Isobenzofuranone derivatives exhibit antileishmanial effect by inhibiting type II DNA topoisomerase and inducing host response

Abstract

Leishmania, a protozoan parasite, causes a wide range of human diseases ranging from the localized self-healing cutaneous lesions to fatal visceral leishmaniasis. Toxicity of traditional first line drugs and emergence of drug-resistant strains have worsened the situation. DNA topoisomerase II in kinetoplastid protozoan parasites are of immense interest as drug target because they take part in replication of unusual kinetoplast DNA network. In this study, we have taken target-based therapeutic approaches to combat leishmaniasis. Two isobenzofuranone compounds, viz., (1) 3,5-bis(4-chlorophenyl)-7-hydroxyisobenzofuran-1(3H)-one (JVPH3) and (2) (4-bromo)-3′-hydroxy-5′-(4-bromophenyl)-benzophenone(JVPH4) were synthesized chemically and characterized by NMR and mass spectrometry analysis. Activity of type II DNA topoisomerase of leishmania (LdTOPII) was monitored by decatenation assay and plasmid cleavage assay. The antiparasitic activity of these compounds was checked in experimental BALB/c mice model of visceral leishmaniasis. Isobenzofuranone derivatives exhibited potent antileishmanial effect on both antimony (Sb) sensitive and resistant parasites. Treatment with isobenzofuranone derivatives on promastigotes caused induction of reactive oxygen species (ROS)-mediated apoptosis like cell death in leishmania. Both the compounds inhibited the decatenation activity of LdTOPII but have no effect on bi-subunit topoisomerase IB. Treatment of LdTOPII with isobenzofuranone derivatives did not stabilize cleavage complex formation both in vitro and in vivo. Moreover, treatment with isobenzofuranone derivatives on Leishmania donovani-infected mice resulted in clearance of parasites in liver and spleen by induction of Th1 cytokines. Taken together, our data suggest that these compounds can be exploited as potential antileishmanial agents targeted to DNA topoisomerase II of the parasite.

Isobenzofuranone derivative JVPH3, an inhibitor of L. donovani topoisomerase II, disrupts mitochondrial architecture in trypanosomatid parasites

“…However, to our knowledge, there is no report to establish the phenotypic changes associated with LdTopII inhibition in this kinetoplastid pathogen. Even in our previous study 4 , we could not identify any remarkable change in parasite morphology by bright field microscopy. The present study establishes that how does the parasite morphology get altered when topoisomerase II is targeted.…”

“…Though we proposed earlier an apoptosis-like death mechanism in L . donovani by JVPH3 4 , we were curious to further investigate the subcellular events occurring within the parasite. So, we performed transmission electron microscopy (TEM) to understand the alterations occurring at cell organelles.…”

“…We previously reported that intraperitoneal administration of JVPH3 resulted in significant decrease in hepatic and splenic parasite burden in an experimental in vivo model of visceral leishmaniasis 4 . In order to establish a molecule as a prospective drug, it is indispensable to understand the molecular mechanism pertaining to its cytotoxic potential.…”

“…Unfortunately, reports on parasite specific topoisomerase II inhibitors having promising in vivo antitrypanosomatid efficacy are substantially meagre. In an earlier study in 2014, we reported the synthesis of an isobenzofuranone derivative, namely 3,5-bis(4-chlorophenyl)-7-hydroxyisobenzofuran-1(3H)-one (JVPH3) 4 where we established that JVPH3 is a synthetic catalytic inhibitor of LdTopII and effective to reduce the L . donovani parasite burden in an experimental model of visceral leishmaniasis (VL).…”

The Antileishmanial Potential of C-3 Functionalized Isobenzofuranones against Leishmania (Leishmania) Infantum Chagasi

“…Indeed, reports in the literature have indicated that anti-cancer drugs that affect cellular proliferation can be used as anti-microbial agents because both cell types share common behaviors concerning their high proliferative capabilities [27][28][29]. Indeed, a recent work evidenced the antileishmanial actions of other two isobenzofuranone derivatives and indicated that these actions were due to the induction of reactive oxygen species (ROS)-mediated apoptosis-like cell death and the inhibition of topoisomerases [30].…”