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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
- Source :
- Chemical biology & drug design, 88 (2016): 820–831. doi:10.1111/cbdd.12811, info:cnr-pdr/source/autori:Stefanachi, Angela; Mangiatordi, Giuseppe Felice; Tardia, Piero; Alberga, Domenico; Leonetti, Francesco; Niso, Mauro; Colabufo, Nicola Antonio; Adamo, Carlo; Nicolotti, Orazio; Cellamare, Saverio/titolo:Design, synthesis, biological evaluation, NMR and DFT studies of structurally simplified trimethoxy benzamides as selective P-glycoprotein inhibitors: the role of molecular flatness/doi:10.1111%2Fcbdd.12811/rivista:Chemical biology & drug design (Print)/anno:2016/pagina_da:820/pagina_a:831/intervallo_pagine:820–831/volume:88
- Publication Year :
- 2016
- Publisher :
- Blackwell, Oxford , Regno Unito, 2016.
-
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 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.
- Subjects :
- 0301 basic medicine
Spectrometry, Mass, Electrospray Ionization
Proton Magnetic Resonance Spectroscopy
Flatness (systems theory)
Combined use
P-glycoprotein
01 natural sciences
Biochemistry
Madin Darby Canine Kidney Cells
Inhibitory Concentration 50
03 medical and health sciences
Dogs
Computational chemistry
Drug Discovery
Animals
molecular flatness
ATP Binding Cassette Transporter, Subfamily B, Member 1
density functional theory
Biological evaluation
Pharmacology
P-glycoprotein Inhibitor
structural simplification
010405 organic chemistry
Chemistry
Hydrogen bond
Organic Chemistry
0104 chemical sciences
030104 developmental biology
Design synthesis
Drug Design
Intramolecular force
Benzamides
Molecular Medicine
Density functional theory
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Chemical biology & drug design, 88 (2016): 820–831. doi:10.1111/cbdd.12811, info:cnr-pdr/source/autori:Stefanachi, Angela; Mangiatordi, Giuseppe Felice; Tardia, Piero; Alberga, Domenico; Leonetti, Francesco; Niso, Mauro; Colabufo, Nicola Antonio; Adamo, Carlo; Nicolotti, Orazio; Cellamare, Saverio/titolo:Design, synthesis, biological evaluation, NMR and DFT studies of structurally simplified trimethoxy benzamides as selective P-glycoprotein inhibitors: the role of molecular flatness/doi:10.1111%2Fcbdd.12811/rivista:Chemical biology & drug design (Print)/anno:2016/pagina_da:820/pagina_a:831/intervallo_pagine:820–831/volume:88
- Accession number :
- edsair.doi.dedup.....e9e4aded7ff96da88a8cd5d9c21f8c09