Activity of natural and synthetic polygodial derivatives against Trypanosoma cruzi amastigotes, trypomastigotes and epimastigotes

Article abstract of DOI:10.1080/14786419.2019.1597350

Our laboratories have been investigating biological effects of a sesquiterpenoid polygodial and its natural and synthetic analogues. Herein, we report the evaluation of these compounds against the three forms of Trypanosoma cruzi, amastigotes, trypomastigotes and epimastigotes. Although polygodial was found to be poorly active, its natural congener epipolygodial and synthetic Wittig-derived analogues showed low micromolar potency against all three forms of the parasite. Synthetic α,β-unsaturated phosphonate 9 compared favorably with clinically approved drugs benznidazole and nifurtimox, and was effective against trypomastigotes, toward which benznidazole showed no activity. (Figure presented.).

Full text of DOI:10.1080/14786419.2019.1597350

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Activity of natural and synthetic polygodial
derivatives against Trypanosoma cruzi amastigotes,
trypomastigotes and epimastigotes
Danielle N. Turner, Jeremy Just, Ramesh Dasari, Jason A. Smith, Alex C.
Bissember, Alexander Kornienko & Snezna Rogelj
To cite this article: Danielle N. Turner, Jeremy Just, Ramesh Dasari, Jason A. Smith, Alex
C. Bissember, Alexander Kornienko & Snezna Rogelj (2019): Activity of natural and synthetic
polygodial derivatives against Trypanosomaꢀcruzi amastigotes, trypomastigotes and epimastigotes,
Natural Product Research, DOI: 10.1080/14786419.2019.1597350
To link to this article: https://doi.org/10.1080/14786419.2019.1597350
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1597350
SHORT COMMUNICATION
Activity of natural and synthetic polygodial derivatives
against Trypanosoma cruzi amastigotes, trypomastigotes
and epimastigotes
Danielle N. Turnera, Jeremy Justb, Ramesh Dasaric, Jason A. Smithb, Alex C.
Bissemberb, Alexander Kornienkoc and Snezna Rogelja
b
aDepartment of Biology, New Mexico Tech, Socorro, New Mexico, USA; School of Natural Sciences
c
– Chemistry, University of Tasmania, Hobart, Tasmania, Australia; Department of Chemistry and
Biochemistry, Texas State University, San Marcos, Texas, USA
ABSTRACT
ARTICLE HISTORY
Received 22 November 2018
Accepted 6 March 2019
Our laboratories have been investigating biological effects of a
sesquiterpenoid polygodial and its natural and synthetic ana-
logues. Herein, we report the evaluation of these compounds
against the three forms of Trypanosoma cruzi, amastigotes, trypo-
mastigotes and epimastigotes. Although polygodial was found to
be poorly active, its natural congener epipolygodial and synthetic
Wittig-derived analogues showed low micromolar potency against
all three forms of the parasite. Synthetic a,b-unsaturated
phosphonate 9 compared favorably with clinically approved drugs
benznidazole and nifurtimox, and was effective against trypomas-
tigotes, toward which benznidazole showed no activity.
KEYWORDS
Trypanosoma cruzi;
polygodial; anti-parasitic;
phosphonate; Wittig
derivatives; terpenes
1. Introduction
According to the World Health Organization, Chagas disease is one of the seventeen
neglected tropical diseases (NTD). Although discovered over a century ago, Chagas
disease is treated with only two drugs, benznidazole and nifurtimox, which have lim-
ited efficacy (Brener 1979). Thus, there is an urgent need to develop novel more
effective therapeutic agents. Natural products have been intensely scrutinized as
potential anti-Chagas agents (Charneau et al. 2015; Fritis et al. 2013; Izumi et al. 2011;
Lopes et al. 2008; Nkwengoua et al. 2009; Pontual et al. 2017), however, very few
CONTACT Alexander Kornienko
a_k76@txstate.edu; Snezna Rogelj
Snezna.Rogelj@nmt.edu
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1597350.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
D. N. TURNER ET AL.
reports describe activity against the three forms of T. cruzi, amastigotes, trypomasti-
gotes and epimastigotes, possibly due to differences in their morphological and func-
tional characteristics (Kollien and Schaub 2000) and difficulty to obtain each in
quantity and quality (Fonseca-Berzal et al. 2018).
A bicyclic sesquiterpene polygodial (1) was first isolated from Polygonum hydropiper
L. (Polygonaceae). It contains a characteristic a,b-unsaturated 1,4-dialdehyde function-
ality that is also shared by over 80 terpenoids isolated from a variety of natural sour-
ces (Jonassohn and Sterner 1997). Evidently, these natural products protect the
producing organisms from predators (Jonassohn and Sterner 1997), which is consistent
with their hot taste to the human tongue and antifeedant activities (Caprioli
et al. 1987).
In the course of our studies of biological effects of the polygodial family of com-
pounds, we have isolated (Just et al. 2015; Deans et al. 2014) and prepared (Just et al.
2015; Dasari et al. 2015; De La Chapa et al. 2018) several natural and synthetic polygo-
dial derivatives. Herein, we report the results of this investigation involving the discov-
ery of a synthetic compound rivalling both approved drugs, benznidazole and
nifurtimox, in its antiproliferative potency.
2. Results and discussion
Compounds 1–9 were evaluated for growth inhibition against the three forms of CL
tdTomato (DTU TcVI) T. cruzi, generated as described in Supplementary Material
(Fonseca-Berzal et al. 2018; Canavaci et al, 2010) (Table S1). Polygodial (1) and 1b-ace-
toxypolygodial (3) showed moderate to poor potency. In contrast, the C9-epimer epi-
polygodial (2) was significantly more potent with the GI50 values approaching single
micromolar digits against all three forms of the parasite. Clearly, the presence of the
dialdehyde structural motif alone is not sufficient for activity and other features, such
as the configuration at C9, are also important. Drimendiol (4) and (–)-drimenol (5),
both possessing the unfavorable stereochemistry at C9 and lacking the aldehyde
groups, were also poorly active or completely inactive. Although Wittig product 6 was
poorly active, compounds 7–9 all showed single digit growth inhibitory potencies,
demonstrating that the incorporation of an a,b-unsaturated system can be beneficial
for antiparasitic activity. The low micromolar potencies of compounds 7–9 compare
favourably with other compounds reported in the recent literature (Fritis et al. 2013;
Lopes et al. 2008), but the fact that they maintain this potency across all three forms
of T. cruzi gives them a significant advantage.
Polygodial-derived a,b-unsaturated phosphonate 9 was selected for competition
assay against the clinically approved anti-trypanosomal drugs benznidazole and nifurti-
mox. Figure S1 shows the antiproliferative activity of compound 9, benznidazole and
nifurtimox at 7–8 lM, concentrations representing the GI50 values of 9 against epimas-
tigotes, amastigotes and trypomastigotes. Compound 9 was found to be slightly more
potent than benznidazole against epimastigotes and amastigotes and significantly
more potent against trypomastigotes, for which benznidazole was completely ineffect-
ive. Although less potent against epimastigotes and amastigotes than nifurtimox, com-
pound 9 was equally effective at inhibiting growth of trypomastigotes. Overall, the

