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Design, synthesis, biological evaluation, NMR and DFT studies of structurally simplified trimethoxy benzamides as selective P‐glycoprotein inhibitors: the role of molecular flatness
Author(s) -
Stefanachi Angela,
Mangiatordi Giuseppe Felice,
Tardia Piero,
Alberga Domenico,
Leonetti Francesco,
Niso Mauro,
Colabufo Nicola Antonio,
Adamo Carlo,
Nicolotti Orazio,
Cellamare Saverio
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12811
Subject(s) - intramolecular force , chemistry , hydrogen bond , stereochemistry , proton nmr , combinatorial chemistry , molecular model , nuclear magnetic resonance spectroscopy , molecule , organic chemistry
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 [Table 1. Chemical structure, biological activity, and experimental measures of lipophilicity of the compounds 5–17]) with the aim to uncover the minimal molecular requirements needed for P‐gp inhibition. The new prepared smaller‐sized compounds exhibited IC 50 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.