Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester

Abstract

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 (IC 50 = 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.

Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities

“…A similar result was found for cinnamic acid bornyl ester and its hydrogenated derivative (39.6 and 50.2 µM, respectively) [43]. However, we have previously reported on cinnamic acid alkyl ester derivatives and we have shown a decrease in activity upon saturation of the double bond of these molecules [19].…”

“…The caffeic acid derivative (5), isolated from V. wallichii, showed an IC50 value of 48.8 μM against L. major promastigotes and high cytotoxicity against a J774.1 cell line [18]. Rosmarinic acid (6) exhibited anti-leishmanial activity against both L. major and L. donovani (IC50 of 59.2 and 74.4 μM, respectively) [19].…”

“…In addition, some studies have shown that caffeic acid esters have high anti-leishmanial activity [16][17][18][19]. Three caffeic acid esters (1-3, see figure 1), which have been isolated from leaves of Piper sanguineispicum, showed anti-leishmanial activity with an IC50 of 2.0, 10 and 1.8 μM, respectively.…”

Anti-Schistosomal Activity of Cinnamic Acid Esters: Eugenyl and Thymyl Cinnamate Induce Cytoplasmic Vacuoles and Death in Schistosomula of Schistosoma mansoni

“…However, these were inactive. By comparison, the bornyl phenylpropionate (30) retained anti-leishmanial activity [15]. For schistosomula, it is possible that the Michael system is responsible for inducing the vacoules-as seen with 23 and 27-and is an essential component to the pharmacophore.…”

“…We followed up on this initial finding with the synthesis of a small compound library of 28 systematically varied derivatives [15]. Here, we screened the entire library (except the cytotoxic acetylated bornyl caffeate) plus three additional compounds (18, 28 and 29) for in vitro activity against S. mansoni schistosomula (post-infective larvae) and compounds 23, 27-30 for in vitro activity against adult worms.…”