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

Abstract

The synthesis of a series of novel 7-aminooxazolo[5,4-<i>d</i>]pyrimidines <b>5</b>, transformations during their synthesis and their physicochemical characteristics have been described. Complete detailed spectral analysis of the intermediates <b>2</b>-<b>4</b>, the <i>N'</i>-cyanooxazolylacetamidine by-products <b>7</b> and final compounds <b>5</b> 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-<i>d</i>]pyrimidines in relation to the possibility of their isomer formation and the related thermodynamic aspects. Additionally, the single-crystal X-ray diffraction analysis for <b>5h</b> was reported. Ten 7-aminooxazolo[5,4-<i>d</i>]pyrimidines <b>5</b> (<b>SCM1</b>-<b>10</b>) were biologically tested in vitro to preliminarily evaluate their immunological, antiviral and anticancer activity. Compounds <b>SCM5</b> and <b>SCM9</b> 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 <b>SCM9</b> 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 <b>SCM5</b> 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.