12535
2015
eng
e0142386
11
10
article
1
2016-01-25
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Cinnamic Acid Bornyl Ester Derivatives from Valeriana wallichii Exhibit Antileishmanial In Vivo Activity in Leishmania major-Infected BALB/c Mice
Human leishmaniasis covers a broad spectrum of clinical manifestations ranging from self-healing cutaneous leishmaniasis to severe and lethal visceral leishmaniasis caused among other species by Leishmania major or Leishmania donovani, respectively. Some drug candidates are in clinical trials to substitute current therapies, which are facing emerging drug-resistance accompanied with serious side effects. Here, two cinnamic acid bornyl ester derivatives (1 and 2) were assessed for their antileishmanial activity. Good selectivity and antileishmanial activity of bornyl 3-phenylpropanoate (2) in vitro prompted the antileishmanial assessment in vivo. For this purpose, BALB/c mice were infected with Leishmania major promastigotes and treated with three doses of 50 mg/kg/day of compound 2. The treatment prevented the characteristic swelling at the site of infection and correlated with reduced parasite burden. Transmitted light microscopy and transmission electron microscopy of Leishmania major promastigotes revealed that compounds 1 and 2 induce mitochondrial swelling. Subsequent studies on Leishmania major promastigotes showed the loss of mitochondrial transmembrane potential (ΔΨm) as a putative mode of action. As the cinnamic acid bornyl ester derivatives 1 and 2 had exhibited antileishmanial activity in vitro, and compound 2 in Leishmania major-infected BALB/c mice in vivo, they can be regarded as possible lead structures for the development of new antileishmanial therapeutic approaches.
PLoS One
10.1371/journal.pone.0142386
urn:nbn:de:bvb:20-opus-125354
PLoS ONE 10(11): e0142386. doi:10.1371/journal. pone.0142386
Anita Masic
Ana Maria Valencia Hernandez
Sudipta Hazra
Jan Glaser
Ulrike Holzgrabe
Banasri Hazra
Uta Schurigt
eng
uncontrolled
leishmania major
eng
uncontrolled
promastigotes
eng
uncontrolled
apoptosis
eng
uncontrolled
mitochondria
eng
uncontrolled
parasitic diseases
eng
uncontrolled
leishmania
eng
uncontrolled
leishmaniasis
eng
uncontrolled
mouse models
Medizin und Gesundheit
open_access
Institut für Molekulare Infektionsbiologie
Förderzeitraum 2015
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12535/Schurigt_journal.pone.0142386.pdf
11283
2014
eng
article
1
2015-05-08
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Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester
Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC50 = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization
10.3390/molecules19021394
urn:nbn:de:bvb:20-opus-112835
Molecules 2014, 19, 1394-1410; doi:10.3390/molecules19021394
Jan Glaser
Martina Schultheis
Sudipta Hazra
Banazri Hazra
Heidrun Moll
Uta Schurigt
Ulrike Holzgrabe
eng
uncontrolled
Valeriana wallichii
eng
uncontrolled
leishmaniasis
eng
uncontrolled
caffeic acid bornyl ester
eng
uncontrolled
structure-activity relationship
Chemie und zugeordnete Wissenschaften
open_access
Institut für Molekulare Infektionsbiologie
Institut für Pharmazie und Lebensmittelchemie
Förderzeitraum 2014
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11283/084_Holzgrabe_Molecules.pdf