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SARs for the antiparasitic plant metabolite pulchrol. : 3. Combinations of new substituents in A/B-rings and A/C-rings

Terrazas, Paola LU ; Salamanca, Efrain ; Dávila, Marcelo ; Manner, Sophie LU ; Gimenez, Alberto and Sterner, Olov LU (2021) In Molecules 26(13).
Abstract
The natural products pulchrol and pulchral, isolated from the roots of the Mexican plant Bourreria pulchra, have previously been shown to possess an antiparasitic activity toward Trypanosoma cruzi, Leishmania braziliensis and L. amazonensis, protozoa responsible for the Chagas disease and leishmaniasis. These infections have been classified as neglected diseases, and still require the development of safer and more efficient alternatives to their current treatments. Recent SAR stud-ies, based on the pulchrol scaffold, showed which effect the exchanges of its substituents have on the antileishmanial and antitrypanosomal activity. Many of the analogues prepared were shown to be more potent in vitro than pulchrol... (More)
The natural products pulchrol and pulchral, isolated from the roots of the Mexican plant Bourreria pulchra, have previously been shown to possess an antiparasitic activity toward Trypanosoma cruzi, Leishmania braziliensis and L. amazonensis, protozoa responsible for the Chagas disease and leishmaniasis. These infections have been classified as neglected diseases, and still require the development of safer and more efficient alternatives to their current treatments. Recent SAR stud-ies, based on the pulchrol scaffold, showed which effect the exchanges of its substituents have on the antileishmanial and antitrypanosomal activity. Many of the analogues prepared were shown to be more potent in vitro than pulchrol and the current drugs used to treat Leishmaniasis and the Chagas disease (Miltefosine and Benznidazole respectively). Moreover, indications of some of the possible interactions that may take place in the binding sites were also identified. In this study, 12 analogues with modifications at two or three different positions in two of the three rings were prepared by synthetic and semi-synthetic procedures. The molecules were assayed in vitro to-ward T. cruzi epimastigotes, L. braziliensis promastigotes and L. amazonensis promastigotes. Some compounds had higher antiparasitic activity than the parent compound pulchrol, and in some cases even Benznidazole and Miltefosine. The best combinations in this subset are with carbonyl functionalities in the A-ring and isopropyl groups in the C-ring, as well as with alkyl substituents in both the A- and C-rings combined with a hydroxyl group in position 1 (C-ring). The latter corresponds to cannabinol, which was shown to be potent toward all parasites. (Less)
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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Trypanosoma cruzi, Leishmania braziliensis, Leishmania amazonensis, pulchrol, pulchral, cannabinol, SARs
in
Molecules
volume
26
issue
13
article number
3944
pages
15 pages
publisher
MDPI AG
external identifiers
  • scopus:85109326372
  • pmid:34203527
ISSN
1420-3049
DOI
10.3390/molecules26133944
language
English
LU publication?
yes
id
d6e583b1-fec9-4ec0-9914-0cd2a86109e8
date added to LUP
2021-05-10 11:24:25
date last changed
2022-04-27 01:51:57
@article{d6e583b1-fec9-4ec0-9914-0cd2a86109e8,
  abstract     = {{The natural products pulchrol and pulchral, isolated from the roots of the Mexican plant <i>Bourreria pulchra</i>, have previously been shown to possess an antiparasitic activity toward <i>Trypanosoma cruzi</i>, <i>Leishmania braziliensis</i> and <i>L. amazonensis</i>, protozoa responsible for the Chagas disease and leishmaniasis. These infections have been classified as neglected diseases, and still require the development of safer and more efficient alternatives to their current treatments. Recent SAR stud-ies, based on the pulchrol scaffold, showed which effect the exchanges of its substituents have on the antileishmanial and antitrypanosomal activity. Many of the analogues prepared were shown to be more potent in vitro than pulchrol and the current drugs used to treat Leishmaniasis and the Chagas disease (Miltefosine and Benznidazole respectively). Moreover, indications of some of the possible interactions that may take place in the binding sites were also identified. In this study, 12 analogues with modifications at two or three different positions in two of the three rings were prepared by synthetic and semi-synthetic procedures. The molecules were assayed in vitro to-ward <i>T. cruzi </i>epimastigotes, <i>L. braziliensis</i> promastigotes and <i>L. amazonensis</i> promastigotes. Some compounds had higher antiparasitic activity than the parent compound pulchrol, and in some cases even Benznidazole and Miltefosine. The best combinations in this subset are with carbonyl functionalities in the A-ring and isopropyl groups in the C-ring, as well as with alkyl substituents in both the A- and C-rings combined with a hydroxyl group in position 1 (C-ring). The latter corresponds to cannabinol, which was shown to be potent toward all parasites.}},
  author       = {{Terrazas, Paola and Salamanca, Efrain and Dávila, Marcelo and Manner, Sophie and Gimenez, Alberto and Sterner, Olov}},
  issn         = {{1420-3049}},
  keywords     = {{Trypanosoma cruzi; Leishmania braziliensis; Leishmania amazonensis; pulchrol; pulchral; cannabinol; SARs}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{13}},
  publisher    = {{MDPI AG}},
  series       = {{Molecules}},
  title        = {{SARs for the antiparasitic plant metabolite pulchrol. : 3. Combinations of new substituents in A/B-rings and A/C-rings}},
  url          = {{http://dx.doi.org/10.3390/molecules26133944}},
  doi          = {{10.3390/molecules26133944}},
  volume       = {{26}},
  year         = {{2021}},
}