title: 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.
authors.affiliation: Molecular Parasitology Laboratory, Indian Institute of Chemical Biology Jadavpur, Kolkata, 700032, India.
authors.forename: Amartya
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Department of Chemistry, Indian Institute of Chemical Biology Jadavpur, Kolkata, 700032, India.
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Vinayagam
authors.affiliation: Molecular Parasitology Laboratory, Indian Institute of Chemical Biology Jadavpur, Kolkata, 700032, India.
authors.forename: Sourav
authors.initials: S
authors.lastname: Saha
authors.affiliation: Molecular Parasitology Laboratory, Indian Institute of Chemical Biology Jadavpur, Kolkata, 700032, India.
authors.forename: Sayan
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Molecular Parasitology Laboratory, Indian Institute of Chemical Biology Jadavpur, Kolkata, 700032, India.
authors.forename: Somenath Roy
authors.initials: SR
authors.lastname: Chowdhury
authors.affiliation: Department of Chemistry, Indian Institute of Chemical Biology Jadavpur, Kolkata, 700032, India.
authors.forename: Parasuraman
authors.initials: P
authors.lastname: Jaisankar
authors.affiliation: Molecular Parasitology Laboratory, Indian Institute of Chemical Biology Jadavpur, Kolkata, 700032, India.
authors.forename: Hemanta K
authors.initials: HK
authors.lastname: Majumder
keywords: Antileishmanial agents; DNA topoisomerase II; Leishmania donovani; apoptosis; isobenzofuranone