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.
Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Würzburg 97074, Germany. jan.glaser@uni-wuerzburg.de.
Jan
J
Glaser
Institute for Molecular Infection Biology, University of Würzburg, Josef-Schneider-Str. 2, Würzburg 97080, Germany. martina.schultheis@uni-wuerzburg.de.
Martina
M
Schultheis
Department of Pharmaceutical Technology, Jadavpur University, Kolkata-700032, India. sudipta_manu@rediffmail.com.
Sudipta
S
Hazra
Department of Pharmaceutical Technology, Jadavpur University, Kolkata-700032, India. banasrihazra@yahoo.co.in.
Banasri
B
Hazra
Institute for Molecular Infection Biology, University of Würzburg, Josef-Schneider-Str. 2, Würzburg 97080, Germany. heidrun.moll@uni-wuerzburg.de.
Heidrun
H
Moll
Institute for Molecular Infection Biology, University of Würzburg, Josef-Schneider-Str. 2, Würzburg 97080, Germany. uta.schurigt@uni-wuerzburg.de.
Uta
U
Schurigt
Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Würzburg 97074, Germany. u.holzgrabe@pharmazie.uni-wuerzburg.de.
Ulrike
U
Holzgrabe
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry*; D002109:Caffeic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects; D018320:Leishmania major / Q000187:drug effects; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D013329:Structure-Activity Relationship; D014632:Valerian / Q000737:chemistry
D000981:Antiprotozoal Agents; D002109:Caffeic Acids; C040048:caffeic acid