Identification and structure–activity relationships for a series of N, N-disubstituted 2-aminobenzothiazoles as potent inhibitors of S. aureus

Cao, Feng; Kinthada, Ramakumar; Boehm, Terri; Cunha, Napoleon D'; Leus, Inga V.; Orth, Cari; Zgurskaya, Helen I.; Walker, John K.

doi:10.1016/j.bmcl.2023.129301

Cited by 5 publications

(2 citation statements)

References 20 publications

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“…Several compound series in the collection were synthesized at Saint Louis University (SLU) as part of on-going EPI and antibacterial projects. The largest source of compounds were a series of EPIs designed to inhibit the AcrAB-TolC pump in E. coli including dihydroimidazoline [53] (174), a related series of benzoylimidazolines [54] (14) and a chemical series of 2,7-diaminoquinoline [55] (68). The two sets of antibacterial compounds included a series of 2-aminobenzothiazoles (79) with an unknown antibacterial target and a series of quaternary amine compounds (108) that target a bacterial condensin enzyme [56].…”

Section: Assembly and Properties Of The Compound Library For Analysesmentioning

confidence: 99%

Predicting Permeation of Compounds across the Outer Membrane ofP. aeruginosaUsing Molecular Descriptors: Advantages and Limitations

Manrique,

Leus,

Ĺopez

et al. 2023

Preprint

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The ability of Gram-negative pathogens to adapt and protect themselves against antibiotics is a growing threat to public health. The low permeability of the outer membrane (OM) in combination with effective multidrug efflux pumps, constitute the two main antibiotic resistance mechanisms. Though much efforts have been devoted to discover new antibiotics that can bypass these defense mechanisms, no new antibiotic classes have been introduced into clinics in the last 35 years. Models that identify specific descriptors of molecular properties and predict the likelihood that a given compound is capable of successfully permeate the OM and inhibit bacterial growth while avoiding efflux could facilitate the discovery of novel classes of antibiotics. Here we evaluate 174 molecular descriptors of 1260 antimicrobial compounds and study their correlations with antibacterial activity in Gramnegative Pseudomonas aeruginosa. While part of these descriptors are computed using traditional approaches based on the physicochemical properties intrinsic to the compounds, ensemble docking and all-atom molecular dynamics (MD) simulations are used to derive additional bacterium-specific mechanistic properties. Descriptors of compound permeation across the OM were calculated using all-atom MD simulations of the compounds in different subregions of the OM model. Descriptors of interactions with efflux pumps were calculated from ensemble docking of compounds targeting specific binding pockets of MexB, the major efflux transporter of P. aeruginosa. Using these descriptors and the measured antibacterial inhibitory concentrations of compounds, we design and implement a statistical protocol to identify a subset of the molecular properties that are predictive of whether a given compound is a strong or weak permeator across the Gram-negative OM. Our results indicate that 88.4% of the compounds that show measurable antibacterial activity, follow very consistent rules of permeation, which highlight the critical role that the interaction between the compound and the OM have at predicting permeation. The remaining 11.6% of the compounds, although less predictive, are characterized by distinctive structural markers that can be used to minimize classification errors. An implementation of the permeation rules and the structural markers uncovered in our study is shown, and it demonstrates the accuracy of our approach in a set of previously unseen compounds. Taken together, our analysis sheds new light on the key molecular properties that drug candidates should have in order to be effective at OM permeation/inhibition of P. aeruginosa, and opens the gate to similar data-driven studies in other Gram-negative pathogens.

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Section: Assembly and Properties Of The Compound Library For Analysesmentioning

confidence: 99%

Predicting Permeation of Compounds across the Outer Membrane ofP. aeruginosaUsing Molecular Descriptors: Advantages and Limitations

Manrique,

Leus,

Ĺopez

et al. 2023

Preprint

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“…Advances in this field have been carefully reviewed in recent papers and books [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. On the other hand, a few highly effective antibacterial low-toxicity compounds have been obtained based on the fused heterocyclic benzothiazole system [ 38 , 39 , 40 , 41 , 42 ]. These findings inspired us to synthesize benzothiazole derivatives of chitosan and study their antibacterial properties in the framework of our current work in the hope that the summation of the antibacterial effects of both chitosan and benzothiazole pharmacophore results in an increased antibacterial activity of the resulting polymers.…”

Section: Introductionmentioning

confidence: 99%

Benzothiazole Derivatives of Chitosan and Their Derived Nanoparticles: Synthesis and In Vitro and In Vivo Antibacterial Effects

Shakola,

Rubanik,

Rubanik

et al. 2023

Polymers

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In this work, we focused on synthesizing and assessing novel chitosan-based antibacterial polymers and their nanoparticles by incorporating benzothiazole substituents. The growing resistance to antibiotics has necessitated the search for alternative antimicrobial compounds. This study aimed to synthesize and evaluate chitosan-based polymers and nanoparticles with benzothiazole substituents for their antibacterial properties and toxicity. The benzothiazole derivatives of chitosan and their nanoparticles were synthesized through electrochemical coupling. The in vivo antibacterial efficacy was tested on white rats with induced peritonitis using a microbial suspension containing S. aureus and E. coli. Additionally, in vitro and in vivo toxicity assessments were conducted. The chitosan-based antibacterial systems showed significant in vivo antibacterial activity, surpassing that of unmodified chitosan and commercial antibiotics. Moreover, the toxicity studies revealed low toxicity levels of the synthesized derivatives, which did not differ significantly from native chitosan. The synthesized chitosan-based polymers and nanoparticles demonstrated potent antibacterial activity and low toxicity, highlighting their potential as effective alternatives to traditional antibiotics. Further investigations in pharmacology and preclinical trials are recommended to explore their application in clinical settings.

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Enantioselective Synthesis of Axially Chiral Diaryl Ethers via NHC Catalyzed Desymmetrization and Following Resolution

Zhou,

Li,

Zhang

et al. 2023

Angewandte Chemie

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Axially chiral diaryl ethers are present in numerous natural products and bioactive molecules. However, only few catalytic enantioselective approaches have been established to access diaryl ether atropisomers. Herein, we report the N‐heterocyclic carbene‐catalyzed enantioselective synthesis of axially chiral diaryl ethers via desymmetrization of prochiral 2‐aryloxyisophthalaldehydes with aliphatic alcohols, phenol derivatives, and heteroaromatic amines. This reaction features mild reaction conditions, good functional group tolerance, broad substrate scope and excellent enantioselectivity. The utility of this methodology is illustrated by late‐stage functionalization, gram‐scale synthesis, and diverse enantioretentive transformations. Control experiments and DFT calculations support the association of NHC‐catalyzed desymmetrization with following kinetic resolution to enhance the enantioselectivity.

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Identification and structure–activity relationships for a series of N, N-disubstituted 2-aminobenzothiazoles as potent inhibitors of S. aureus

Cited by 5 publications

References 20 publications

Predicting Permeation of Compounds across the Outer Membrane ofP. aeruginosaUsing Molecular Descriptors: Advantages and Limitations

Predicting Permeation of Compounds across the Outer Membrane ofP. aeruginosaUsing Molecular Descriptors: Advantages and Limitations

Benzothiazole Derivatives of Chitosan and Their Derived Nanoparticles: Synthesis and In Vitro and In Vivo Antibacterial Effects

Enantioselective Synthesis of Axially Chiral Diaryl Ethers via NHC Catalyzed Desymmetrization and Following Resolution

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