Propafenone analogue with additional H‐bond acceptor group shows increased inhibitory activity on P‐glycoprotein

Abstract

P‐glycoprotein (P‐gp) is an ATP‐dependent efflux pump that has a marked impact on the absorption, distribution, and excretion of therapeutic drugs. As P‐gp inhibition can result in drug–drug interactions and altered drug bioavailability, identifying molecular properties that are linked to inhibition is of great interest in drug development. In this study, we combined chemical synthesis, in vitro testing, quantitative structure–activity relationship analysis, and docking studies to investigate the role of hydrogen bond (H‐bond) donor/acceptor properties in transporter–ligand interaction. In a previous work, it has been shown that propafenone analogs with a 4‐hydroxy‐4‐piperidine moiety exhibit a generally 10‐fold higher P‐gp inhibitory activity than expected based on their lipophilicity. Here, we specifically expanded the data set by introducing substituents at position 4 of the 4‐phenylpiperidine moiety to assess the importance of H‐bond donor/acceptor features in this region. The results suggest that indeed an H‐bond acceptor, such as hydroxy and methoxy, increases the affinity by forming a H‐bond with Tyr310.

Antifungal activity of compounds from Gordonia sp. WA8-44 isolated from the gut of Periplaneta americana and molecular docking studies

“…This protein is a potential therapeutic target for treating Candida infections because it is responsible for most of the glucanase activity in the Candida cell wall [ 55 ]. Although Actinomycin X 2 and Actinomycin D are similar in chemical structure, Actinomycin D exhibited stronger anti - C. albicans activity due to its six additional H-bonding interactions with 1,3Beta-Glucanase [ 56 ]. Likewise, in the Hamdoon's study, methylated taxifolin demonstrated enhanced binding affinity towards various pro- and antiapoptotic proteins compared to taxifolin, thereby displaying heightened anticancer efficacy [ 57 ].…”

Preparation of cationized albumin nanoparticles loaded indirubin by high pressure hemogenizer

“…The tight junction proteins between the brain capillary endothelial cells are mainly responsible for static barrier properties, resulting in the poor transfer of almost all drugs [6]. Besides, ATP-binding cassette efflux transporter P-glycoprotein play a key role to transport the huge chemotherapeutic agents and hydrophobic compounds outside the brain capillary endothelial cells [7,8]. To overcome this problem, the nanostructure can be used as colloidal drug carriers to enhance the bioavailability of drugs by increasing their diffusion through biological membranes and protect them against enzymes.…”