Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors

Kwak, Seung-Hwa; Cochrane, C. Skyler; Ennis, Amanda F.; Lim, Won Young; Webster, Caroline G.; Cho, Jae; Fenton, B.A.; Zhou, Pei; Hong, Jiyong

doi:10.1016/j.bioorg.2020.104055

Cited by 14 publications

(33 citation statements)

References 18 publications

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“…Recently, among the extended N-acyl chain analogs, the compound 35 lead to the strongest inhibition of LpxH activity with 64% which slightly close to the most active compound with phenyl group such as 36 and 37 leading to an inhibition of 79 and 48%, respectively. 172 Compound 35 appeared as the most efficient with a MIC value against K. pneumoniae of 1.6 µg/mL higher than that encountered for 33 and slightly close to that of 34 ranging from 64 and 2.8 µg/mL, respectively (Figure 9). 169,172 Even if some promising inhibitors of the Lipid A biosynthesis pathway have been discovered some others Lpx enzymes such as LpxB, M also constitute a promising way for finding novel antibiotics against Gram-negative.…”

Section:  Lpxdmentioning

confidence: 87%

“…172 Compound 35 appeared as the most efficient with a MIC value against K. pneumoniae of 1.6 µg/mL higher than that encountered for 33 and slightly close to that of 34 ranging from 64 and 2.8 µg/mL, respectively (Figure 9). 169,172 Even if some promising inhibitors of the Lipid A biosynthesis pathway have been discovered some others Lpx enzymes such as LpxB, M also constitute a promising way for finding novel antibiotics against Gram-negative.…”

Section:  Lpxdmentioning

confidence: 87%

“…Recently, a diffusion disk assay suggested that 33 may be an effective inhibitor of K. pneumoniae LpxH, and Kwak et al report the crystal structure of the K. pneumoniae LpxH/ 33 complex . It was reported that the modification of the phenyl or N-acyl indoline groups of 34 led to compounds able to inhibit the LpxH of K. pneumoniae at a low concentration (0.1 μM).…”

Section: Introductionmentioning

confidence: 99%

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Chemical Highlights Supporting the Role of Lipid A in Efficient Biological Adaptation of Gram-Negative Bacteria to External Stresses

2021

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The outer membrane (OM) of Gram-negative bacteria provides an efficient barrier against external noxious compounds such as antimicrobial agents. Associated with drug target modification it contributes to the overall failure of chemotherapy. In the complex OM architecture, Lipid A plays an essential role by anchoring the lipopolysaccharide in the membrane and ensuring the spatial organization between lipids, proteins, and sugars.Currently, the targets of almost all antibiotics are intracellularly located and required for translocation across membranes. We report herein an integrated view of Lipid A synthesis, membrane assembly, a structure comparison at the molecular structure level of numerous Gram-negative bacterial species as well as its recent use as a target for original antibacterial molecules. This review paves the way for a new vision of a key membrane component that acts during bacterial adaptation to environmental stresses and for the development of new weapons against microbial resistance to usual antibiotics.

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Section:  Lpxdmentioning

confidence: 87%

Section:  Lpxdmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Chemical Highlights Supporting the Role of Lipid A in Efficient Biological Adaptation of Gram-Negative Bacteria to External Stresses

2021

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“…Therefore, piperazine is often used as a link in drug structural modification. Some compounds with piperazine moiety had good biological activity, such as antiviral, 25,26 antibacterial 27,28 and insecticidal activities 29,30 …”

Section: Introductionmentioning

confidence: 99%

“…24 Therefore, piperazine is often used as a link in drug structural modification. Some compounds with piperazine moiety had good biological activity, such as antiviral, 25,26 antibacterial 27,28 and insecticidal activities. 29,30 For these reasons, it is clear that ferulic acid can be applied as a lead structure to discover new antiviral agents.…”

Section: Introductionmentioning

confidence: 99%

Ferulic acid derivatives with piperazine moiety as potential antiviral agents

Yuan

Wang

Liú

et al. 2022

Pest Management Science

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Background Plant virus diseases are difficult to control and severely threaten the productivity of crops, which leads to huge financial losses. To discover the new antiviral drugs, 34 novel ferulic acid derivatives with piperazine moiety were synthesized, and the antiviral activities were systematically screened as well. Results Bioassay results indicated that most of the target compounds had outstanding antiviral activities against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) in vivo. In particular, compound E2 exhibited remarkable curative activities to TMV and CMV with EC50 values of 189.0 and 401.7 μg/mL compared to those for ningnanmycin (387.0, 519.3 μg/mL) and ribavirin (542.1, 721.5 μg/mL). And then the mechanisms of compound E2 were studied by chlorophyll content, differentially expressed proteins and genes tests. Conclusion The excellent antiviral activity of compound E2 was closely associated with the increase in host photosynthesis, which was confirmed by chlorophyll content, differentially expressed proteins and genes assays. Compound E2 can be considered as a lead structure for the discovery of new antiviral agents. © 2022 Society of Chemical Industry.

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Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH

et al. 2023

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Despite the widespread emergence of multidrug‐resistant nosocomial Gram‐negative bacterial infections and the major public health threat it brings, no new class of antibiotics for Gram‐negative pathogens has been approved over the past five decades. Therefore, there is an urgent medical need for developing effective novel antibiotics against multidrug‐resistant Gram‐negative pathogens by targeting previously unexploited pathways in these bacteria. To fulfill this crucial need, we have been investigating a series of sulfonyl piperazine compounds targeting LpxH, a dimanganese‐containing UDP‐2,3‐diacylglucosamine hydrolase in the lipid A biosynthetic pathway, as novel antibiotics against clinically important Gram‐negative pathogens. Inspired by a detailed structural analysis of our previous LpxH inhibitors in complex with K. pneumoniae LpxH (KpLpxH), here we report the development and structural validation of the first‐in‐class sulfonyl piperazine LpxH inhibitors, JH‐LPH‐45 (8) and JH‐LPH‐50 (13), that achieve chelation of the active site dimanganese cluster of KpLpxH. The chelation of the dimanganese cluster significantly improves the potency of JH‐LPH‐45 (8) and JH‐LPH‐50 (13). We expect that further optimization of these proof‐of‐concept dimanganese‐chelating LpxH inhibitors will ultimately lead to the development of more potent LpxH inhibitors for targeting multidrug‐resistant Gram‐negative pathogens.

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Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors

Cited by 14 publications

References 18 publications

Chemical Highlights Supporting the Role of Lipid A in Efficient Biological Adaptation of Gram-Negative Bacteria to External Stresses

Chemical Highlights Supporting the Role of Lipid A in Efficient Biological Adaptation of Gram-Negative Bacteria to External Stresses

Ferulic acid derivatives with piperazine moiety as potential antiviral agents

Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH

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