Novel Synthetic Polyamines Have Potent Antimalarial Activities in vitro and in vivo by Decreasing Intracellular Spermidine and Spermine Concentrations

Kamal El Bissati, Henry Redel, Li Min Ting, Joseph D. Lykins, Martin J. McPhillie, Rajendra Upadhya, Patrick M. Woster, Nigel Yarlett, Kami Kim, Louis M. Weiss

Research output: Contribution to journalArticle

Abstract

Twenty-two compounds belonging to several classes of polyamine analogs have been examined for their ability to inhibit the growth of the human malaria parasite Plasmodium falciparum in vitro and in vivo. Four lead compounds from the thiourea sub-series and one compound from the urea-based analogs were found to be potent inhibitors of both chloroquine-resistant (Dd2) and chloroquine-sensitive (3D7) strains of Plasmodium with IC50 values ranging from 150 to 460 nM. In addition, the compound RHW, N1,N7-bis (3-(cyclohexylmethylamino) propyl) heptane-1,7-diamine tetrabromide was found to inhibit Dd2 with an IC50 of 200 nM. When RHW was administered to P. yoelii-infected mice at 35 mg/kg for 4 days, it significantly reduced parasitemia. RHW was also assayed in combination with the ornithine decarboxylase inhibitor difluoromethylornithine, and the two drugs were found not to have synergistic antimalarial activity. Furthermore, these inhibitors led to decreased cellular spermidine and spermine levels in P. falciparum, suggesting that they exert their antimalarial activities by inhibition of spermidine synthase.

Original languageEnglish (US)
Number of pages1
JournalFrontiers in Cellular and Infection Microbiology
Volume9
DOIs
StatePublished - Jan 1 2019

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Spermidine
Spermine
Chloroquine
Antimalarials
Polyamines
Inhibitory Concentration 50
Spermidine Synthase
Eflornithine
Heptanes
Thiourea
Diamines
Plasmodium
Parasitemia
Falciparum Malaria
Plasmodium falciparum
Urea
Parasites
Growth
Pharmaceutical Preparations
In Vitro Techniques

Keywords

  • malaria
  • Plasmodium
  • polyamine
  • spermidine
  • spermidine synthase
  • spermine
  • thiourea

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

Cite this

Novel Synthetic Polyamines Have Potent Antimalarial Activities in vitro and in vivo by Decreasing Intracellular Spermidine and Spermine Concentrations. / El Bissati, Kamal; Redel, Henry; Ting, Li Min; Lykins, Joseph D.; McPhillie, Martin J.; Upadhya, Rajendra; Woster, Patrick M.; Yarlett, Nigel; Kim, Kami; Weiss, Louis M.

In: Frontiers in Cellular and Infection Microbiology, Vol. 9, 01.01.2019.

Research output: Contribution to journalArticle

El Bissati, Kamal ; Redel, Henry ; Ting, Li Min ; Lykins, Joseph D. ; McPhillie, Martin J. ; Upadhya, Rajendra ; Woster, Patrick M. ; Yarlett, Nigel ; Kim, Kami ; Weiss, Louis M. / Novel Synthetic Polyamines Have Potent Antimalarial Activities in vitro and in vivo by Decreasing Intracellular Spermidine and Spermine Concentrations. In: Frontiers in Cellular and Infection Microbiology. 2019 ; Vol. 9.
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