title: Design, synthesis, biological evaluation, NMR and DFT studies of structurally simplified trimethoxy benzamides as selective P-glycoprotein inhibitors: the role of molecular flatness.
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 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 IC50in 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.
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università di Bari Aldo Moro, Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanachi
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università di Bari Aldo Moro, Bari, Italy.
authors.forename: Giuseppe Felice
authors.initials: GF
authors.lastname: Mangiatordi
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università di Bari Aldo Moro, Bari, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Tardia
authors.affiliation: Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, PSL Research University, Paris, France.|Institut Universitaire de France, Paris, France.
authors.forename: Domenico
authors.initials: D
authors.lastname: Alberga
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università di Bari Aldo Moro, Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università di Bari Aldo Moro, Bari, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università di Bari Aldo Moro, Bari, Italy.
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, PSL Research University, Paris, France.|Institut Universitaire de France, Paris, France.
authors.forename: Carlo
authors.initials: C
authors.lastname: Adamo
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università di Bari Aldo Moro, Bari, Italy. orazio.nicolotti@uniba.it.|Dipartimento di Fisica, INFN & TIRES, Università di Bari Aldo Moro, Bari, Italy. orazio.nicolotti@uniba.it.
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università di Bari Aldo Moro, Bari, Italy. saverio.cellamare@uniba.it.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cellamare
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides
keywords: P-glycoprotein; density functional theory; molecular flatness; structural simplification