Research Article Chalcone Derivatives as Potential Inhibitors of P-Glycoprotein and NorA: An In Silico and In Vitro Study Minh-Tri Le, 1,2 Dieu-Thuong Thi Trinh , 3,4 Trieu-Du Ngo , 1 Viet-Khoa Tran-Nguyen , 1 Dac-Nhan Nguyen , 1 Tung Hoang, 1 Hoang-Minh Nguyen, 1 Tran-Giang-Son Do , 1 Tan Thanh Mai , 1 Thanh-Dao Tran , 1 and Khac-Minh Thai 1 1 Department of Medicinal Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, 41 Dinh Tien Hoang, Dist 1, Ho Chi Minh City 700000, Vietnam 2 School of Medicine, Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc District, Ho Chi Minh City 700000, Vietnam 3 Faculty of Traditional Medicine, University of Medicine and Pharmacy, Ho Chi Minh City 700000, Vietnam 4 University Medical Center Ho Chi Minh City, University of Medicine and Pharmacy, Ho Chi Minh City 700000, Vietnam Correspondence should be addressed to Thanh-Dao Tran; daott@ump.edu.vn and Khac-Minh Thai; thaikhacminh@gmail.com Received 14 July 2021; Accepted 9 March 2022; Published 26 March 2022 Academic Editor: Fu-Ming Tsai Copyright © 2022 Minh-Tri Le et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The human P-glycoprotein (P-gp) and the NorA transporter are the major culprits of multidrug resistance observed in various bacterial strains and cancer cell lines, by extruding drug molecules out of the targeted cells, leading to treatment failures in clinical settings. Inhibiting the activity of these efflux pumps has been a well-known strategy of drug design studies in this regard. In this manuscript, our earlier published machine learning models and homology structures of P-gp and NorA were utilized to screen a chemolibrary of 95 in-house chalcone derivatives, identifying two hit compounds, namely, F88 and F90, as potential modulators of both transporters, whose activity on Staphylococcus aureus strains overexpressing NorA and resistant to ciprofloxacin was subsequently confirmed. The findings of this study are expected to guide future research towards developing novel potent chalconic inhibitors of P-gp and/or NorA. 1. Introduction Multidrug resistance (MDR) is one of the main obstacles that challenge the clinical treatment of tumors and infec- tions in humans during the last decade. Tumors and bacteria protect themselves from chemotherapeutic agents and antibiotics through different mechanisms, one of which is drug extrusion induced by membrane transport proteins known as efflux pumps [1]. In particular, the human P- glycoprotein (P-gp) and the NorA protein of Staphylococcus aureus (SA) are among the most researched targets, due to their vital role in transporting drugs out of cells, leading to resistance to anticancer medications and antibiotics [1–3]. In 1976, the human P-glycoprotein (P-gp) was first described as an ATP-dependent membrane transporter responsible for active drug efflux [4]. The protein, also known as ABCB1 (ATP-binding cassette subfamily B member 1) or MDR1 (multidrug resistance protein 1), is presented throughout the body, in different normal tissues such as the brain, liver, kidney, and intestines [5]. P-gp plays a crucial role in protection against xenobiotics. Nevertheless, it also negatively influences the ADMET (absorption, distribution, metabolism, excretion, and toxic- ity) properties of many medications as well as drug-like molecules [6]. On the other hand, the microbial efflux pump NorA is one of the major facilitator superfamily (MFS) transporters which utilize the proton gradient as an energy source to drive the extrusion of their substrates and confer MDR upon Gram-positive bacteria [7]. The activity of this protein is thought to be the cause of Hindawi BioMed Research International Volume 2022, Article ID 9982453, 9 pages https://doi.org/10.1155/2022/9982453