The voltage-gated potassium channel Kv1.3 constitutes an attractive target for the selective suppression of effector memory T cells in autoimmune diseases. We have previously reported the natural product khellinone, 1a, as a versatile lead molecule and identified two new classes of Kv1.3 blockers: (i) chalcone derivatives of khellinone, and (ii) khellinone dimers linked through the 6-position. Here we describe the multiple parallel synthesis of a new class of khellinone derivatives selectively alkylated at either the 4- or 7-position via the phenolic OH and show that several chloro, bromo, methoxy, and nitro substituted benzyl derivatives inhibit Kv1.3 with submicromolar potencies. Representative examples of the most potent compounds from each subclass, 11m (5-acetyl-4-(4a??-chloro)benzyloxy-6-hydroxy-7-methoxybenzofuran) and 14m (5-acetyl-7-(4a??-bromo)benzyloxy-6-hydroxy-4-methoxybenzofuran), block Kv1.3 with EC 50 values of 480 and 400 nM, respectively. Both compounds exhibit moderate selectivity over other Kv1-family channels and HERG, are not cytotoxic, and suppress human T cell proliferation at low micromolar concentrations.