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16α‐Hydroxycleroda‐3,13 (14)Z‐dien‐15,16‐olide from Polyalthia longifolia : a safe and orally active antileishmanial agent
Author(s) -
Misra Pragya,
Sashidhara Koneni V,
Singh Suriya Pratap,
Kumar Awanish,
Gupta Reema,
Chaudhaery Shailendra S,
Gupta Souvik Sen,
Majumder HK,
Saxena Anil K,
Dube Anuradha
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00609.x
Subject(s) - topoisomerase , leishmania donovani , biology , pharmacology , cytotoxic t cell , in vivo , cytotoxicity , biological activity , in vitro , biochemistry , chemistry , immunology , leishmaniasis , genetics , visceral leishmaniasis
Background and purpose: New antileishmanials from natural products are urgently needed due to the emergence of drug resistance complicated by severe cytotoxic effects. 16α‐Hydroxycleroda‐3,13 (14)Z‐dien‐15,16‐olide (Compound 1) from Polyalthia longifolia was found to be a potential antileishmanial and non‐cytotoxic, as evidenced by long‐term survival (>6 months) of treated animals. This prompted us to determine its target and, using molecular modelling, identify the interactions responsible for its specific antileishmanial activity. Experimental approach: In vitro activity of compound was assessed using intracellular transgenic green fluorescent protein‐stably expressed Leishmania donovani parasites. In vivo activity and survival of animals post‐treatment were evaluated in L. donovani‐ infected hamsters. Known property of clerodane diterpenes as potent human DNA topoisomerase inhibitors led us to evaluate the inhibition of recombinant L. donovani topoisomerase I using relaxation assay. Mode of cell death induced by Compound 1 was assessed by phosphotidylserine exposure post‐treatment. Molecular modelling studies were conducted with DNA topoisomerase I to identify the binding interactions responsible for its activity. Key results: Bioassay‐guided fractionation led to isolation of Compound 1 as a non‐cytotoxic, orally active antileishmanial. Compound 1 inhibited recombinant DNA topoisomerase I which, ultimately, induced apoptosis. Molecular docking studies indicated that five strong hydrogen‐bonding interactions and hydrophobic interactions of Compound 1 with L. donovani DNA‐topoisomerase are responsible for its antileishmanial activity. Conclusions and implications: The data reveal Compound 1 is a potent and safe antileishmanial. The study further exploited the structural determinants responsible for its non‐cytotoxic and potent activity, to raise the feasibility of specifically targeting the target enzyme responsible for its activity through rational drug design.