Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds

Kah Yean Lum; Jonathan M White; Daniel J G Johnson; Vicky M Avery; Rohan A Davis

doi:10.3762/bjoc.19.11

Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds

Beilstein J Org Chem. 2023 Jan 31:19:107-114. doi: 10.3762/bjoc.19.11. eCollection 2023.

Authors

Kah Yean Lum¹, Jonathan M White², Daniel J G Johnson¹, Vicky M Avery^{1

3}, Rohan A Davis^{1

4}

Affiliations

¹ Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia.
² School of Chemistry and Bio21 Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
³ Discovery Biology, Griffith University, Nathan, QLD 4111, Australia.
⁴ NatureBank, Griffith University, Nathan, QLD 4111, Australia.

Abstract

Nine new fluorinated analogues were synthesised by late-stage functionalisation using Diversinate™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4). The structures of all analogues were fully characterised by NMR, UV and MS data analysis; three triazolopyrazines were confirmed by X-ray crystal structure analysis. The inhibitory activity of all compounds against the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and the cytotoxicity against a human embryonic kidney (HEK293) cell line were tested. Some of the compounds demonstrated moderate antimalarial activity with IC₅₀ values ranging from 0.2 to >80 µM; none of the compounds displayed any cytotoxicity against HEK293 cells at 80 µM. Antimalarial activity was significantly reduced when C-8 of the triazolopyrazine scaffold was substituted with CF₃ and CF₂H moieties, whereas incorporation of a CF₂Me group at the same position completely abolished antiplasmodial effects.

Keywords: DiversinateTM; Open Source Malaria; antimalarial; characterisation; fluorine; scaffold; triazolopyrazine.

Grants and funding

The authors acknowledge the Australian Research Council (ARC) for support towards NMR and MS equipment (grants LE0668477, LE140100119, and LE0237908). The authors acknowledge the National Health and Medical Research Council (NHMRC) (Grant APP1024314 to R.A.D.).