{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:03:17Z","timestamp":1768975397278,"version":"3.49.0"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2014,1,27]],"date-time":"2014-01-27T00:00:00Z","timestamp":1390780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 \u00b5M). 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.<\/jats:p>","DOI":"10.3390\/molecules19021394","type":"journal-article","created":{"date-parts":[[2014,1,28]],"date-time":"2014-01-28T03:27:01Z","timestamp":1390879621000},"page":"1394-1410","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester"],"prefix":"10.3390","volume":"19","author":[{"given":"Jan","family":"Glaser","sequence":"first","affiliation":[{"name":"Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg, Am Hubland, W\u00fcrzburg 97074, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Schultheis","sequence":"additional","affiliation":[{"name":"Institute for Molecular Infection Biology, University of W\u00fcrzburg, Josef-Schneider-Str. 2,  W\u00fcrzburg 97080, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudipta","family":"Hazra","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Jadavpur University, Kolkata-700032, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Banasri","family":"Hazra","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Jadavpur University, Kolkata-700032, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidrun","family":"Moll","sequence":"additional","affiliation":[{"name":"Institute for Molecular Infection Biology, University of W\u00fcrzburg, Josef-Schneider-Str. 2,  W\u00fcrzburg 97080, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uta","family":"Schurigt","sequence":"additional","affiliation":[{"name":"Institute for Molecular Infection Biology, University of W\u00fcrzburg, Josef-Schneider-Str. 2,  W\u00fcrzburg 97080, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrike","family":"Holzgrabe","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg, Am Hubland, W\u00fcrzburg 97074, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e35671","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis worldwide and global estimates of its incidence","volume":"7","author":"Alvar","year":"2012","journal-title":"PLoS One"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.cimid.2004.03.004","article-title":"Leishmaniasis: Current situation and new perspectives","volume":"27","author":"Desjeux","year":"2004","journal-title":"Comp. Immun. Microbiol. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2204","DOI":"10.1371\/journal.pntd.0002204","article-title":"Advancing sino-indian cooperation to combat tropical diseases","volume":"7","author":"Hotez","year":"2013","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1007\/s00436-010-2127-0","article-title":"Valeriana wallichii root extracts and fractions with activity against Leishmania spp.","volume":"108","author":"Ghosh","year":"2011","journal-title":"Parasitol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6553","DOI":"10.1016\/j.bmcl.2008.10.046","article-title":"Synthesis of trans-caffeate analogues and their bioactivities against HIV-1 integrase and cancer cell lines","volume":"18","author":"Xia","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Xia, C.-N., and Hu, W.-X. (2005). Synthesis of caffeic acid esters. J. Chem. Res., 332\u2013334.","DOI":"10.3184\/0308234054323869"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1016\/0031-9422(76)85099-6","article-title":"Neue Terpen-Inhaltsstoffe aus Verbesina-Arten","volume":"15","author":"Bohlmann","year":"1976","journal-title":"Phytochemistry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1016\/S0031-9422(96)00723-6","article-title":"A comparative study on three chemo-types of the liverwort Conocephalum Conicum using volatile constituents","volume":"44","author":"Toyota","year":"1997","journal-title":"Phytochemistry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/S0031-9422(00)95264-6","article-title":"Chirality of terpenoids isolated from the liverwort Conocephalum Conicum","volume":"21","author":"Suire","year":"1982","journal-title":"Phytochemistry"},{"key":"ref_10","first-page":"1161","article-title":"Phytochemical investigation of Verbesina turbacensis Kunth: Trypanosome cysteine protease inhibition by (\u2212)-bornyl esters","volume":"5","author":"Ogungbe","year":"2010","journal-title":"Nat. Prod. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/cber.19781110124","article-title":"Nat\u00fcrlich vorkommende Terpen-Derivate, 109: Neue Eudesman-Derivate und andere Sesquiterpene aus Verbesina-Arten","volume":"111","author":"Bohlmann","year":"1978","journal-title":"Chem. Ber."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/BF00497441","article-title":"The caffeoylics as a new family of natural antiviral compounds","volume":"72","author":"Dustmann","year":"1985","journal-title":"Naturwissenschaften"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1016\/j.bmcl.2006.12.059","article-title":"N-Caffeoylphenalkylamide derivatives as bacterial efflux pump inhibitors","volume":"17","author":"Michalet","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Otero, E., Robledo, S.M., Diaz, S., Carda, M., Mu\u00f1oz, D., Pa\u00f1os, J., V\u00e9lez, I.D., and Cardona, W. (2013). Synthesis and leishmanicidal activity of cinnamic acid esters: Structure\u2013activity relationship. Med. Chem. Res.","DOI":"10.1007\/s00044-013-0741-y"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1002\/adsc.200303093","article-title":"Simple, Mild, and Practical esterification, Thioesterification, and amide formation utilizing p-toluenesulfonyl chloride and