Synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones, dihydro analogues and photodimers
Previous studies have identified the 3,6-dialkyl-4-hydroxy-pyran-2-one marine microbial metabolites pseudopyronines A and B to be modest growth inhibitors of Mycobacterium tuberculosis and a range of tropical diseases including Plasmodium falciparum and Leishmania donovani . In an effort to expand t...
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Published in | Bioorganic & medicinal chemistry Vol. 20; no. 4; pp. 1482 - 1493 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
02.01.2012
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Online Access | Get full text |
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Abstract | Previous studies have identified the 3,6-dialkyl-4-hydroxy-pyran-2-one marine microbial metabolites pseudopyronines A and B to be modest growth inhibitors of
Mycobacterium tuberculosis
and a range of tropical diseases including
Plasmodium falciparum
and
Leishmania donovani
. In an effort to expand the structure-activity relationship of this compound class towards. infectious diseases, a library of natural product and natural product-like 4-methoxy-6-styryl-pyran-2-ones and a subset of catalytically reduced examples were synthesised. In addition, the photochemical reactivity of several of the 4-methoxy-6-styryl-pyran-2-ones were investigated yielding head-to-head and head-to-tail cyclobutane dimers as well as examples of asymmetric aniba-dimer A-type dimers. All compounds were evaluated for cytotoxicity and activity against
M. tuberculosis, P. falciparum, L. donovani, Trypanosoma brucei rhodesiense
and
T. cruzi
. Of the styryl-pyranones, natural product
3
and non-natural styrene and naphthalene substituted examples
13, 18, 21, 22
and
23
exhibited antimalarial activity (IC
50
< 10 μM) with selectivity indices (SI) > 10. Δ
7
Dihydro analogues were typically less active or lacked selectivity. Head-to-head and head-to-tail photodimers
5
and
34
exhibited moderate IC
50
s of 2.3 to 17 μM towards several of the parasitic organisms, while the aniba-dimer-type asymmetric dimers
31
and
33
were identified as being moderately active towards
P. falciparum
(IC
50
1.5 and 1.7 μM) with good selectivity (SI ∼ 80). The 4-
tert
-butyl aniba-dimer A analogue
33
also exhibited activity towards
L. donovani
(IC
50
4.5 μM), suggesting further elaboration of this latter scaffold could lead to the identification of new leads for the dual treatment of malaria and leishmaniasis. |
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AbstractList | Previous studies have identified the 3,6-dialkyl-4-hydroxy-pyran-2-one marine microbial metabolites pseudopyronines A and B to be modest growth inhibitors of
Mycobacterium tuberculosis
and a range of tropical diseases including
Plasmodium falciparum
and
Leishmania donovani
. In an effort to expand the structure-activity relationship of this compound class towards. infectious diseases, a library of natural product and natural product-like 4-methoxy-6-styryl-pyran-2-ones and a subset of catalytically reduced examples were synthesised. In addition, the photochemical reactivity of several of the 4-methoxy-6-styryl-pyran-2-ones were investigated yielding head-to-head and head-to-tail cyclobutane dimers as well as examples of asymmetric aniba-dimer A-type dimers. All compounds were evaluated for cytotoxicity and activity against
M. tuberculosis, P. falciparum, L. donovani, Trypanosoma brucei rhodesiense
and
T. cruzi
. Of the styryl-pyranones, natural product
3
and non-natural styrene and naphthalene substituted examples
13, 18, 21, 22
and
23
exhibited antimalarial activity (IC
50
< 10 μM) with selectivity indices (SI) > 10. Δ
7
Dihydro analogues were typically less active or lacked selectivity. Head-to-head and head-to-tail photodimers
5
and
34
exhibited moderate IC
50
s of 2.3 to 17 μM towards several of the parasitic organisms, while the aniba-dimer-type asymmetric dimers
31
and
33
were identified as being moderately active towards
P. falciparum
(IC
50
1.5 and 1.7 μM) with good selectivity (SI ∼ 80). The 4-
tert
-butyl aniba-dimer A analogue
33
also exhibited activity towards
L. donovani
(IC
50
4.5 μM), suggesting further elaboration of this latter scaffold could lead to the identification of new leads for the dual treatment of malaria and leishmaniasis. |
Author | Copp, Brent R. Kaiser, Marcel Boyd, Peter D. W. Boshoff, Helena I. McCracken, Stephen T. |
AuthorAffiliation | a School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand b Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland c University of Basel, CH-4003 Basel, Switzerland d Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA |
AuthorAffiliation_xml | – name: a School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand – name: c University of Basel, CH-4003 Basel, Switzerland – name: d Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA – name: b Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland |
Author_xml | – sequence: 1 givenname: Stephen T. surname: McCracken fullname: McCracken, Stephen T. organization: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland University of Basel, CH-4003 Basel, Switzerland Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA – sequence: 2 givenname: Marcel surname: Kaiser fullname: Kaiser, Marcel organization: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland University of Basel, CH-4003 Basel, Switzerland Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA – sequence: 3 givenname: Helena I. surname: Boshoff fullname: Boshoff, Helena I. organization: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland University of Basel, CH-4003 Basel, Switzerland Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA – sequence: 4 givenname: Peter D. W. surname: Boyd fullname: Boyd, Peter D. W. organization: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland University of Basel, CH-4003 Basel, Switzerland Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA – sequence: 5 givenname: Brent R. surname: Copp fullname: Copp, Brent R. organization: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, CH-4002 Basel, Switzerland University of Basel, CH-4003 Basel, Switzerland Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA |
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Title | Synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones, dihydro analogues and photodimers |
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