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. 2021 Apr 21;26(9):2421.
doi: 10.3390/molecules26092421.

Synthesis of New Triazolopyrazine Antimalarial Compounds

Daniel J G Johnson  1 , Ian D Jenkins  1 , Cohan Huxley  1 , Mark J Coster  1 , Kah Yean Lum  1   2 , Jonathan M White  3 , Vicky M Avery  1   4 , Rohan A Davis  1   2
Affiliations

Synthesis of New Triazolopyrazine Antimalarial Compounds

Daniel J G Johnson et al. Molecules. .

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.

Keywords: Diversinate™; Open Source Malaria; X-ray; antimalarial; difluoroethylation; drug discovery; late-stage functionalization; mechanism; methylation; photoredox; radical disproportionation; synthesis; triazolopyrazine.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Some analogues under investigation by the OSM, including OSM-S-369, which was further investigated in this work [6].
Scheme 1
Scheme 1
Synthesis of compound 2.
Scheme 2
Scheme 2
Synthesis of compound 3 and side product 4.
Figure 2
Figure 2
ORTEP drawing of compound 3.
Scheme 3
Scheme 3
Synthesis of compounds 5 and 6.
Figure 3
Figure 3
Key HMBC (→), ROESY (↔), and COSY (—) correlations for 5.
Figure 4
Figure 4
ORTEP drawing of compound 5.
Scheme 4
Scheme 4
Synthesis of 8, 10, and 11 via photoredox-catalyzed methylation (for structure of the iridium catalyst, see Ref. [16]).
Scheme 5
Scheme 5
Photoredox-catalyzed methylation of the scaffolds 2, 3, and 5.
Figure 5
Figure 5
Key HMBC (→), ROESY (↔), and COSY (—) correlations for 13.
Scheme 6
Scheme 6
Introduction of fluoroalkyl groups via Diversinate™ chemistry.
Scheme 7
Scheme 7
Proposed mechanism for the formation of compound 15 and dechlorinated product 16.
Figure 6
Figure 6
ORTEP drawing of compounds 7 and 18.
See this image and copyright information in PMC

References

    1. Shapiro G. 3,3-Difluoropiperidine Carbamate Heterocyclic Compounds as NR2B NMDA Receptor Antagonists. 10294230B2. U.S. Patent. 2015 Jun 1;
    1. Pasternak A., Pio B., Chobanian R., Harry, Shi Z.-C., Dong S., Guo Y., Walsh P., Shawn, Guo Z. Inhibitors of the renal outer medullary potassium channel. J. Org. Chem. 2020;85:13438–13452. doi: 10.1517/13543776.2015.1050792. - DOI - PubMed
    1. Lee S., Çil O., Diez-Cecilia E., Anderson M.O., Verkman A.S. Nanomolar-potency 1,2,4-triazoloquinoxaline inhibitors of the kidney urea transporter UT-A1. J. Med. Chem. 2018;61:3209–3217. doi: 10.1021/acs.jmedchem.8b00343. - DOI - PMC - PubMed
    1. Ali I., Lee J., Go A., Choi G., Lee K. Discovery of novel [1,2,4]triazolo[4,3-a]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment. Bioorg. Med. Chem. Lett. 2017;27:4606–4613. doi: 10.1016/j.bmcl.2017.09.025. - DOI - PubMed
    1. Open Source Malaria Project wiki; Open Source Malaria project/Series 4. [(accessed on 20 January 2021)]; Available online: https://github.com/OpenSourceMalaria/Series4/wiki.

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