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.

Tetrazole and oxadiazole derivatives as bioisosteres of tariquidar and elacridar: New potent P-gp modulators acting as MDR reversers / Braconi L.; Dei S.; Contino M.; Riganti C.; Bartolucci G.; Manetti D.; Romanelli M.N.; Perrone M.G.; Colabufo N.A.; Guglielmo S.; Teodori E.. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1768-3254. - ELETTRONICO. - 259:(2023), pp. 115716.0-115716.0. [10.1016/j.ejmech.2023.115716]

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

Braconi L.;Dei S.
;
Bartolucci G.;Manetti D.;Romanelli M. N.;Teodori E.
2023

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.
2023
259
0
0
Goal 3: Good health and well-being
Braconi L.; Dei S.; Contino M.; Riganti C.; Bartolucci G.; Manetti D.; Romanelli M.N.; Perrone M.G.; Colabufo N.A.; Guglielmo S.; Teodori E.
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1329632
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