Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads

Santosh R. Kotturi; Brinda Somanadhan; Jun Hong Ch'Ng; Kevin S.W. Tan; Mark S. Butler; Martin J. Lear

doi:10.1016/j.tetlet.2014.02.008

Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads

Santosh R. Kotturi, Brinda Somanadhan, Jun Hong Ch'Ng, Kevin S.W. Tan, Mark S. Butler, Martin J. Lear

SCI - Chemistry

Research output: Contribution to journal › Article

4 Citations (Scopus)

Abstract

We report not only the convergent total synthesis of falcitidin, a natural inhibitor of falcipain-2 from myxobacterium Chitinophaga, but also its diversification into a new antimalarial class of N-acyl tetrapeptides (Acyl-His-Ile-Val-Pro-NH₂). Despite the lack of whole-cell activity of falcitidin itself, our study led to the identification of a trifluoromethyl (CF₃) analogue displaying sub-micromolar IC₅₀ activity against Plasmodium falciparum 3D7 in a standard blood-cell assay, but only when N-tritylated on its histidine (imidazole) residue.

Original language	English
Pages (from-to)	1949-1951
Number of pages	3
Journal	Tetrahedron Letters
Volume	55
Issue number	11
DOIs	https://doi.org/10.1016/j.tetlet.2014.02.008
Publication status	Published - 2014 Mar 12

Keywords

Antimalarial agents
Falcitidin
Natural products
Tetrapeptide
Trifluoromethyl

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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Kotturi, S. R., Somanadhan, B., Ch'Ng, J. H., Tan, K. S. W., Butler, M. S., & Lear, M. J. (2014). Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads. Tetrahedron Letters, 55(11), 1949-1951. https://doi.org/10.1016/j.tetlet.2014.02.008

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abstract = "We report not only the convergent total synthesis of falcitidin, a natural inhibitor of falcipain-2 from myxobacterium Chitinophaga, but also its diversification into a new antimalarial class of N-acyl tetrapeptides (Acyl-His-Ile-Val-Pro-NH2). Despite the lack of whole-cell activity of falcitidin itself, our study led to the identification of a trifluoromethyl (CF3) analogue displaying sub-micromolar IC50 activity against Plasmodium falciparum 3D7 in a standard blood-cell assay, but only when N-tritylated on its histidine (imidazole) residue.",

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AU - Somanadhan, Brinda

AU - Ch'Ng, Jun Hong

AU - Tan, Kevin S.W.

AU - Butler, Mark S.

AU - Lear, Martin J.

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AB - We report not only the convergent total synthesis of falcitidin, a natural inhibitor of falcipain-2 from myxobacterium Chitinophaga, but also its diversification into a new antimalarial class of N-acyl tetrapeptides (Acyl-His-Ile-Val-Pro-NH2). Despite the lack of whole-cell activity of falcitidin itself, our study led to the identification of a trifluoromethyl (CF3) analogue displaying sub-micromolar IC50 activity against Plasmodium falciparum 3D7 in a standard blood-cell assay, but only when N-tritylated on its histidine (imidazole) residue.

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