Synthesis and evaluation of trimethoxyphenyl isoxazolidines as inhibitors of secretory phospholipase A2 with anti-inflammatory activity

  • Authors:
    • M. P. Sadashiva
    • A. Nataraju
    • H. Mallesha
    • R. Rajesh
    • B. S. Vishwanath
    • K. S. Rangappa
  • View Affiliations

  • Published online on: November 1, 2005     https://doi.org/10.3892/ijmm.16.5.895
  • Pages: 895-904
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Abstract

A series of trimethoxyphenyl isoxazolidine derivatives, 5a(i-v) and 5b(i-v), bearing different constituents at the 5th position of the isoxazolidine ring were synthesized and evaluated in vitro and in vivo for their inhibitory activity against purified group I and II phospholipase A2 (PLA2) enzymes from snake venom and human inflammatory synovial fluid. Irrespective of modification to the pharmacophore (isoxazolidine ring), they exhibited greater specificity for group II PLA2. The length of alkyl or aryl group at the 5th position, which alters the hydrophobic and aromatic property, was responsible for enhancing the inhibition towards PLA2 enzymes. All of the compounds quench the fluorescent property of the purified PLA2 enzyme, and quenching increases with the increase in length of alkyl or aryl group. The inhibitory effect of compounds appeared to be due to the direct interaction of compounds with the enzyme. Inhibition is substrate-dependent, and the inhibitor likely competes with the substrate for the same binding site of the enzyme. The IC50 value for the most potent interacting inhibitor 5b(v) was 54.8 µM. The most active interacting compounds 5a(v) and 5b(v) from in vitro inhibition of PLA2 activity showed similar potency in in vivo neutralization of PLA2-induced mouse paw edema and hemolytic activity.

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November 2005
Volume 16 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Sadashiva MP, Nataraju A, Mallesha H, Rajesh R, Vishwanath BS and Rangappa KS: Synthesis and evaluation of trimethoxyphenyl isoxazolidines as inhibitors of secretory phospholipase A2 with anti-inflammatory activity. Int J Mol Med 16: 895-904, 2005
APA
Sadashiva, M.P., Nataraju, A., Mallesha, H., Rajesh, R., Vishwanath, B.S., & Rangappa, K.S. (2005). Synthesis and evaluation of trimethoxyphenyl isoxazolidines as inhibitors of secretory phospholipase A2 with anti-inflammatory activity. International Journal of Molecular Medicine, 16, 895-904. https://doi.org/10.3892/ijmm.16.5.895
MLA
Sadashiva, M. P., Nataraju, A., Mallesha, H., Rajesh, R., Vishwanath, B. S., Rangappa, K. S."Synthesis and evaluation of trimethoxyphenyl isoxazolidines as inhibitors of secretory phospholipase A2 with anti-inflammatory activity". International Journal of Molecular Medicine 16.5 (2005): 895-904.
Chicago
Sadashiva, M. P., Nataraju, A., Mallesha, H., Rajesh, R., Vishwanath, B. S., Rangappa, K. S."Synthesis and evaluation of trimethoxyphenyl isoxazolidines as inhibitors of secretory phospholipase A2 with anti-inflammatory activity". International Journal of Molecular Medicine 16, no. 5 (2005): 895-904. https://doi.org/10.3892/ijmm.16.5.895