Synthesis of N-1,2-benzisoxazolin-3-ones as potential antifungal agents,
bioisosters of seleno-compound ebselen
Fregnan, A.M.*1; Fernandes Junior, A.A. 1; Souza, T.B. 1; Carvalho, D.T1.
[email protected]
1
Faculdade de Ciências Farmacêuticas - Universidade Federal de Alfenas-UNIFAL MG. Rua Gabriel Monteiro da Silva,
700 Centro - Alfenas / MG CEP: 37130-000.
Keywords: ebselen, benzisoxazolinones, antifungal agents
Introduction
The search for new agents with antifungal activity
is intensifying in recent years. The enzyme
H+-ATPase present in the fungi plasma membrane is
a promising new target, since it is not found in host
cells. Ebselen, a seleno-organic compound, proved to
be a good inhibitor of this H+-ATPase and it is used in
some studies as a standard compound to inhibit this
enzyme1.
In adition to that, heterocycles known as
benzisoxazolinones, chemically similar to ebselen,
were not well explored as bioactive agents up to now.
In this context, it is proposed herein the synthesis of
benzisoxazolinone derivatives, designed according to
the medicinal chemistry strategy of bioisosterism, for
further exploitation as antifungal candidates.
for their activity against Candida species sp. through
microdilution tests, in which the IC50 values will be
calculated. In addition, the most promising products
will have their cytotoxicity profiles evaluated to
determine the selectivity index. Also, the better
compounds will be evaluated as inhibitors of fungal
H+-ATPase.
i: Hexamethylenetetramine, glacial acetic acid, 140ºC; ii: Ag2O,
NaOH, 25ºC; iii: AcCl, pyridine, 25ºC; iv: SOCl2, DMF, CH2Cl2,
25ºC; NHROH, Na2CO3, CH2Cl2,THF, 25ºC; vi: DIAD, Ph3P, THF,
25ºC.
Results and Discussion
New compounds, analogues to ebselen, were
designed and synthesized. They have an oxygen in
substitution to selene atom in the bicyclic system and
differ to each other by groups attached to aromatic
ring (Figure 1).
Figure 2. Synthetic route for achieving the
benzisoxazolinone derivatives.
Conclusions
Six new compounds were synthesized as
bioisosters of ebselen for antifungal evaluation. Their
good chemical stability and structural rigidity may
serve as a general structural motif for medicinal
chemistry applications. Some compounds were
obtained in low yields and optimizations are being
performed in purification methods.
Figure 1. Comparision of
synthesized benzisoxazolinone.
ebselen
and
Final compounds were obtained by a six-step
synthetic route (Figure 2). The cyclization is the key
point to obtain the heterocycle and this was achieved
by a Mitsunobu reaction with DIAD and Ph3P in THF
at room temperature, as an adaptation of what was
reported by Shi.2
The obtained products were characterized by the
usual spectrometric methods and will be evaluated
Acknowledgements
The authors are thankful to CAPES for the
scholarship and to CNPq and CAPES for additional
financial support.
____________________
1
ARINO, J. Microbiology and Molecular Biology Reviews. 2010 74,
95-120. PARNHAM, M. Biochemical Pharmacology. 2013, 86,
1248–1253.
2
SHI, G. Q. Tetrahedron Letters. 2000 , 41, 2295–2298.