Antimalarial activity of natural and synthetic prodiginines

Kancharla Papireddy, Martin Smilkstein, Jane Xu Kelly, Amany Shweta, Shaimaa M. Salem, Mamoun Alhamadsheh, Stuart W. Haynes, Gregory L. Challis, Kevin A. Reynolds

Research output: Contribution to journalArticleResearchpeer-review

79 Citations (Scopus)

Abstract

Prodiginines are a family of linear and cyclic oligopyrrole red-pigmented compounds. Herein we describe the in vitro antimalarial activity of four natural (IC 50 = 1.7-8.0 nM) and three sets of synthetic prodiginines against Plasmodium falciparum. Set 1 compounds replaced the terminal nonalkylated pyrrole ring of natural prodiginines and had diminished activity (IC 50 > 2920 nM). Set 2 and set 3 prodiginines were monosubstituted or disubstituted at either the 3 or 5 position of the right-hand terminal pyrrole, respectively. Potent in vitro activity (IC 50 = 0.9-16.0 nM) was observed using alkyl or aryl substituents. Metacycloprodiginine and more potent synthetic analogues were evaluated in a P. yoelii murine patent infection using oral administration. Each analogue reduced parasitemia by more than 90% after 25 (mg/kg)/day dosing and in some cases provided a cure. The most favorable profile was 92% parasite reduction at 5 (mg/kg)/day, and 100% reduction at 25 (mg/kg)/day without any evident weight loses or clinical overt toxicity.

Original languageEnglish
Pages (from-to)5296-5306
Number of pages11
JournalJournal of Medicinal Chemistry
Volume54
Issue number15
DOIs
Publication statusPublished - 11 Aug 2011
Externally publishedYes

Cite this

Papireddy, K., Smilkstein, M., Kelly, J. X., Shweta, A., Salem, S. M., Alhamadsheh, M., ... Reynolds, K. A. (2011). Antimalarial activity of natural and synthetic prodiginines. Journal of Medicinal Chemistry, 54(15), 5296-5306. https://doi.org/10.1021/jm200543y
Papireddy, Kancharla ; Smilkstein, Martin ; Kelly, Jane Xu ; Shweta, Amany ; Salem, Shaimaa M. ; Alhamadsheh, Mamoun ; Haynes, Stuart W. ; Challis, Gregory L. ; Reynolds, Kevin A. / Antimalarial activity of natural and synthetic prodiginines. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 15. pp. 5296-5306.
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Papireddy, K, Smilkstein, M, Kelly, JX, Shweta, A, Salem, SM, Alhamadsheh, M, Haynes, SW, Challis, GL & Reynolds, KA 2011, 'Antimalarial activity of natural and synthetic prodiginines', Journal of Medicinal Chemistry, vol. 54, no. 15, pp. 5296-5306. https://doi.org/10.1021/jm200543y

Antimalarial activity of natural and synthetic prodiginines. / Papireddy, Kancharla; Smilkstein, Martin; Kelly, Jane Xu; Shweta, Amany; Salem, Shaimaa M.; Alhamadsheh, Mamoun; Haynes, Stuart W.; Challis, Gregory L.; Reynolds, Kevin A.

In: Journal of Medicinal Chemistry, Vol. 54, No. 15, 11.08.2011, p. 5296-5306.

Research output: Contribution to journalArticleResearchpeer-review

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Papireddy K, Smilkstein M, Kelly JX, Shweta A, Salem SM, Alhamadsheh M et al. Antimalarial activity of natural and synthetic prodiginines. Journal of Medicinal Chemistry. 2011 Aug 11;54(15):5296-5306. https://doi.org/10.1021/jm200543y