Novel Dihydropyrimidinone Derivatives as Potential P-Glycoprotein Modulators

Sabera Bijani; Faraz Shaikh; Sheefa Mirza; Shirley Weng In Siu; Nayan Jain; Rakesh Rawal; Nigel G J Richards; Anamik Shah; Ashish Radadiya

doi:10.1021/acsomega.1c05839

Novel Dihydropyrimidinone Derivatives as Potential P-Glycoprotein Modulators

ACS Omega. 2022 May 2;7(19):16278-16287. doi: 10.1021/acsomega.1c05839. eCollection 2022 May 17.

Authors

Sabera Bijani^{1

2}, Faraz Shaikh^{1

3}, Sheefa Mirza^{4

5}, Shirley Weng In Siu³, Nayan Jain⁶, Rakesh Rawal^{4

6}, Nigel G J Richards⁷, Anamik Shah^{1

8}, Ashish Radadiya^{1

7}

Affiliations

¹ Center of Excellence, National Facility for Drug Discovery Complex, Department of Chemistry, Saurashtra University, Rajkot 360005, India.
² Department of Chemistry, Marwadi University, Rajkot 360003, India.
³ Department of Computer and Information Science, University of Macau, Macau 999078, China.
⁴ The Gujarat Cancer & Research Institute, Ahmedabad 380009, India.
⁵ Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
⁶ Department of Life Sciences, School of Sciences, Gujarat University, Ahmedabad 380009, India.
⁷ School of Chemistry, Cardiff University, Cardiff CF10 3AT, UK.
⁸ Astha, Saurashtra University Karmachari Cooperative Society, B/H Forensic Lab., Street No. 2, University Road, Rajkot 360005, India.

Abstract

P-glycoprotein (Pgp), an ATP binding cassette (ABC) transporter, is an ATP-dependent efflux pump responsible for cancer multidrug resistance. As part of efforts to identify human Pgp (hPgp) inhibitors, we prepared a series of novel triazole-conjugated dihydropyrimidinones using a synthetic approach that is well suited for obtaining compound libraries. Several of these dihydropyrimidinone derivatives modulate human P-glycoprotein (hPgp) activity with low micromolar EC₅₀ values. Molecular docking studies suggest that these compounds bind to the M-site of the transporter.