1. Academic Validation
  2. Tetrazole and oxadiazole derivatives as bioisosteres of tariquidar and elacridar: New potent P-gp modulators acting as MDR reversers

Tetrazole and oxadiazole derivatives as bioisosteres of tariquidar and elacridar: New potent P-gp modulators acting as MDR reversers

  • Eur J Med Chem. 2023 Nov 5:259:115716. doi: 10.1016/j.ejmech.2023.115716.
Laura Braconi 1 Silvia Dei 2 Marialessandra Contino 3 Chiara Riganti 4 Gianluca Bartolucci 1 Dina Manetti 1 Maria Novella Romanelli 1 Maria Grazia Perrone 3 Nicola Antonio Colabufo 3 Stefano Guglielmo 5 Elisabetta Teodori 1
Affiliations

Affiliations

  • 1 Department of Neuroscience, Psychology, Drug Research and Child Health - Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy.
  • 2 Department of Neuroscience, Psychology, Drug Research and Child Health - Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Italy. Electronic address: silvia.dei@unifi.it.
  • 3 Department of Pharmacy - Drug Sciences, University of Bari "A. Moro", via Orabona 4, 70125, Bari, Italy.
  • 4 Department of Oncology, University of Turin, Via Santena 5/bis, 10126, Torino, Italy.
  • 5 Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, 10125, Torino, Italy.
Abstract

New 2,5- and 1,5-disubstituted tetrazoles, and 2,5-disubstituted-1,3,4-oxadiazoles were synthesized as tariquidar and elacridar derivatives and studied as multidrug resistance (MDR) reversers. Their behaviour on the three ABC transporters P-gp, MRP1 and BCRP was investigated. All compounds inhibited the P-gp transport activity in MDCK-MDR1 cells overexpressing P-gp, showing EC50 values even in the low nanomolar range (compounds 15, 22). Oxadiazole derivatives were able to increase the antiproliferative effect of doxorubicin in MDCK-MDR1 and in HT29/DX cells confirming their nature of P-gp modulators, with derivative 15 being the most potent in these assays. Compound 15 also displayed a dual inhibitory effect showing good activities towards both P-gp and BCRP. A computational study suggested a common interaction pattern on P-gp for most of the potent compounds. The bioisosteric substitution of the amide group of lead compounds allowed identifying a new set of potent oxadiazole derivatives that modulate MDR through inhibition of the P-gp efflux activity. If compared to previous amide derivatives, the introduction of the heterocycle rings greatly enhances the activity on P-gp, introduces in two compounds a moderate inhibitory activity on MRP1 and maintains in some cases the effect on BCRP, leading to the unveiling of dual inhibitor 15.

Keywords

ABC transporter modulators; MDR reversers; Multidrug resistance; Oxadiazole; P-glycoprotein; Tetrazole.

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