Journal article

Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines

Daniel L Priebbenow, Mitch Mathiew, Da-Hua Shi, Jitendra R Harjani, Julia G Beveridge, Marina Chavchich, Michael D Edstein, Sandra Duffy, Vicky M Avery, Robert T Jacobs, Stephen Brand, David M Shackleford, Wen Wang, Longjin Zhong, Given Lee, Erin Tay, Helena Barker, Elly Crighton, Karen L White, Susan A Charman Show all

Journal of Medicinal Chemistry | AMER CHEMICAL SOC | Published : 2021

Abstract

Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds. These efforts led to the identification of second-generation highly potent antimalarial bis-triazines, exemplified by triazine 23, which exhibited significantly improved in vitro metabolic stability (8 and 42 μL/min/mg protein in human and mouse liver microsomes). The disubstituted triazine dimer 23 was also observed to suppress pa..

View full abstract

University of Melbourne Researchers

Grants

Awarded by Australian Research Council


Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by NHMRC Synergy grant


Funding Acknowledgements

D.L.P. acknowledges funding support from the Australian Research Council (DE200100949). The National Health and Medical Research Council of Australia (NHMRC) is thanked for Research Support (#1030704, 1080146) and Fellowship support for J.B.B. (2012-2016 Senior Research Fellowship #1020411, 2017.Principal Research Fellowship #1117602). This work was also supported by an NHMRC Synergy grant (#1185354). Also acknowledged are the 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 and the Center for Drug Candidate Optimisation (CDCO) are supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. Delphine Baud, Maelle Duffey, and Virginia Crivelli are acknowledged for their contributions to the coordination of the various studies at MMV partner facilities. Technical assistance from Jaya Jayaseelan, Golnar Golbaghi, and Meiyu Hu is also gratefully acknowledged. The ongoing support of the MMV to VMA is also acknowledged. We are grateful to Kerryn Rowcliffe for technical support in in vitro drug susceptibility assays and thank the Australian Red Cross Blood Service for the provision of human blood, plasma, and sera for in vitro cultivation of P. falciparum lines at Monash University, ADFMIDI, and Griffith University. We also thank Karin Van Breda, Ivor Harris, Anthony Kent, and Stephen McLeod-Robertson for the in vivo efficacy testing of 23 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.