N-Methylimidazole","volume":"345","author":"Wakasugi","year":"2003","journal-title":"Adv. Synth. Catal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1128\/AAC.02201-12","article-title":"A Novel Leishmania major amastigote assay in 96-well format for rapid drug screening and its use for discovery and evaluation of a new class of leishmanicidal quinolinium salts","volume":"57","author":"Bringmann","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s00436-012-2818-9","article-title":"Antileishmanial activity of cryptolepine analogues and apoptotic effects of 2,7-dibromocryptolepine against Leishmania donovani promastigotes","volume":"111","author":"Hazra","year":"2012","journal-title":"Parasitol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.bmcl.2009.11.033","article-title":"In vitro and in vivo anti-leishmania activity of polysubstituted synthetic chalcones","volume":"20","author":"Aponte","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.phymed.2012.07.011","article-title":"Marchantin A, a macrocyclic bisbibenzyl ether, isolated from the liverwort Marchantia polymorpha, inhibits protozoal growth in vitro","volume":"19","author":"Jensen","year":"2012","journal-title":"Phytomedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11101-009-9154-4","article-title":"Nature of hydroxycinnamate-protein interactions","volume":"9","author":"Rawel","year":"2010","journal-title":"Phytochem. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1271\/bbb.60.909","article-title":"Synthesis and antifungal activity of cinnamic acid esters","volume":"60","author":"Tawata","year":"1996","journal-title":"Biosci. Biotech. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1021\/jf010963x","article-title":"Novel compounds from Piper Methysticum forst (Kava-kava) roots and their effect on cyclooxygenase enzyme","volume":"50","author":"Wu","year":"2002","journal-title":"J. Agric. Food Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3605","DOI":"10.1080\/00397919708007083","article-title":"Synthesis of chiral 2-arylpropenoic esters by the palladium catalyzed carbonylation of arylacetylenes","volume":"27","author":"Monteiro","year":"1997","journal-title":"Synth. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1351\/PAC-CON-11-06-05","article-title":"Simple halogen-free synthesis of aryl cinnamates using Mo-keggin heteropoly acids as catalyst","volume":"84","author":"Palermo","year":"2012","journal-title":"Pure Appl. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"155","DOI":"10.15227\/orgsyn.068.0155","article-title":"Transesterification of methyl esters of aromatic and \u03b1,\u03b2\u2010unsaturated acids with bulky alcohols: (\u2212)\u2010Menthyl cinnamate and (\u2212)\u2010menthyl nicotinate","volume":"68","year":"1990","journal-title":"Org. Synth."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5717","DOI":"10.1021\/jo010121x","article-title":"Highly diastereoselective synthesis of vinylcyclopropane derivatives with (\u2212)-8-phenylmenthol as chiral auxiliary","volume":"66","author":"Ye","year":"2001","journal-title":"J. Org. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"14775","DOI":"10.1021\/ja075824w","article-title":"Widely useful DMAP-catalyzed esterification under auxiliary base- and solvent-free conditions","volume":"129","author":"Sakakura","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"ref_28","unstructured":"Mikhajlovich, G.B., Pastukhova, N.P., and Kamneva, E.A. (2012). Method of Producing Adamantyl Esters of Unsaturated Acides. (RU 2448950 C1)."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/ddr.21015","article-title":"Design, synthesis, and preliminary evaluation of substituted cinnamic acid esters as selective matrix metalloproteinase inhibitors","volume":"73","author":"Shi","year":"2012","journal-title":"Drug Dev. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7608","DOI":"10.1021\/ic400686e","article-title":"Facile formation of stable tris(imido)phosphate trianions as their tri-and hexanuclear Pd(II) complexes in protic solvents","volume":"52","author":"Gupta","year":"2013","journal-title":"Inorg. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7404","DOI":"10.1016\/j.bmc.2006.07.027","article-title":"Flavonoids and cinnamic acid esters as inhibitors of fungal 17\u03b2-hydroxysteroid dehydrogenase: A synthesis, QSAR and modelling study","volume":"14","author":"Sova","year":"2006","journal-title":"Bioorg. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3184\/030823403322655761","article-title":"Useful synthesis of aryl cinnamates: Synthesis of difengpin","volume":"2003","author":"Mali","year":"2003","journal-title":"J. Chem. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/S0031-9422(00)84791-3","article-title":"Obliquin derivatives and other constituents from australian Helichrysum species","volume":"26","author":"Jakupovic","year":"1987","journal-title":"Phytochemistry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5028","DOI":"10.1128\/AAC.00327-10","article-title":"Aziridine-2,3-dicarboxylate-based cysteine cathepsin inhibitors induce cell death in Leishmania major associated with accumulation of debris in autophagy-related lysosome-like vacuoles","volume":"54","author":"Schurigt","year":"2010","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/19\/2\/1394\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:07:41Z","timestamp":1760216861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/19\/2\/1394"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,27]]},"references-count":34,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2014,2]]}},"alternative-id":["molecules19021394"],"URL":"https:\/\/doi.org\/10.3390\/molecules19021394","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1,27]]}}}