NATURAL PRODUCT RESEARCH
3
results show that phosphonate 9 compares favorably with the clinically used anti-try-
panosomal drugs, especially against trypomastigotes, the infective form.
To visualize the effects of polygodial analogues on the growth of the parasite in
infected human cells, we utilized confocal microscopy. Figure S2A demonstrates that
treatment of tdTomato T. cruzi-infected human retinal pigment epithelial (ARPE) cells
with compound 7, used at 20 lM causes a significant reduction in the intracellular par-
asites. Importantly, the ARPE replication/viability is not affected. Figure S2B shows that
two successive treatments with compound 9, used at 5 lM, leads to no signs of the
presence of intracellular parasites 7 days after treatment, resulting in long-term cure of
the cells.
3. Conclusion
The evaluation of polygodial and its natural and synthetic analogues against T. cruzi
showed that while polygodial was poorly effective, its natural congener epipolygodial
and synthetically-derived Wittig analogues produced low micromolar activity against
all three forms of the parasite. Furthermore, a synthetic a,b-unsaturated phosphonate
9 compared favorably with clinically approved drugs benznidazole and nifurtimox, and
was effective against trypomastigotes, toward which benznidazole showed no activity.
The results of this investigation demonstrate the anti-trypanosomal potential of poly-
godial analogues and encourage further studies aimed at identification of a lead com-
pound toward pre-clinical development.
Acknowledgement
The authors thank Dr. R.L. Tarleton for his generous gift of the CL tdTomato (DTU TcVI)
Trypanosoma cruzi parasites.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This project was supported by grants from the US National Institute of General Medical Sciences
(Grant P20GM103451), NMT Presidential Research Support and Australian Government for a
Research Training Program Scholarship.
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