2′-Deoxyuridines with a 5-Heteroaromatic Substituent: Synthesis and Biological Evaluation

Abstract

A series of novel 2′-deoxyuridines with a thienyl substituent in the 5-position were synthesized as potential anti-HSV-1 agents. The brominated derivatives (1d, 1e and 3b) were obtained via halogenation reactions of the protected 5-(thien-2-yl)-2′-deoxyuridine and 5-(thien-3-yl)-2′-deoxyuridine, respectively. The palladium-catalysed cross-coupling reaction with stannylated thiophene was used for the synthesis of ( E)-5-(2-thienylvinyl)-2′-deoxyuridine and 5-(5,2′-dithien-2-yl)-2′-deoxyuridine. These compounds show moderate to good activity against herpes simplex virus type 1 (HSV-1) in the order of decreasing activity 1d>4>1e>3b∼5. Finally, two substituted 5-isoxazol derivatives of 2′-deoxyuridine (6a and 6b) were obtained via a 1,3-dipolar cycloaddition of the protected 5-ethynyl-2′-deoxyuridine. These new compounds demonstrated poor affinity for the virus-specific enzyme thymidine kinase.