Oxindole and its derivatives: A review on recent progress in biological activities.

An update on small molecule strategies targeting leishmaniasis

The parasites of the order kinetoplastidae including Leishmania
spp. emerge from most ancient phylogenic branches of
unicellular eukaryotic lineages. In their life cycle, topoisomerase
I plays a significant role in carrying out vital cellular
processes. Camptothecin (CPT), an inhibitor of DNA topoisomerase
I, induces programmed cell death (PCD) both in the
amastigotes and promastigotes form of L. donovani parasites.
CPT-induced cellular dysfunction in L. donovani promastigotes
is characterized by several cytoplasmic and nuclear
features of apoptosis. CPT inhibits cellular respiration that
results in mitochondrial hyperpolarization taking place by
oligomycin-sensitive F0-F1 ATPase-like protein in leishmanial
cells. During the early phase of activation, there is an increase
in reactive oxygen species (ROS) inside cells, which causes
subsequent elevation in the level of lipid peroxidation and
decrease in reducing equivalents like GSH. Endogenous ROS
formation and lipid peroxidation cause eventual loss of
mitochondrial membrane potential. Furthermore, cytochrome
c is released into the cytosol in a manner independent of
involvement of CED3/CPP32 group of proteases and unlike
mammalian cells it is insensitive to cyclosporin A. These
events are followed by activation of both CED3/CPP32 and
ICE group of proteases in PCD of Leishmania. Taken together,
our study indicates that different biochemical events leading
to apoptosis in leishmanial cells provide information that could
be exploited to develop newer potential therapeutic targets.
Cell Death and Differentiation (2004) 11, 924–936.

Saurav Chatterjee

Papers

Synthesis and biological evaluation of polyhydroxylated oxindole derivatives as potential antileishmanial agent.