1-(4-Phenoxybenzyl) 5-Aminouracil Derivatives and Their Analogues - Novel Inhibitors of Human Adenovirus Replication

Abstract

Adenovirus infections are characterized by widespread distribution. The lack of causal therapy, which is effective in treating this group of diseases, explains the need for new therapeutic drugs. Notably, anti-adenoviral activity of [4-(phenoxy)benzyl]-5-(phenylamino)-6-azauracil, 1-[4-(phenoxy)benzyl]-5-(morpholino) uracil, 1-[4-(4-chlorophenoxy)benzyl]-5-(morpholino) uracil, and 1-[4-(4-fluorophenoxy)-benzyl]-5-(morpholino) uracil was observed.

Keywords: 5-aminouracil derivatives; Human adenovirus; adenovirus replication; inhibitors of adenovirus replication.

Fig. 1

Scheme for the synthesis of 1-[4-(phenoxy)benzyl]- 5-(phenylamino)-6-azauracil (1), 1-[4-(phenoxy)benzyl]-5-[(3,5- dichlorophenyl)amino]-6-azauracil (2), and 1-[4-(phenoxy)benzyl]- (3), 1-[4-(4-chlorophenoxy) benzyl]-(4), 1-[4-(4-fluorophenoxy) benzyl]-5-(morpholino)uracil derivatives (5).

Fig. 2

Scheme for the synthesis of 5-(morpholino)uracil derivatives 6–8

Fig. 3

Assessment of the relative HAdV5-eGFP genome copy number in HEK293 cells treated with the test compounds. The differences between experimental and control samples were statistically significant at * p < 0.05; *** p < 0.001.

Fig. 4

Anti-adenoviral activity of 5-aminouracil derivatives. TC50 and IC₅₀ of compounds 1 (A) and 3 (B). Differences between experimental and control samples were statistically significant at * p < 0.05; *** p < 0.001.

Fig. 5

The survival of HEK293 cells transduced with HAdV5-eGFP and treated with the 5-aminouracil derivatives 1 and 3. (A) The results were obtained using the MTT assay. 100% corresponds to optical density value of intact HEK293 cells (control sample). All reported values are means of three independent measurements with standard deviations. The differences between experimental and control samples were statistically significant in all cases (p < 0.05). (B) Data was obtained using the resazurin assay. One hundred percent corresponds to the fluorescence intensity of intact HEK293 cells (control sample). All reported values are means of three independent measurements with standard deviations. The differences between DMSO samples and other samples were statistically significant in all cases (p < 0.05). The differences between intact cells samples and samples of group “3” were statistically insignificant.