A theoretical study of benzaldehyde derivatives as tyrosinase inhibitors using Ab initio calculated NQCC parameters

Document Type : Original article


1 Department of Chemistry, Payame Noor University, Tehran, Iran

2 Department of Ceramic, Materials and Energy Research Center, Karaj, Iran


Tyrosinase is a multifunctional copper-containing enzyme. It can catalyze two distinct reactions of melanin synthesis and benzaldehyde derivatives, which are potential tyrosinase inhibitors.  To find the relationships between charge distributions of benzaldehyde and their pharmaceutical behavior, the present study aimed at investigating nuclear quadrupole coupling constants of quadrupolare nuclei in the functional benzaldehyde group and calculating some its derivatives. In addition, the differences between the electronic structures of various derivatives of this depigmenting drug were examined. All ab initio calculations were carried out using Gaussian 03. The results predicted benzaldehyde derivatives to be bicentral inhibitors; nevertheless, the oxygen or hydrogen contents of the aldehyde group were not found to be the only active sites. Furthermore with the presence of the aldehyde group, the terminal methoxy group in C4 was found to contribute to tyrosinase inhibitory activities. In addition, an oxygen atom with high charge density in the side chain was found to play an important role in its inhibitory effect.


1. Briganti S, Camera E, Picardo M. Chemical and instrumental approaches to treat hyperpigmentation. Pigment Cell Res 2003;16:101-108.
2. Sanchez-Ferrer A, Rodriguez-Lopez JN, Garcia-Canovas F, Garcia-Carmona F. Tyrosinase: a comprehensive review of its mechanism. Biochim Biophys Acta 1995; 1247:1-5.
3. Seo SY, Sharma VK, Sharma N. Mushroom tyrosinase: recent prospects. J Agric Food Chem 2003;51;2837-2853.
4. Maeda K, Fukuda M. In vitro effectiveness of several whitening cosmetic components in human melanocytes. J Soc Cosmet Chem 1991;42:361-368.
5. Delogu G, Podda G, Corda M, Fadda MB, Fais A, Era B. Synthesis and biological evaluation of novel series of bis-salicylaldehydes as mushroom tyrosinase inhibitors. Bioorg Med Chem Lett 2010;20:6138-6140.
6. Gong S. Kinetics of inhibition effect of 4-hydroxy-3-methoxybenzoic acid on mushroom tyrosinase. Adv Mater Res 2013;641-642:967-970
7. Maghsoudi S, Adibi H, Hamzeh M, Ashrafi-Kooshk MR, Rezaei-Tavirani M, Khodarahmi R. Kinetic of mushroom tyrosinase inhibition by benzaldehyde derivatives. J Rep Pharm Sci 2013;2:156-164.
8. Iyidogan NF, Bayindirh A. Effect of L-cysteine, kojic acid and 4 hexylresorcinol combination on inhibition of enzymatic browning in Amasya apple juice. J Food Eng 2004;62:299-304.
9. Matsuura R, Ukeda H, Sawamura M. Tyrosinase inhibitory activity of citrus essential oils. J Agric Food Chem 2006;54:2309-2313.          
10. Nerya O, Musa R, Khatib RS, Tamir Vaya J. Chalcones as potent tyrosinase inhibitors: The effect of hydroxyl positions and numbers. Phytochem Phytochem 2004;65:1389-1395.
11. Kubo I, Kinst-Hori I. Tyrosinase inhibitors from cumin. J Agric Food Chem 1998; 46:5338-5341.
12. Nihei KI, Yamagiwa Y, Kamikawa T, Kubo I. 2-Hydroxy-4-isopropylbenzaldehyde, a
potent partial tyrosinase inhibitor. Bioorg Med Chem Lett 2004; 14: 681-683.
13. Lucken EAC. Nuclear quadrupole coupling constants. Academic Press, London, 1969, Ch.1-4.
14. Andrew RL. Molecular modeling principles and applications. Longman, Singapore Publishers, Singapore, 1997, Ch. 5.
15. Graybeal JD. Molecular spectroscopy. McGraw Hill, Singapore, 1988, Ch. 10.
16. Slichter CP. Principles of magnetic resonance. Springer-Verlag, New York, 1992, Ch. 10.
17. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Zakrzewski VG, Montgomery JA, Stratmann RE Jr, Burant JC, Dapprich S, Millam JM, Daniels AD, Kudin KN, Strain MC, Farkas O, Tomasi J, Barone V, Cossi M, Cammi R, Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Petersson GA, Ayala PY, Cui Q, Morokuma K, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J, Ortiz JV, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Gomperts R, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Gonzalez C, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Andres JL, Gonzalez C, Head-Gordon M, Replogle ES, Pople JA. GAUSSIAN 03, Gaussian Inc. Pittsburgh, PA, 2003.
18. Becke AD. Density functional thermo-chemistry, III. The role of exact exchange. J Chem Phys 1993;98:5648-5652.
19. Lee C, Yang W, Parr RG. Development of the Colle-Salvetti correlation energy formula into a functional of the electron density. Phys Rev B 1988; 37:785-789.
20.Miehlich B, Savin A, Stoll H, Preuss H. Results obtained with the correlation  energy  density  functional  of Becke  and  Lee, Yang  and  Parr.  Chem Phys Lett 1989;157:200-206.
21. Cohen MH, Reif F. Quadrupole effects in nuclear magnetic resonance studies of solids. Solid State Phys 1975;5:321-438.
22. Hadipour NL, Rafiee MA, Javaheri M, Mousavi MK. Ab-initio calculations of NQR 35Cl frequency in organo-germanium chlorides and its dependency on Ge-O Distance. Chem Phys Lett 2002;356:445-450.
23. Rafiee MA, Hadipour NL, Naderi-Manesh H. The correlation study of quinoline derivatives and their pharmaceutical behavior by ab initio calculated NQR parameters. J Comput  Aided Mol  Des  2004;18:215-220.
24.pyykko P.Spectroscopic nuclear quadrupole moments.Mol Phys 2001:99:1617-1629.
25. Rafiee MA, Hadipour NL, Naderimanesh, H. The role of charge distribution on the antimalarial activity of artemisinin analogues. J Chem Inf Model 2005;45:366-370.
26. Rafiee MA, Partoee T. Investigation of the binding affinity between styrylquinoline inhibitors and HIV integrase using calculated nuclear Quadrupole coupling constant (NQCC) parameters (A theoretical ab initio study). Bull Korean Chem Soc 2011;32: 208-212.
27. Kubo I, Kinst-Hori I. 2-Hydroxy-4-methoxybenzaldehyde: a potent tyrosinase
inhibitor from African medicinal plants. Planta Med 1999;65:19-22.
28. de la Lande A, Maddaluno J, Parisel O, Darden TA, Piquemal JP. Theoretical study of the docking of competitive inhibitors at a model of tryrosinase enzyme active site: joint broken symmetry/spin-flip DFT study. Interdiscip Sci 2010;2:3-11.
29. Yi W, Cao R, Peng W, Wen H, Yan Q, Zhou B, Ma L, Song H. Synthesis and biological evaluation of novel 4-hydroxybenzaldehyde derivatives as tyrosinase inhibitors. Eur J Med Chem 2010;45:639-646.