Recent developments in the medicinal chemistry of single boron atom-containing compounds

Song, Shu; Gao, Ping; Sun, Lin; Kang, Dongwei; Kongsted, Jacob; Poongavanam, Vasanthanathan; Zhan, Peng; Liu, Xinyong

doi:10.1016/j.apsb.2021.01.010

Cited by 84 publications

(63 citation statements)

References 123 publications

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“…These are natural plant-based compounds [16,17], synthetic low molecular weight inhibitors [10,[18][19][20][21][22], β-lactams [23][24][25][26], amino acid derivatives and peptides [27]. Boron-based inhibitors attract special attention [28][29][30]. Recent advances in developing the therapeutically relevant boron-containing compounds [31,32] even resulted in the FDA-approved anticancer drug bortezomib [33].…”

Section: Introductionmentioning

confidence: 99%

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Krivitskaya

Khrenova

2021

Molecules

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Boronic acids are prospective compounds in inhibition of metallo-β-lactamases as they form covalent adducts with the catalytic hydroxide anion in the enzymatic active site upon binding. We compare this chemical reaction in the active site of the New Delhi metallo-β-lactamase (NDM-1) with the hydrolysis of the antibacterial drug imipenem. The nucleophilic attack occurs with the energy barrier of 14 kcal/mol for imipenem and simultaneously upon binding a boronic acid inhibitor. A boron atom of an inhibitor exhibits stronger electrophilic properties than the carbonyl carbon atom of imipenem in a solution that is quantified by atomic Fukui indices. Upon forming the prereaction complex between NDM-1 and inhibitor, the lone electron pair of the nucleophile interacts with the vacant p-orbital of boron that facilitates the chemical reaction. We analyze a set of boronic acid compounds with the benzo[b]thiophene core complexed with the NDM-1 and propose quantitative structure-sroperty relationship (QSPR) equations that can predict IC50 values from the calculated descriptors of electron density. These relations are applied to classify other boronic acids with the same core found in the database of chemical compounds, PubChem, and proposed ourselves. We demonstrate that the IC50 values for all considered benzo[b]thiophene-containing boronic acid inhibitors are 30–70 μM.

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Section: Introductionmentioning

confidence: 99%

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Krivitskaya

Khrenova

2021

Molecules

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“…An overview of boron-based small molecules in disease detection and treatment is presented ( Theraja, et al, 2017 ). The combination of theoretical and crystallographic approaches has provided important insight into the molecular stabilization of boron-based compounds in various target proteins, such as proteasomes, tyrosine kinases, histone deacetylases, GPCRs, glutamate racemases, amino acid transporters, autotaxin, and in particular β-lactamases ( Calvopiña, et al, 2017 ; Bello, 2018 ; Cahill et al, 2019 ; Song et al, 2021 ). Based on crystallographic and NMR data, mechanism of proton transfer in class A β-lactamase catalysis and inhibition by Avibactam were described ( Pemberton et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“… Vega-Valdez et al, 2020 ). A very comprehensive overview of the mechanisms of β-lactamase inhibition by boron-based inhibitors, including cyclic boronates, and their applications in biomedicine is reported ( Brem et al, 2016 ; Cahill et al, 2017 ; Cahill et al, 2019 ; Tooke et al, 2019 ; Tooke et al, 2020 ; Song et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Exploring Covalent Docking Mechanisms of Boron-Based Inhibitors to Class A, C and D β-Lactamases Using Time-dependent Hybrid QM/MM Simulations

Charzewski

Krzyśko

Lesyng

2021

Front. Mol. Biosci.

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Recently, molecular covalent docking has been extensively developed to design new classes of inhibitors that form chemical bonds with their biological targets. This strategy for the design of such inhibitors, in particular boron-based inhibitors, holds great promise for the vast family of β-lactamases produced, inter alia, by Gram-negative antibiotic-resistant bacteria. However, the description of covalent docking processes requires a quantum-mechanical approach, and so far, only a few studies of this type have been presented. This study accurately describes the covalent docking process between two model inhibitors - representing two large families of inhibitors based on boronic-acid and bicyclic boronate scaffolds, and three β-lactamases which belong to the A, C, and D classes. Molecular fragments containing boron can be converted from a neutral, trigonal, planar state with sp2 hybridization to the anionic, tetrahedral sp3 state in a process sometimes referred to as morphing. This study applies multi-scale modeling methods, in particular, the hybrid QM/MM approach which has predictive power reaching well beyond conventional molecular modeling. Time-dependent QM/MM simulations indicated several structural changes and geometric preferences, ultimately leading to covalent docking processes. With current computing technologies, this approach is not computationally expensive, can be used in standard molecular modeling and molecular design works, and can effectively support experimental research which should allow for a detailed understanding of complex processes important to molecular medicine. In particular, it can support the rational design of covalent boron-based inhibitors for β-lactamases as well as for many other enzyme systems of clinical relevance, including SARS-CoV-2 proteins.

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“…Emerging evidence indicates that boron-based drugs can also be considered as viral protease inhibitors. These compounds showed potent enzyme inhibitory activity [22] , [23] . The administration of these compounds on humans with virus infections has led to attractive results such as inhibition of severe fever with thrombocytopenia syndrome virus or prevention of influenza virus growth [24] .…”

Section: Introductionmentioning

confidence: 99%

Possible therapeutic effects of boron citrate and oleoylethanolamide supplementation in patients with COVID-19: A pilot randomized, double-blind, clinical trial

Akbari

Ostadrahimi

Tutunchi

et al. 2022

Journal of Trace Elements in Medicine and Biology

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Background The present study aimed to assess the therapeutic effects of boron citrate and oleoylethanolamide supplementation in patients with COVID-19. Methods Forty adult patients with a diagnosis of COVID-19 were recruited in the present study. Patients were randomized in a 1:1:1:1 allocation ratio to 1of 4 treatment groups: (A) 5 mg of boron citrate twice a day, (B) 200 mg of oleoylethanolamide twice a day, (C) both therapies, or (D) routine treatments without any study medications. At pre-and post-intervention phase, some clinical and biochemical parameters were assessed. Results Supplementation with boron citrate alone or in combination with oleoylethanolamide significantly improved O2 saturation and respiratory rate (p<0.01). At the end of the study, significant increases in white blood cell and lymphocyte count were observed in the boron citrate and combined groups (p<0.001). Boron citrate supplementation led to a significant decrease in serum lactate dehydrogenase (p=0.026) and erythrocyte sedimentation rate (p=0.014), compared with other groups. Furthermore, boron citrate in combination with oleoylethanolamide resulted in a significant reduction in the high-sensitivity C-reactive protein and interleukin-1β concentrations (p=0.031 and p=0.027, respectively). No significant differences were found among four groups post-intervention, in terms of hemoglobin concentrations, platelet count, and serum interleukin-6 levels. At the end of the study, common symptoms of COVID-19 including cough, fatigue, shortness of breath, and myalgia significantly improved in the supplemented groups, compared to the placebo (p<0.05). Conclusion Supplementation with boron citrate alone or in combination with oleoylethanolamide could improve some clinical and biochemical parameters in COVID-19 patients.

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Recent developments in the medicinal chemistry of single boron atom-containing compounds

Cited by 84 publications

References 123 publications

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Exploring Covalent Docking Mechanisms of Boron-Based Inhibitors to Class A, C and D β-Lactamases Using Time-dependent Hybrid QM/MM Simulations

Possible therapeutic effects of boron citrate and oleoylethanolamide supplementation in patients with COVID-19: A pilot randomized, double-blind, clinical trial

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