Synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones, dihydro analogues and photo-dimers

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 th...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2012-02, Vol.20 (4), p.1482-1493
Main Authors: McCracken, Stephen T., Kaiser, Marcel, Boshoff, Helena I., Boyd, Peter D.W., Copp, Brent R.
Format: Article
Language:English
Subjects:
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
antimalarials
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Antiparasitic agents
Antitubercular Agents - chemical synthesis
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Biological and medical sciences
Coumarins - chemical synthesis
Coumarins - chemistry
Coumarins - pharmacology
cytotoxicity
Dimerization
Fatty Acids, Monounsaturated - chemical synthesis
Fatty Acids, Monounsaturated - chemistry
Fatty Acids, Monounsaturated - pharmacology
infectious diseases
Inhibitory Concentration 50
Leishmania donovani
Leishmania donovani - drug effects
leishmaniasis
Light
Malaria
Medical sciences
metabolites
Molecular Structure
Mycobacterium tuberculosis
naphthalene
Natural product
Pharmacology. Drug treatments
Photochemical dimerisation
Plasmodium falciparum
Plasmodium falciparum - drug effects
Pyran-2-one
Pyrones - chemical synthesis
Pyrones - chemistry
Pyrones - pharmacology
structure-activity relationships
styrene
Trypanosoma brucei rhodesiense
Trypanosoma cruzi
Trypanosoma rhodesiense
Tuberculosis
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Summary: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 synthesized. 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 Trypanosoma 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 (IC50 10. Δ7 Dihydro analogues were typically less active or lacked selectivity. Head-to-head and head-to-tail photodimers 5 and 34 exhibited moderate IC50s of 2.3 to 17μM 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 (IC50 1.5 and 1.7μM) with good selectivity (SI ∼80). The 4-tert-butyl aniba-dimer A analogue 33 also exhibited activity towards L. donovani (IC50 4.5μM), suggesting further elaboration of this latter scaffold could lead to the identification of new leads for the dual treatment of malaria and leishmaniasis.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.12.053