The emergence of drug resistance in canceris a serious threat. Upregulation ofABC/P-gptransporters significantly contributes to thisemergence.Despite30 years of efforts,the search for effective ABC/P-gp inhibitors withminimaltoxicity to human cells, isstill underway.Inspired by Nocardioazine A, a marine alkaloid that inhibitsP-gp, we report a regioselective pathway to createindole-C3-benzyl cyclo-L-Trp-L-Trp DKPs. We have reported thatexo-C3-N-Dbn--Trp2 (13) as a lead ABCB1 inhibitor that is more effective than Verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells and had no adverse effect on cell proliferation.Herein, we report several suchC3-functionalized pyrroloindolines as ABCB1 inhibitors.Results arising from the molecular docking studies indicate that the interactions at the access tunnel between ABCB1 and the inhibitor result in a powerful predictor for the efficacy of the inhibitor. Based on fluorescence-based assays, we conclude that the most efficacious inhibitor is the p-cyano-derived exo-C3-N-Dbn--Trp2 (33a), closely followed by several analogues. We correlate that the predictions based on the inhibitor interactions at the access tunnel provide clues about the design of improved ABCB1 inhibitors. This work lays the foundation for the design of a new class of inhibitors from acyclo-L-Trp-L-Trp DKP scaffold.