A series of 3-substituted imidazo[1,2-a]pyridines was synthesized as potential antiviral agents. In continuation of studies on bridgehead nitrogen heterocycles, imidazo[1,2-a]pyridines possessing the acyclovir side chain and sulfur isoster in the 3-position were prepared. Condensation of suitably substituted 2-aminopyridines with α-halogenocarbonyl derivatives gave imidazo[1,2-a]pyridines 6a-c (50-82% yield). Vilsmeier-Haack reaction gave 3-formyl derivatives 7a-c (50-80% yield), which were reduced to alcohols 8a-c (90-95%) using sodium borohydride. Nucleophilic substitution with ethylene glycol or 2-mercaptoethanol gave derivatives 9a-c (30-70%) and 10a-c (65-95%). The antiviral activity of 9a-c and 10b,c against various viruses showed that compound 9b was active against both thymidine kinase-positive (TK+) and -negative (TK-) strains of varicella-zoster virus (VZV) at a 10-fold lower concentration than the cytotoxic concentration, and compound 9c was active at a 2- to 8-fold lower concentration. None of the test compounds was active against cytomegalovirus (CMV) or herpes simplex virus (HSV), and no selective activity was noted against other viruses. 3-Thioesters of the acyclovir side chain of imidazo[1,2-a]pyridine may be regarded as a potential new class of antiviral agents. Further studies focused on the modification of the side chain and nature of the substituents in the heterocycle are in progress.