Antibacterials

Bremner, John B.

doi:10.1007/978-981-16-0999-2_1

Cited by 2 publications

(3 citation statements)

References 72 publications

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“…This core became the foundation for a new class of antibacterials, among which are vaborbactam, approved in combination (Messner et al , 2022 ), and taniborbactam, still in clinical development (Liu et al , 2020 ). Finally, drug repurposing by deep‐learning analysis is another use of computational tools for the discovery of novel antibacterial scaffolds (Stokes et al , 2020 ; Bremner, 2021 ).…”

Section: The Need For New Antibioticsmentioning

confidence: 99%

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

et al. 2022

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Antibacterial resistance is one of the greatest threats to human health. The development of new therapeutics against bacterial pathogens has slowed drastically since the approvals of the first antibiotics in the early and mid-20 th century. Most of the currently investigated drug leads are modifications of approved antibacterials, many of which are derived from natural products. In this review, we highlight the challenges, advancements and current standing of the clinical and preclinical antibacterial research pipeline. Additionally, we present novel strategies for rejuvenating the discovery process and advocate for renewed and enthusiastic investment in the antibacterial discovery pipeline.

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Section: The Need For New Antibioticsmentioning

confidence: 99%

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

et al. 2022

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“…Ring-fused nitrogen heterocycles form important scaffolds in drug design and development [ 1 , 2 , 3 ]. Such compounds include many alkaloidal natural products, for example the bioactive protoberberine alkaloids such as berberine ( 1 ) [ 4 ] and coptisine ( 4 ) [ 5 ] and reduced derivatives like the dihydro- ( 2 and 5 ) [ 6 ] or tetrahydro-protoberberines ( 3 and 6 ) ( Figure 1 ) together with modified protoberberines [ 7 , 8 ] and [ 9 ] (pp. 65–68, 95–102).…”

Section: Introductionmentioning

confidence: 99%

“…This computational work has now been significantly extended with an emphasis on the influence on conformational preferencing, overall shape and charge distributions. The computational evaluation has also been taken further to include ring-embedded imino ( 10 ) ([ 9 ], pp. 79–81) or azo ( 11 ) group nitrogens (see Figure 4 below for structures of ( 10 ) and ( 11 )) and atoms or groups Y across the 10-membered ring system, the aim of which was to assess whether some flattening of the ring could be achieved while maintaining additional control of conformational preferencing [ 21 ] through transannular N … Y interactions.…”

Section: Introductionmentioning

confidence: 99%

Computational Evaluation of N-Based Transannular Interactions in Some Model Fused Medium-Sized Heterocyclic Systems and Implications for Drug Design

Griffith

Bremner

2023

Molecules

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As part of a project on fused medium-sized ring systems as potential drugs, we have previously demonstrated the usefulness of Density Functional Theory (DFT) to evaluate amine nitrogen-based transannular interactions across the central 10-membered ring in the bioactive dibenzazecine alkaloid, protopine. A range of related hypothetical systems have been investigated, together with transannular interactions involving ring-embedded imino or azo group nitrogens and atoms or groups (Y) across the ring. Electrostatic potential energies mapped onto electron density surfaces in the different ring conformations were evaluated in order to characterise these conformations. Unexpectedly, the presence of sp2 hybridised nitrogen atoms in the medium-sized rings did not influence the conformations appreciably. The strength and type of the N…Y interactions are determined primarily by the nature of Y. This is also the case when the substituent on the interacting nitrogen is varied from CH3 (protopine) to H or OH. With Y = BOH, very strong interactions were observed in protopine analogues, as well as in rings incorporating imino or azo groups. Strong to moderate interactions were observed with Y = CS, CO and SO in all ring systems. Weaker interactions were observed with Y = S, O and weaker ones again with an sp3 hybridised carbon (Y = CH2). The transannular interactions can influence conformational preferencing and shape and change electron distributions at key sites, which theoretically could modify properties of the molecules while providing new or enhanced sites for biological target interactions, such as the H or OH substituent. The prediction of new strong transannular interaction types such as with Y = BOH and CS should be helpful in informing priorities for synthesis and other experimental studies.

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Antibacterials

Cited by 2 publications

References 72 publications

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

Computational Evaluation of N-Based Transannular Interactions in Some Model Fused Medium-Sized Heterocyclic Systems and Implications for Drug Design

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