Substituted sulfonamide bioisosteres of 8-hydroxyquinoline as zinc-dependent antibacterial compounds

McGowan, John E.; Harper, Andrew D.; Davison, Emma K.; Jeong, Joo Young; Mros, Sonya; Harbison-Price, Nichaela; Zuylen, Essie M. Van; Knottenbelt, Melanie K.; Heikal, Adam; Ferguson, Scott; McConnell, Michelle; Cook, Gregory M.; Krittaphol, Woravimol; Walker, Greg F.; Brimble, Margaret A.; Rennison, David

doi:10.1016/j.bmcl.2020.127110

Cited by 7 publications

(4 citation statements)

References 28 publications

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“…In this case, this could indicate the ability of these MBIs to have a greater perturbation to the active site of a metalloenzyme upon binding. This may also be relevant to the use of 8-sulfonamidoquinoline and its derivatives as biological Zn(II) sensors, metal chelators, and ionophores. − For 6,5-membered sulfonamide rings, monodentate (MBI 21 ) and bidentate binding modes (MBIs 23 and 24 ) were found with the [Tp Ph,Me Zn( MBI )] system. Note that the nitrogen atoms of MBI 23 and 24 (p K a1 = 4.45 and 4.56, Table ) are more basic compared to MBI 21 (p K a1 < 2), which potentially translates to a stronger donor ability to the metal center.…”

Section: Resultsmentioning

confidence: 99%

Developing Metal-Binding Isosteres of 8-Hydroxyquinoline as Metalloenzyme Inhibitor Scaffolds

et al. 2022

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The use of metal-binding pharmacophores (MBPs) in fragment-based drug discovery has proven effective for targeted metalloenzyme drug development. However, MBPs can still suffer from pharmacokinetic liabilities. Bioisostere replacement is an effective strategy utilized by medicinal chemists to navigate these issues during the drug development process. The quinoline pharmacophore and its bioisosteres, such as quinazoline, are important building blocks in the design of new therapeutics. More relevant to metalloenzyme inhibition, 8-hydroxyquinoline (8-HQ) and its derivatives can serve as MBPs for metalloenzyme inhibition. In this report, 8-HQ isosteres are designed and the coordination chemistry of the resulting metal-binding isosteres (MBIs) is explored using a bioinorganic model complex. In addition, the physicochemical properties and metalloenzyme inhibition activity of these MBIs were investigated to establish drug-like profiles. This report provides a new group of 8-HQ-derived MBIs that can serve as novel scaffolds for metalloenzyme inhibitor development with tunable, and potentially improved, physicochemical properties.

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Section: Resultsmentioning

confidence: 99%

Developing Metal-Binding Isosteres of 8-Hydroxyquinoline as Metalloenzyme Inhibitor Scaffolds

et al. 2022

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“…Derivatives 37a – h (Figure ) were active against Streptococcus uberis in the presence of zinc, and in the absence of zinc, the activity decreased. In general, compounds substituted with hydrophobic groups, such as derivatives 37a – d , have presented better activity than compounds with hydrophilic substituents ( 37e – h ) . This suggests that lipophilic complexes resulting from 2-substituted-8-sulfonylaminoquinoline can also act as ionophore transporting zinc ions through the cell membrane, causing zinc release and, consequently, affecting the bacteria.…”

Section: Structural Changes At the 8hq Core Based On The Microorganis...mentioning

confidence: 99%

“…Unlike the studies previously mentioned, in which structural changes were unfavorable for the antimicrobial activity, 8sulfonamides derived from the replacement of an 8-hydroxy group seem to be promising compounds. 121 Several substitutions were made at the sulfonamide. However, we will address the main findings of this work regarding the phenyl substitutions.…”

Section: ■ Introductionmentioning

confidence: 99%

Novel Antimicrobial 8-Hydroxyquinoline-Based Agents: Current Development, Structure–Activity Relationships, and Perspectives

et al. 2021

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The search for new antimicrobials is imperative due to the emergent resistance of new microorganism strains. In this context, revisiting known classes like 8-hydroxyquinolines could be an interesting strategy to discover new agents. The 8-hydroxyquinoline derivatives nitroxoline and clioquinol are used to treat microbial infections; however, these drugs are underused, being available in few countries or limited to topical use. After years of few advances, in the last two decades, the potent activity of clioquinol and nitroxoline against several targets and the privileged structure of 8-hydroxyquinoline nucleus have prompted an increased interest in the design of novel antimicrobial, anticancer, and anti-Alzheimer agents based on this class. Herein, we discuss the current development and antimicrobial structure–activity relationships of this class in the perspective of using the 8-hydroxyquinoline nucleus for the search for novel antimicrobial agents. Furthermore, the most investigated molecular targets concerning 8-hydroxyquinoline derivatives are explored in the final section.

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“…Ionophores transferring cations belonging to group 1 and 2 of the periodic table are not the only ones exhibiting bactericidal activity. Significant interest has been raised to the antibacterial properties of transition metal complexes with ionophores [ 183 ]. Among them, Zn(II) ionophores seem to be those of potentially large application.…”

Section: Antibacterial Zn(ii) Ionophoresmentioning

confidence: 99%

Zinc(II)—The Overlooked Éminence Grise of Chloroquine’s Fight against COVID-19?

et al. 2020

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Zn(II) is an inhibitor of SARS-CoV-2′s RNA-dependent RNA polymerase, and chloroquine and hydroxychloroquine are Zn(II) ionophores–this statement gives a curious mind a lot to think about. We show results of the first clinical trials on chloroquine (CQ) and hydroxychloroquine (HCQ) in the treatment of COVID-19, as well as earlier reports on the anticoronaviral properties of these two compounds and of Zn(II) itself. Other FDA-approved Zn(II) ionophores are given a decent amount of attention and are thought of as possible COVID-19 therapeutics.

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Substituted sulfonamide bioisosteres of 8-hydroxyquinoline as zinc-dependent antibacterial compounds

Cited by 7 publications

References 28 publications

Developing Metal-Binding Isosteres of 8-Hydroxyquinoline as Metalloenzyme Inhibitor Scaffolds

Developing Metal-Binding Isosteres of 8-Hydroxyquinoline as Metalloenzyme Inhibitor Scaffolds

Novel Antimicrobial 8-Hydroxyquinoline-Based Agents: Current Development, Structure–Activity Relationships, and Perspectives

Zinc(II)—The Overlooked Éminence Grise of Chloroquine’s Fight against COVID-19?

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