Elsevier

Bioorganic & Medicinal Chemistry

Volume 14, Issue 17, 1 September 2006, Pages 6027-6033
Bioorganic & Medicinal Chemistry

Oxazolones: New tyrosinase inhibitors; synthesis and their structure–activity relationships

https://doi.org/10.1016/j.bmc.2006.05.014Get rights and content

Abstract

The tyrosinase inhibitory potential of seventeen synthesized oxazolone derivatives has been evaluated and their structure–activity relationships developed in the present work. All the synthesized derivatives, 319, demonstrated excellent in vitro tyrosinase inhibitory properties having IC50 values in the range of 1.23 ± 0.37–17.73 ± 2.69 μM, whereas standard inhibitors l-mimosine and kojic acid have IC50 values 3.68 ± 0.02 and 16.67 ± 0.52 μM,, respectively. Compounds 48 having IC50 values 3.11 ± 0.95, 3.51 ± 0.25, 3.23 ± 0.66, 1.23 ± 0.37, and 2.15 ± 0.75, respectively, were found to be very active members of the series, even better than both the standard inhibitors. However, compounds 3, 911, 13, 14, 16, 17, and 19 were found to be better than kojic acid but not l-mimosine. (2-Methyl-4-[E,2Z)-3-phenyl-2-propenyliden]-1,3-oxazol-5(4H)-one (7) bearing a cinnamyol residue at C-4 of oxazolone moiety and an IC50 = 1.23 ± 0.37 μM was found to be the most active one among all tested compounds. These studies reveal that the substitution of functional group (s) at C-4 and C-2 positions plays a vital role in the activity of this series of compounds. It is concluded that compound 7 may act as a potential lead molecule to develop new drugs for the treatment of tyrosinase based disorders.

Graphical abstract

Seventeen oxazolone derivatives were synthesized, characterized, and screened for tyrosinase inhibition.

  1. Download : Download full-size image

Introduction

Tyrosinase (EC 1.14.18.1), a multifunctional copper-containing enzyme, is widely distributed in the plant and animal kingdom. It is responsible for catalyzing ortho-hydroxylation of phenols and ortho-phenol oxidation to corresponding quinones.1, 2, 3, 4 Tyrosinase inhibitors are clinically useful for the treatment of skin diseases associated with melanin hyperpigmentation and applied in cosmetics for whitening and depigmentation after sunburn.5 Melanin is a heteropolymer of indole compounds and is produced inside melanosomes by the action of the tyrosinase enzyme on the tyrosinase precursor material in melanocytes. It has recently been discovered that some other factors such as metal ions and the TRP-1 and TRP-2 enzymes also contribute to the production of melanin. However, tyrosinase plays a critical role in the regulation of melanin biosynthesis. Therefore, many tyrosinase inhibitors that suppress melanogenesis have been widely studied with the aim of developing preparations for the treatment of hyperpigmentation.6

In insects, several enzymes have been reported7 to generate o-diphenols and quinones that cure pigmentation heal wounds, encapsulate parasite or help sclerotize. Such enzymes may be an alternative target site for the control of insect pests. In food industry, tyrosinase is effective for the enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Controlling enzymatic browning is essential during fruit pulp manufacturing process.

Oxazolones exhibit a wide spectrum of pharmacological activities including anticancer, antimicrobial, antifungal, antagonistic, sedative, etc. Oxazolones that are internal anhydrides of acyl amino acids make an important class of five-membered heterocycles. These are highly versatile intermediates used for the synthesis of several organic molecules, including amino acids, peptides,8, 9, 10, 11, 12, 13 antimicrobial or antitumor compounds,14, 15 immunomodulators,16 heterocyclic precursors,17, 18, 19, 20 for biosensors coupling, and/or photosensitive composition devices for proteins.21 Some oxazolones have shown a wide range of pharmaceutical properties.22 These can easily be prepared from N-acyl amino acids by dehydration.

In continuation of our research work on oxazolone derivatives as potential lead compounds in our drug discovery program,23, 24, 25, 26, 27 we synthesized a variety of oxazolones and screened them randomly for their tyrosinase inhibitory properties.

Section snippets

Chemistry

In recent past, we investigated a variety of classes of compounds for their potential use in medicinal chemistry. In the present study, seventeen oxazolones 319 were synthesized from commercially available glycine with acetic anhydride or benzoyl chloride in the presence of anhydrous sodium acetate followed by Erlenmeyer condition with appropriate aldehyde in very high yields.28, 29, 30 All the oxazolones were isomerized by heating them with polyphosphoric acid on a water bath at 80–90 °C for 2 

Conclusion

Present studies suggested that the substitutions of functional group (s) at C-4 and C-2 positions of oxazolone are crucial for tyrosinase inhibitory activity of this class of compounds. It is concluded that an extension of conjugation through an aliphatic double bond present at C-4 position of oxazolone moiety and a phenyl ring present at C-2 play a pivotal role in activity. Of this series, the most active compound 7 may act as a potential lead molecule for the future research in the field of

General experimental

Melting points were determined on a Büchi 434 melting point apparatus and are uncorrected. NMR was performed on a Bruker AM 300 and 500 MHz, respectively. CHN analysis was performed on a Carlo Erba Strumentazion-Mod-1106, Italy. Ultraviolet (UV) spectra were recorded on Perkin-Elmer Lambda-5 UV/vis spectrometer for MEOH. Infrared (IR) spectra were recorded on JASCO IR-A-302 Spectrometer. Electron impact mass spectra (EIMS) were recorded on a Finnigan MAT-311A, Germany. Thin-layer chromatography

Acknowledgment

This work was financially supported by Pakistan Science Foundation (PSF) under ‘Research Grant To Active Scientist/Technologist of Pakistan.’

References and notes (31)

  • K. Gottwald et al.

    Tetrahedron

    (1999)
  • J. Meiwes et al.

    Tetrahedron: Asymmetry

    (1997)
  • D. Seebach et al.

    Tetrahedron

    (1997)
  • C. Cativiela et al.

    Tetrahedron

    (1997)
  • E. Buñuel et al.

    Tetrahedron

    (1995)
  • D. Donati et al.

    Tetrahedron

    (1996)
  • A.P. Martinez et al.

    Tetrahedron

    (1964)
  • M.L. Gelmi et al.

    Tetrahedron

    (1997)
  • M.A. Mesaik et al.

    Bioorg. Med. Chem.

    (2004)
  • S. Kojima et al.

    Tetrahedron Lett.

    (1998)
  • M.T.H. Khan et al.

    Bioorg. Med. Chem.

    (2005)
    K.M. Khan et al.

    Chem. Biodivers.

    (2005)
  • F. McCapra et al.

    J. Chem. Soc., Chem. Commun.

    (1988)
  • Y. Iwakura et al.

    Tetrahedron

    (1967)
  • (a)A ratio of 1:10 of the oxazolones to PPA was used to get...Y.S. Rao

    J. Org. Chem.

    (1976)
  • C.R. Hider et al.

    Biol. Chem. J.

    (1998)
  • Cited by (0)

    View full text