(A) The two-step synthetic method is used first to produce the desired isophthaloyl chloride intermediate and then the macrocyclic final products (1a-4c). R1 (yellow) is representative of the substituent on the two isophthalamide units, and R2 (blue) denotes the substituent of the two peripheral heterocyclic rings. (B) The previously reported method by Ishikawa et a The Cl -efflux kini (% s -1 ) rates facilitated by the tetralactams (0.05 mol%) in systems containing untreated vesicles or vesicles treated with either Vln or Mon (0.1 mol%). b The ENC factors of the tetralactams were calculated by dividing the kini rate achieved for the Mon-treated system by the kini rate achieved in the Vln-treated system. c Sigmoidal-shape kinetic curve observed likely due to slow partitioning of the transporters to the lipid bilayer membranes. The rates reported are the maximal rates obtained by differentiating the kinetic curves. d Accurate kini rates could not be obtained due to poor transporter solubility during the assay. e Due to high activity, the transporter loading of 3c was decreased from 0.05 mol% to 0.0005 mol%. The CLogP values were calculated using the online ALOGPS 2.1 applet from VCCLAB. The transporter was too inactive and did not reach the required 50% Cl - efflux, preventing an EC50 value from being calculated. d Previously reported by Gale and co-workers.