Design, synthesis, biological evaluation, NMR and DFT studies of structurally-simplified trimethoxy benzamides as P-glycoprotein selective inhibitors: the role of molecular flatness

In a recent investigation carried out on a panel of trimethoxybenzanilides, we showed that the formation of an intramolecular hydrogen bond is a key element for tuning P-gp inhibitory activity. In this study, we designed new structurally simplified trimethoxy benzamides (5–17, Table) with the aim to uncover the minimal molecular requirements needed for P-gp inhibition. The new prepared smaller-sized compounds exhibited IC50 in the low micromolar range. The combined use of NMR and DFT studies suggested that molecular flatness is causatively related to the P-gp inhibition. Our results clearly pointed out that concerted theoretical and experimental approaches herein presented might be very helpful in addressing the design of structurally simplified and highly efficient compounds biasing P-gp protein.