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PC-61

Natural and semisynthetic ecdysteroids: Design and optimisation toward

potential new trypanocide leads

2
1
1
Márton Háznagy, Máté Vágvölgyi, Gábor Girst, Sandhya R. Krishnan, Kaushavi
1
2
Cholke, Jürg Gertsch, Attila Hunyadi* ,1,3,4
2

1 Institute of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary
2 Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern,
Switzerland
3 HUN-REN-SZTE Biologically Active Natural Products Research Group, Eötvös u. 6, H-6720
Szeged, Hungary
4 Graduate Institute of Natural Products, Kaohsiung Medical University, Shih-Chuan 1st Rd.
100, Kaohsiung 807, Taiwan R.O.C
* E-mail: hunyadi.attila@szte.hu

Abstract
Trypanosoma cruzi (T. cruzi), the protozoan pathogen responsible for Chagas disease, a
neglected tropical illness, is transmitted to humans through bites of hematophagous kissing
bugs, as well as via transfusion of infected blood or organ transplantation. WHO data indicate
that Chagas disease currently affects up to 7 million individuals worldwide and results in several
thousand deaths each year. Given the scarcity of effective treatments, the development of new
therapeutic agents is urgently required.Ecdysteroids represent a class of natural steroids that are
typically polar due to their numerous hydroxyl groups, and contain a characteristic 7-ene-6-one

group on their B-ring. Studies have indicated that ecdysone influences Rhodnius prolixus—a
key vector of Chagas disease—as well as the growth and differentiation of the protozoan

parasite during its life cycle in the insect host. Here we present the antiprotozoal screening of
fifty-two ecdysteroids against T. cruzi, and subsequent design and preparation of potential new
leads for this indication. Two promising pharmacophores were identified, i.e., 6-tert-butyl
oxime ether and cinnamate ester moieties. With these in mind, six new derivatives were
designed and synthesized, among which three compounds exhibited notable antiparasitic
activity. The most potent compound, substituted with cinnamate at C-2 and an oxime ether at
C-6, showed an IC₅₀ of 2.7 µM in FACS-based assays and a 6.8-fold selectivity toward
epimastigotes compared to host cells, marking it as a promising antitrypanosomal lead.

Keywords: Infectios disease; Ecdysteroids; Semisynthesis