Slow-Onset, Potent Inhibition of Mandelate Racemase by 2-Formylphenylboronic Acid. An Unexpected Adduct Clasps the Catalytic Machinery

Biochemistry ◽  
2021 ◽  
Author(s):  
Colin D. Douglas ◽  
Lia Grandinetti ◽  
Nicole M. Easton ◽  
Oliver P. Kuehm ◽  
Joshua A. Hayden ◽  
...  
Biochemistry ◽  
2014 ◽  
Vol 53 (7) ◽  
pp. 1169-1178 ◽  
Author(s):  
Mitesh Nagar ◽  
Adam D. Lietzan ◽  
Martin St. Maurice ◽  
Stephen L. Bearne

Biochemistry ◽  
2020 ◽  
Vol 59 (33) ◽  
pp. 3026-3037
Author(s):  
Amar Nath Sharma ◽  
Lia Grandinetti ◽  
Erin R. Johnson ◽  
Martin St. Maurice ◽  
Stephen L. Bearne

2020 ◽  
Vol 20 (23) ◽  
pp. 2106-2117
Author(s):  
Martin Krátký ◽  
Šárka Štěpánková ◽  
Michaela Brablíková ◽  
Katarína Svrčková ◽  
Markéta Švarcová ◽  
...  

Background: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias’ treatment. Objective: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. Methods: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman’s method. We calculated also physicochemical and structural parameters for CNS delivery. Results: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. Conclusion: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.


2020 ◽  
Vol 16 (4) ◽  
pp. 531-543
Author(s):  
Shaheen Faizi ◽  
Tahira Sarfaraz ◽  
Saima Sumbul ◽  
Almas Jabeen ◽  
Sobia A. Halim ◽  
...  

Background: In continuation of our work on Mannich reaction on 8-hydroxyquinoline, fifteen different combinations of aromatic aldehydes and aniline were subjected to Mannich reaction from which twelve products (eight Mannich bases, two imines and two intramolecularly cyclized products with benzofuranone skeleton) were obtained. Among them six compounds (1, 2, 6, 8, 9 and 12) are the new compounds. The structures of the compounds were characterized by UV, IR, MS and 1H NMR. Method: The compounds were tested for the inhibition of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and Interleukin-1β (IL-1β) at a concentration of 25 µg/mL. The cytokines were produced by THP-1 cells differentiated with PMA for 24hrs and stimulated with LPS for 4 hrs and supernatant were analyzed through ELISA technique. Results and Discussion: Compounds 1-5, 8 and 9 inhibited the production of TNF-α and IL-1β. Compounds 1, 3, and 8 exerted potent inhibitions of TNF-α with 71%, 71%, and 83% inhibition, respectively. Compounds 1 and 8 significantly inhibited the production of IL-1β with 64% and 78% inhibition, respectively. Conclusion: Compounds 1 and 8 significantly inhibited the production of IL-1β with 64% and 78% inhibition, respectively. Notably compound 8 showed the most potent inhibition of these cytokines. Additionally, the effect of compounds on viability of THP-1 cells was also evaluated. Moreover, molecular docking was carried out to study the mechanism of inhibition of TNF-α production.


2021 ◽  
pp. 1-3
Author(s):  
Anda David ◽  
Frédéric Docquier

How do weather shocks influence human mobility and poverty, and how will long-term climate change affect future migration over the course of the 21st century? These questions have gained unprecedented attention in public debates as global warming is already having severe impacts around the world, and prospects for the coming decades get worse. Low-latitude countries in general, and their agricultural areas in particular, have contributed the least to climate change but are the most adversely affected. The effect on people's voluntary and forced displacements is of major concern for both developed and developing countries. On 18 October 2019, Agence Française de Développement (AFD) and Luxembourg Institute of Socio-Economic Research (LISER) organized a workshop on Climate Migration with the aim of uncovering the mechanisms through which fast-onset variables (such as weather anomalies, storms, hurricanes, torrential rains, floods, landslides, etc.) and slow-onset variables (such as temperature trends, desertification, rising sea level, coastal erosion, etc.) influence both people's incentives to move and mobility constraints. This special issue gathers five papers prepared for this workshop, which shed light on (or predict) the effect of extreme weather shocks and long-term climate change on human mobility, and stress the implications for the development community.


2021 ◽  
Vol 14 (1) ◽  
pp. 38
Author(s):  
Hyo Jeong Lee ◽  
Pyeonghwa Jeong ◽  
Yeongyu Moon ◽  
Jungil Choi ◽  
Jeong Doo Heo ◽  
...  

Rearranged during transfection (RET), a receptor tyrosine kinase, is activated by glial cell line-derived neurotrophic factor family ligands. Chromosomal rearrangement or point mutations in RET are observed in patients with papillary thyroid and medullary thyroid carcinomas. Oncogenic alteration of RET results in constitutive activation of RET activity. Therefore, inhibiting RET activity has become a target in thyroid cancer therapy. Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. The indirubin derivative LDD-2633 was tested for RET kinase inhibitory activity. In vitro, LDD-2633 showed potent inhibition of RET kinase activity, with an IC50 of 4.42 nM. The growth of TT thyroid carcinoma cells harboring an RET mutation was suppressed by LDD-2633 treatment via the proliferation suppression and the induction of apoptosis. The effects of LDD-2633 on the RET signaling pathway were examined; LDD-2633 inhibited the phosphorylation of the RET protein and the downstream molecules Shc and ERK1/2. Oral administration of 20 or 40 mg/kg of LDD-2633 induced dose-dependent suppression of TT cell xenograft tumor growth. The in vivo and in vitro experimental results supported the potential use of LDD-2633 as an anticancer drug for thyroid cancers.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 49.1-50
Author(s):  
S. Swain ◽  
C. Coupland ◽  
V. Strauss ◽  
C. Mallen ◽  
C. F. Kuo ◽  
...  

Background:Multimorbidity (≥2 chronic conditions) escalates the risk of adverse health outcomes. However, its burden in people with osteoarthritis (OA) remains largely unknown.Objectives:To identify the clusters of patients with multimorbidity and associated factors in OA and non-OA populations and to estimate the risk of developing multimorbidity clusters after the index date (after diagnosis).Methods:The study used the Clinical Practice Research Datalink – a primary care database from the UK. Firstly, age, sex and practice matched OA and non-OA people aged 20+ were identified to explore patterns and associations of clusters of multimorbidity within each group. Non-OA controls were assigned with same index date as that of matched OA cases. Secondly, multimorbidity trajectories for 20 years after the index date were examined in people without any comorbidities at baseline in both OA and non-OA groups. Latent class analysis was used to identify clusters and latent class growth modelling was used for cluster trajectories. The associations between clusters and age, sex, body mass index (BMI), alcohol use, smoking habits at baseline were quantified through multinomial logistic regression.Results:In total, 47 long-term conditions were studied in 443,822 people (OA- 221922; non-OA- 221900), with a mean age of 62 years (standard deviation ± 13 years), and 58% being women. The prevalence of multimorbidity was 76.6% and 68.9% in the OA and non-OA groups, respectively. In the OA group five clusters were identified including relatively healthy (18%), ‘cardiovascular (CVD) and musculoskeletal (MSK)’ (12.3%), metabolic syndrome (28.2%), ