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

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

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

Chem Biol Drug Des. 2016 Jun 22;

Authors: Stefanachi A, Mangiatordi GF, Tardia P, Alberga D, Leonetti F, Niso M, Colabufo NA, Adamo C, Nicolotti O, Cellamare S

Abstract
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 the present study, we designed new structurally-simplified trimethoxy benzamides (5-17, Table 1) 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. This article is protected by copyright. All rights reserved.


PMID: 27331911 [PubMed - as supplied by publisher]



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