El Bissati, K, Redel, H, Ting, L-M et al. (7 more authors) (2019) Novel Synthetic Polyamines Have Potent Antimalarial Activities in vitro and in vivo by Decreasing Intracellular Spermidine and Spermine Concentrations. Frontiers in Cellular and Infection Microbiology, 9. 9. ISSN 2235-2988
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.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Editors: |
|
Copyright, Publisher and Additional Information: | © 2019 El Bissati, Redel, Ting, Lykins, McPhillie, Upadhya, Woster, Yarlett, Kim and Weiss. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | polyamine; Plasmodium; malaria; spermidine; spermine; spermidine synthase; thiourea |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 01 Mar 2019 15:20 |
Last Modified: | 25 Jun 2023 21:44 |
Status: | Published |
Publisher: | Frontiers Media |
Identification Number: | 10.3389/fcimb.2019.00009 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:143099 |