A series of new matrinic derivatives with an 11-adamantyl group were designed, synthesized and evaluated for their anti-influenza A H3N2 activities, based on the privileged structure strategy.SAR analysis indicated that introduction of an 11-adamantyl by ester linker might be helpful for the activity. Among them, compound 7b exhibited promising anti-H3N2 activities with IC50 value of 5.14 μM, slightly better than that of amantadine. Its activity was further confirmed at the protein level. In primary mechanism, compound 7b could inhibit virus replication cycle at early stage by targeting M2 protein, consistent with that of amantadine. This study represents a successful application of combined strategy of privileged amantadine segment for further structural optimization and development of a new class of anti-influenza agents.