Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold
1,2,4-Triazolo[4,3-a]pyrazines have previously been explored by the Open Source Malaria project as potent in vitro and in vivo antimalarial drug leads. With a view to generating a library of unique antimalarial 1,2,4-triazolo[4,3-a]pyrazines and exploring regiochemical preference for nucleophilic am...
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Beilstein-Institut
2025-06-01
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| Series: | Beilstein Journal of Organic Chemistry |
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| Online Access: | https://doi.org/10.3762/bjoc.21.90 |
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| author | Henry S. T. Smith Ben Giuliani Kanchana Wijesekera Kah Yean Lum Sandra Duffy Aaron Lock Jonathan M. White Vicky M. Avery Rohan A. Davis |
| author_facet | Henry S. T. Smith Ben Giuliani Kanchana Wijesekera Kah Yean Lum Sandra Duffy Aaron Lock Jonathan M. White Vicky M. Avery Rohan A. Davis |
| author_sort | Henry S. T. Smith |
| collection | DOAJ |
| description | 1,2,4-Triazolo[4,3-a]pyrazines have previously been explored by the Open Source Malaria project as potent in vitro and in vivo antimalarial drug leads. With a view to generating a library of unique antimalarial 1,2,4-triazolo[4,3-a]pyrazines and exploring regiochemical preference for nucleophilic amines, we utilised the known synthetic 5-chloro-3-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine (1) as a scaffold for aminations with 14 commercially available primary amines. Reacting scaffold 1 with excess primary amine at room temperature for 16 h generated the desired amine analogues in respectable yields (18–87%) and high purity (≥95%) following chromatography workup. The structures of the 14 previously undescribed amine analogues 2–15 were fully characterised following 1D/2D NMR, UV, and HRMS data analyses. X-ray crystallographic analysis of crystals obtained from the aminated products 2, 7, 10, and 15 are also reported here. The new library of amine-substituted triazolopyrazines was screened against the Plasmodium falciparum 3D7 strain. The tertiary alkylamine products 10–14 displayed antimalarial activity with IC50 values ranging from 9.90 to 23.30 µM against P. falciparum 3D7, with compounds 10–12 demonstrating no toxicity at 80 µM against the human embryonic kidney cell line HEK293. |
| format | Article |
| id | doaj-art-e22d6db6c4944afbac67fddc5168874d |
| institution | DOAJ |
| issn | 1860-5397 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Beilstein-Institut |
| record_format | Article |
| series | Beilstein Journal of Organic Chemistry |
| spelling | doaj-art-e22d6db6c4944afbac67fddc5168874d2025-08-20T03:12:35ZengBeilstein-InstitutBeilstein Journal of Organic Chemistry1860-53972025-06-012111126113410.3762/bjoc.21.901860-5397-21-90Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffoldHenry S. T. Smith0Ben Giuliani1Kanchana Wijesekera2Kah Yean Lum3Sandra Duffy4Aaron Lock5Jonathan M. White6Vicky M. Avery7Rohan A. Davis8Institute for Biomedicine and Glycomics, Griffith University, Brisbane, QLD 4111, Australia Institute for Biomedicine and Glycomics, Griffith University, Brisbane, QLD 4111, Australia Institute for Biomedicine and Glycomics, Griffith University, Brisbane, QLD 4111, Australia Institute for Biomedicine and Glycomics, Griffith University, Brisbane, QLD 4111, Australia Discovery Biology, Griffith University, Brisbane, QLD 4111, Australia Discovery Biology, Griffith University, Brisbane, QLD 4111, Australia School of Chemistry and Bio21 Institute, The University of Melbourne, Melbourne, VIC 3010, Australia, Discovery Biology, Griffith University, Brisbane, QLD 4111, Australia Institute for Biomedicine and Glycomics, Griffith University, Brisbane, QLD 4111, Australia 1,2,4-Triazolo[4,3-a]pyrazines have previously been explored by the Open Source Malaria project as potent in vitro and in vivo antimalarial drug leads. With a view to generating a library of unique antimalarial 1,2,4-triazolo[4,3-a]pyrazines and exploring regiochemical preference for nucleophilic amines, we utilised the known synthetic 5-chloro-3-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine (1) as a scaffold for aminations with 14 commercially available primary amines. Reacting scaffold 1 with excess primary amine at room temperature for 16 h generated the desired amine analogues in respectable yields (18–87%) and high purity (≥95%) following chromatography workup. The structures of the 14 previously undescribed amine analogues 2–15 were fully characterised following 1D/2D NMR, UV, and HRMS data analyses. X-ray crystallographic analysis of crystals obtained from the aminated products 2, 7, 10, and 15 are also reported here. The new library of amine-substituted triazolopyrazines was screened against the Plasmodium falciparum 3D7 strain. The tertiary alkylamine products 10–14 displayed antimalarial activity with IC50 values ranging from 9.90 to 23.30 µM against P. falciparum 3D7, with compounds 10–12 demonstrating no toxicity at 80 µM against the human embryonic kidney cell line HEK293.https://doi.org/10.3762/bjoc.21.90amine substitutionantimalarialopen source malariatriazolopyrazine1,2,4-triazolo[4,3-a]pyrazines |
| spellingShingle | Henry S. T. Smith Ben Giuliani Kanchana Wijesekera Kah Yean Lum Sandra Duffy Aaron Lock Jonathan M. White Vicky M. Avery Rohan A. Davis Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold Beilstein Journal of Organic Chemistry amine substitution antimalarial open source malaria triazolopyrazine 1,2,4-triazolo[4,3-a]pyrazines |
| title | Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold |
| title_full | Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold |
| title_fullStr | Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold |
| title_full_unstemmed | Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold |
| title_short | Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold |
| title_sort | investigations of amination reactions on an antimalarial 1 2 4 triazolo 4 3 a pyrazine scaffold |
| topic | amine substitution antimalarial open source malaria triazolopyrazine 1,2,4-triazolo[4,3-a]pyrazines |
| url | https://doi.org/10.3762/bjoc.21.90 |
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