Structure-Activity Relationship Study of Sesquiterpene Lactones and Their Semi-Synthetic Amino Derivatives as Potential Antitrypanosomal Products

Molecules

Stefanie Zimmermann¹  Gerda Fouché³  Maria De Mieri¹  Yukiko Yoshimoto²  Toyonobu Usuki²  Rudzani Nthambeleni³  Christopher J. Parkinson⁴  Christiaan van der Westhuyzen³  Marcel Kaiser⁵  Matthias Hamburger¹ 

[1] Department Pharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland; E-Mails:;Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda, Tokyo 102-8554, Japan; E-Mails:;CSIR Biosciences, Meiring Naudé Road, Brummeria, Pretoria 0001, Gauteng, South Africa; E-Mails:;School of Biomedical Sciences, Charles Sturt University, Orange, NSW 2800, Australia; E-Mail:;Department Medical Parasitology & Infection Biology, Swiss TPH, Socinstrasse 57, 4000 Basel, Switzerland; E-Mail:

关键词: cynaropicrin;    sesquiterpene lactones;    antitrypanosomal;    cytotoxicity;    structure-activity-relationship;    dimethylamino analogues;    T. b. rhodesiense acute mouse model;   

DOI  :  10.3390/molecules19033523

来源: mdpi

【 摘 要 】

Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness) and mammalian cancer cells (rat bone myoblast L6 cells). It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.