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
  • 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.