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Open AccessArticle

Synthesis and Biological Activity of New 7-Amino-oxazolo[5,4-d]Pyrimidine Derivatives

1
Department of Organic Chemistry, Faculty of Pharmacy, Wroclaw Medical University, 211A Borowska Street, 50-556 Wroclaw, Poland
2
Department of Experimental Therapy, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolf Weigl Street, 53-114 Wroclaw, Poland
3
Department of Drug Technology, Faculty of Pharmacy, Wroclaw Medical University, 211A Borowska Street, 50-556 Wroclaw, Poland
4
Faculty of Chemistry, University of Wroclaw, 14 Joliot-Curie, 50-383 Wroclaw, Poland
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(15), 3558; https://doi.org/10.3390/molecules25153558
Received: 17 July 2020 / Revised: 29 July 2020 / Accepted: 3 August 2020 / Published: 4 August 2020
(This article belongs to the Section Medicinal Chemistry)
The synthesis of a series of novel 7-aminooxazolo[5,4-d]pyrimidines 5, transformations during their synthesis and their physicochemical characteristics have been described. Complete detailed spectral analysis of the intermediates 24, the N′-cyanooxazolylacetamidine by-products 7 and final compounds 5 has been carried out using MS, IR, 1D and 2D NMR spectroscopy. Theoretical research was carried out to explain the privileged formation of 7-aminooxazolo[5,4-d]pyrimidines in relation to the possibility of their isomer formation and the related thermodynamic aspects. Additionally, the single-crystal X-ray diffraction analysis for 5h was reported. Ten 7-aminooxazolo[5,4-d]pyrimidines 5 (SCM110) were biologically tested in vitro to preliminarily evaluate their immunological, antiviral and anticancer activity. Compounds SCM5 and SCM9 showed the best immunoregulatory profile. The compounds displayed low-toxicity and strongly inhibited phytohemagglutinin A-induced proliferation of human peripheral blood lymphocytes and lipopolysaccharide-induced proliferation of mouse splenocytes. Compound SCM9 caused also a moderate suppression of tumor necrosis factor α (TNF-α) production in a human whole blood culture. Of note, the compounds also inhibited the growth of selected tumor cell lines and inhibited replication of human herpes virus type-1 (HHV-1) virus in A-549 cell line. Molecular investigations showed that the compounds exerted differential changes in expression of signaling proteins in Jurkat and WEHI-231 cell lines. The activity of SCM5 is likely associated with elicitation of cell signaling pathways leading to cell apoptosis. The compounds may be of interest in terms of therapeutic utility as inhibitors of autoimmune disorders, virus replication and antitumor agents. View Full-Text
Keywords: oxazolo[5,4-d]pyrimidines; acetamidines; imidates; synthesis; spectral analysis; X-ray crystallography; immunosuppression; proliferation; apoptosis; antiviral activity oxazolo[5,4-d]pyrimidines; acetamidines; imidates; synthesis; spectral analysis; X-ray crystallography; immunosuppression; proliferation; apoptosis; antiviral activity
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Sochacka-Ćwikła, A.; Regiec, A.; Zimecki, M.; Artym, J.; Zaczyńska, E.; Kocięba, M.; Kochanowska, I.; Bryndal, I.; Pyra, A.; Mączyński, M. Synthesis and Biological Activity of New 7-Amino-oxazolo[5,4-d]Pyrimidine Derivatives. Molecules 2020, 25, 3558.

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