2. Academic Validation
  3. Trimethoxybenzanilide-based P-glycoprotein modulators: an interesting case of lipophilicity tuning by intramolecular hydrogen bonding

Trimethoxybenzanilide-based P-glycoprotein modulators: an interesting case of lipophilicity tuning by intramolecular hydrogen bonding

  • J Med Chem. 2014 Aug 14;57(15):6403-18. doi: 10.1021/jm500697c.
Piero Tardia 1,  Angela Stefanachi,  Mauro Niso,  Diana Antonella Stolfa,  Giuseppe Felice Mangiatordi,  Domenico Alberga,  Orazio Nicolotti,  Gianluca Lattanzi,  Angelo Carotti,  Francesco Leonetti,  Roberto Perrone,  Francesco Berardi,  Amalia Azzariti,  Nicola Antonio Colabufo,  Saverio Cellamare
Affiliations

Affiliation

  • 1 Dipartimento di Farmacia-Scienze del Farmaco, Università di Bari "Aldo Moro" , Via Orabona 4, 70125 Bari, Italy.
PMID: 25093931 DOI: 10.1021/jm500697c
Abstract

One of the principal reasons for the chemotherapy failure is the overexpression of drug efflux pumps, ABCB1 (also known as MDR1 or P-gp) and ABCC1 (also known as MRP1), whose inhibition remains a priority to circumvent drug resistance. We have recently shown a clear trend between lipophilicity and P-glycoprotein inhibitory activity for a class of galloyl-based modulators targeting P-glycoprotein and MRP1. Herein we report a new series of polymethoxy benzamides, whose lipophilicity was modulated through the establishment of an intramolecular hydrogen bond (IMHB) which allows reaching of P-gp inhibitory activity at the submicromolar IC50 level. The present study provides a strong rationale for candidates in the presence of IMHB as a key element for a high P-gp inhibitory activity.

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