Synthesis of New Triazolopyrazine Antimalarial Compounds |
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| Authors: | Daniel J G Johnson Ian D Jenkins Cohan Huxley Mark J Coster Kah Yean Lum Jonathan M White Vicky M Avery Rohan A Davis |
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| Institution: | 1.Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Brisbane, QLD 4111, Australia; (D.J.G.J.); (I.D.J.); (C.H.); (M.J.C.); (K.Y.L.); (V.M.A.);2.NatureBank, Griffith University, Brisbane, QLD 4111, Australia;3.School of Chemistry and Bio21 Institute, The University of Melbourne, Melbourne, VIC 3010, Australia;4.Discovery Biology, Griffith University, Brisbane, QLD 4111, Australia |
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| Abstract: | A radical approach to late-stage functionalization using photoredox and Diversinate™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC50 values ranging from 0.3 to >20 µM; none of the compounds displayed any toxicity against HEK293 at 80 µM. |
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| Keywords: | Open Source Malaria drug discovery synthesis triazolopyrazine late-stage functionalization photoredox Diversinate™ methylation difluoroethylation antimalarial X-ray radical disproportionation mechanism |
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