUMO, E HOMO–E LUMO gap, cLogP, electrostatic (FNSA1 and RNCS) as well as geometry (YZ SHADOW/YZ RECTANGLE) descriptors, indicating that electron affinity, along with molecular shape and electrostatic effects play a significant role in the compound’s described activities. These models provide some insight on the molecular mechanism of action of these derivatives and assist in the prediction of action in vitro as well as the design of more potent derivatives in the search for effective antiatherosclerosis agents.
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Notes
We used in the final models the unprotonated form of the compounds. Estimated (calculated) pka values for these compounds are 6.9 (±3). Thus, it is expected that the average, corresponding to 62–86% of the population of each compound is in the unprotonated form. It should be mentioned, however, that several models using the protonated molecules were also derived (results not shown).
References
Brown AJ, Mander EL, Gelissen IC, Kritharides L, Dean RT, Jessup W (2000) Cholesterol and oxysterol metabolism and subcellular distribution in macrophage foam cells. Accumulation of oxidized esters in lysosomes. J Lipid Res 41:226–237
Carpenter KL, Taylor SE, Ballantine JA, Fussell B, Halliwell B, Mitchinson MJ (1993) Lipids and oxidised lipids in human atheroma and normal aorta. Biochim Biophys Acta 1167:121–130
Charlton-Menys V, Durrington PN (2007) Squalene synthase inhibitors: clinical pharmacology and cholesterol-lowering potential. Drugs 67:11–16
Cheng Z, Ren J, Li Y, Chang W, Chen Z (2002) Study on the multiple mechanisms underlying the reaction between hydroxyl radical and phenolic compounds by qualitative structure and activity relationship. Bioorg Med Chem 10:4067–4073
Cheng Z, Ren J, Li Y, Chang W, Chen Z (2003) Establishment of a quantitative structure–activity relationship model for evaluating and predicting the protective potentials of phenolic antioxidants on lipid peroxidation. J Pharm Sci 92:475–484
Chou JT, Jurs PC (1979) Computer-assisted computation of partition coefficients from molecular structures using fragment constants. J Chem Inf Comput Sci 19:172–178
Davidson MH (2007) Squalene synthase inhibition: a novel target for the management of dyslipidemia. Curr Atheroscler Rep 9:78–80
Gramatica P (2007) Principles of QSAR models validation: internal and external. QSAR Comb Sci 26:694–701
Karelson M, Lobanov VS, Katritzky AR (1996) Quantum-chemical descriptors in QSAR/QSPR studies. Chem Rev 96:1027–1044
Katritzky AR, Lobanov VS, Karelson M (1995) CODESSA—comprehensive descriptors for structural and statistical analysis: training manual. University of Florida, Gainesville, USA
Khlebnikov AI, Schepetkin IA, Domina NG, Kirpotina LN, Quinn MT (2007) Improved quantitative structure-activity relationship models to predict antioxidant activity of flavonoids in chemical, enzymatic, and cellular systems. Bioorg Med Chem 15:1749–1770
Kleinova M, Hewitt M, Brezova V, Madden JC, Cronin MT, Valko M (2007) Antioxidant properties of carotenoids: QSAR prediction of their redox potentials. Gen Physiol Biophys 26:97–103
Kourounakis AP, Charitos C, Rekka EA, Kourounakis PN (2008) Lipid-lowering (hetero)aromatic tetrahydro-1, 4-oxazine derivatives with antioxidant and squalene synthase inhibitory activity. J Med Chem 51:1865–5861
Leo AJ, Hansch C (1971) Linear free-energy relationships between partitioning solvent systems. J Org Chem 36:1539–1544
Lien EJ, Guo ZR, Li RL, Su CT (1982) Use of dipole moment as a parameter in drug–receptor interaction and quantitative structure–activity relationship studies. J Pharm Sci 71:641–655
Nikitakis A, Kourounakis A (2008) QSAR of substituted morpholine derivatives with antioxidant and squalene synthase inhibitory activities. In: Proceedings of the 13th hellenic symposium of medicinal chemistry, Athens, Greece, March 14–15, 2008
Pearson RG (1986) Absolute electronegativity and hardness correlated with molecular orbital theory. Proc Natl Acad Sci USA 83:8440–8441
Pearson RG (1989) Absolute electronegativity and hardness—applications to organic chemistry. J Org Chem 54:1423–1430
Pedretti A, Villa L, Vistoli G (2002) VEGA: a versatile program to convert, handle and visualize molecular structure on Windows-based PCs. J Mol Graph Model 21:47–49
Rackova L, Snirc V, Majekova M, Majek P, Stefek M (2006) Free radical scavenging and antioxidant activities of substituted hexahydropyridoindoles. Quantitative structure–activity relationships. J Med Chem 49:2543–2548
SPARTAN’04 (2004) WAVEFUNCTION, Inc., Irvine, CA
Stanton DT, Jurs PC (1990) Development and use of charged partial surface area structural descriptors in computer assisted quantitative structure property relationship studies. Anal Chem 62:2323–2329
Tetko IV, Tanchuk VY (2002) Application of associative neural networks for prediction of lipophilicity in ALOGPS 2.1 program. J Chem Inf Comput Sci 42:1136–1145
Todeschini VC (2000) Handbook of molecular descriptors. Wiley, New York
van der Waterbeemd Han (ed) (1994) Advanced computer-assisted techniques in drug discovery. VCH Weinheim, New York, pp 111–130
Acknowledgments
The authors wish to thank Dr. A. Katritzky for kindly providing and allowing the use of CODESSA software and the Special Account for Research Grants of the University of Athens (Grant 70/4/7842) for financial support.
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Nikitakis, A., Kourounakis, A.P. QSAR of substituted morpholines with antioxidant and squalene synthase inhibitory activity. Med Chem Res 20, 566–575 (2011). https://doi.org/10.1007/s00044-010-9351-0
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DOI: https://doi.org/10.1007/s00044-010-9351-0