The Novel l- and d-Amino Acid Derivatives of Hydroxyurea and Hydantoins: Synthesis, X-ray Crystal Structure Study, and Cytostatic and Antiviral Activity Evaluations

Abstract

The novel l- and d-amino acid derivatives of hydroxyurea 5a − o were prepared by aminolysis of N-(1-benzotriazolecarbonyl)amino acid amides 4a − o with hydroxylamine. The hydantoin derivatives 6a − e,m,p were synthesized by base-catalyzed cyclization of amides 4, common precursors for 5 and 6. X-ray crystal structure analysis shows that the C5 atom in 6e possesses the S configuration, which is consistent with the configuration of the starting reagent, l-leucine. Among l-amino acid derivatives of hydroxyurea, 5h and 5i inhibited specifically murine leukemia and human T-lymphocytes (IC₅₀ = 10−19 μM) and showed selectivity with respect to normal human fibroblasts (WI 38). d-Amino acid derivatives of hydroxyurea 5m and 5o inhibited the growth of all tumor cell lines (IC₅₀ = 4.8−83.9 μM), but not the growth of normal fibroblasts (WI 38; IC₅₀ > 100 μM). Results on antiviral evaluations showed that N-(1-benzotriazolecarbonyl)amino acid amide 4m and hydantoin 6m had marked activity against the Davis strain of CMV (4m, EC₅₀ = 3.2 μg/mL; 6m, EC₅₀ = 4.0 μg/mL). However, these compounds showed also rather expressed cytotoxicity (4m, CC₅₀ = 43.4 μg/mL; 6m, CC₅₀ = 12.5 μg/mL^-1).