3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity

L Xue; DH Shi; JR Harjani; F Huang; JG Beveridge; T Dingjan; K Ban; S Diab; S Duffy; L Lucantoni; S Fletcher; FCK Chiu; S Blundell; K Ellis; SA Ralph; G Wirjanata; S Teguh; R Noviyanti; M Chavchich; D Creek; RN Price; J Marfurt; SA Charman; ME Cuellar; JM Strasser; JL Dahlin; MA Walters; MD Edstein; VM Avery; JB Baell

Journal article

3,3′-Disubstituted 5,5′-Bi(1,2,4-triazine) Derivatives with Potent in Vitro and in Vivo Antimalarial Activity

L Xue, DH Shi, JR Harjani, F Huang, JG Beveridge, T Dingjan, K Ban, S Diab, S Duffy, L Lucantoni, S Fletcher, FCK Chiu, S Blundell, K Ellis, SA Ralph, G Wirjanata, S Teguh, R Noviyanti, M Chavchich, D Creek Show all

Journal of Medicinal Chemistry | AMER CHEMICAL SOC | Published : 2019

DOI: 10.1021/acs.jmedchem.8b01799

Abstract

A series of 3,3′-disubstituted 5,5′-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC50 (50% inhibitory concentration) of 0.008 μM, had high in vitro potency against P. falciparum lines resistant to chloroquine (W2, IC50 = 0.0047 ± 0.0011 μM) and artemisinin (MRA1240, IC50 = 0.0086 ± 0.0010 μM). Excellent ex vivo potency of 6k was shown against clinical field isolates of both P. falciparum (IC50 = 0.022-0.034 μM) and Plasmodium vivax (IC50 = 0.0093-0.031 μM) from the blood of outpatients with uncomplicated malaria. Despite 6k being cleared relatively rapidly in mice, it suppresse..

View full abstract

University of Melbourne Researchers

Stuart Ralph Author

Related Projects (1)

NEW TREATMENTS FOR MALARIA TARGETING BOTH THE SEXUAL AND ASEXUAL STAGES OF THE CAUSATIVE PARASITE, PLASMODIUM FALCIPARUMNEW TREATMENTS FOR MALARIA TARGETING BOTH THE SEXUAL AND ASEXUAL STAGES OF THE CAUSATIVE PARASITE, PLASMODIUM FALCIPARUM

We have discovered a potent antimalarial compound class. In this research plan we will improve their metabolic stability such that we can pr..

Grants

Awarded by Australian Government

Funding Acknowledgements

The National Health and Medical Research Council of Australia (NHMRC) is thanked for Research Support (no. 1102147) and Fellowship support for J.B. (2012-2016 Senior Research Fellowship no. 1020411, 2017, Principal Research Fellowship no. 1117602). Acknowledged is Australian Federal Government Education Investment Fund Super Science Initiative and the Victorian State Government, Victoria Science Agenda Investment Fund for infrastructure support, and the facilities and the scientific and technical assistance of the Australian Translational Medicinal Chemistry Facility (ATMCF), Monash Institute of Pharmaceutical Sciences (MIPS). ATMCF is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We are grateful to Kerryn Rowcliffe for technical support in in vitro drug susceptibility testing and thank the Australian Red Cross Blood Service for the provision of human blood and sera for in vitro cultivation of P. falciparum lines at ADFMIDI. We also thank Donna MacKenzie, Geoffrey Birrell, and Stephen McLeod -Robertson for the in vivo efficacy testing of 6k in the P. berghei rodent model. The views expressed in this article are those of the authors and do not necessarily reflect those of the Australian Defence Force Joint Health Command or any extant Australian Defence Force policy.