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Title
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Amino acid based prodrugs of a fosmidomycin surrogate as antimalarial and antitubercular agents
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Author
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Abstract
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| Fosmidomycin is a natural antibiotic with promising IspC (DXR, 1-deoxy-D-xylulose-5-phosphate reductoisomerase) inhibitory activity. This enzyme catalyzes the first committed step of the non-mevalonate isoprenoid biosynthesis pathway, which is essential in Plasmodium falciparum and Mycobacterium tuberculosis. Mainly as a result of its high polarity, fosmidomycin displays suboptimal pharmacokinetic properties. Furthermore, fosmidomycin is inactive against M. tuberculosis as a result of its inability to penetrate the bacterial cell wall. Temporarily masking the phosphonate moiety as a prodrug has the potential to solve both issues. We report the application of two amino acid based prodrug approaches on a fosmidomycin surrogate. Conversion of the phosphonate moiety into tyrosine-derived esters increases the in vitro activity against asexual blood stages of P. falciparum, while phosphonodiamidate prodrugs display promising antitubercular activities. Selected prodrugs were tested in vivo in a P. berghei malaria mouse model. These results indicate good in vivo antiplasmodial potential. |
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Language
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English
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Source (journal)
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Bioorganic and medicinal chemistry. - Oxford
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Publication
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Oxford
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2019
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ISSN
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0968-0896
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DOI
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10.1016/J.BMC.2019.01.016
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Volume/pages
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27
:5
(2019)
, p. 729-747
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ISI
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000458293000007
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Pubmed ID
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30692024
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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