Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance

Abstract

Supporting information for this article is given via a link at the end of the document.

Identification and Empiric Evaluation of New Inhibitors of the Multidrug Transporter P-Glycoprotein (ABCB1)

“…Our ligand-based pharmacophore model postulated one hydrogen bond acceptor (HBA), three hydrophobic groups (Hyd1, Hyd2, and Hyd3), and one aromatic (Aro) feature for the selection of highly potent inhibitors of ABCB1. Previous efforts to develop pharmacophore models for ABCB1 inhibition consistently identified the presence of hydrophobic groups and hydrogen-bond acceptors as essential features [ 13 , 26 , 42 ]. However, the distance matrices varied slightly from our results.…”

“…Zhang et al [ 42 ] developed a pharmacophore model on the basis of 16 compounds, and reported three hydrophobic groups and one hydrogen bond acceptor as the crucial pharmacophoric features. Similarly, Ilza et al [ 26 ] delineated three hydrophobic groups and a hydrogen bond acceptor as the important features on the basis of aligning three active compounds, while Kaczor et al [ 13 ] used a dataset of 17 arylideneimidazolone derivatives including five active inhibitors and twelve inactive compounds to identify the importance of an aromatic group and hydrogen bond acceptor. Our pharmacophore model included all of the aforementioned features because we used a diverse dataset of 98 compounds that were described as selective for ABCB1 and that we were able to dock into a molecular model based on structure data for the human transporter.…”

“…The development of effective and specific ABCB1-inhibitors has long been a goal to overcome multidrug resistance (MDR) [ 4 , 13 , 14 ]. In this context, a number of first-, second- and third-generation inhibitors of ABCB1 have been identified and tested, but, so far, none have achieved approval [ 3 , 15 , 16 ].…”

“…The third generation of inhibitors, including tariquidar, elacridar and zosuquidar, are more potent and efficacious than the first- and second generation-inhibitors, but were linked to various toxicity-related issues [ 3 ]. Collectively, the development of clinically useful ABCB1 inhibitors has been beset with a lack of efficacy, selectivity, and poor toxicity profiles [ 4 , 13 , 15 ].…”

Easy S-Alkylation of Arylthioureas and 2-Mercaptobenzothiazoles Using Tetraalkylammonium Salts under Transition-Metal-Free Conditions

“…These alkylating reagents have an important role in the construction of a series of C–S bonds (Scheme ). Taking classical methylation as an example, methylation of thioureas has traditionally been carried out using unstable, volatile, or toxic methylating agents . Alternatively, sulfuric esters can be used as an alkylation source as well, but they are generally highly toxic and explosive .…”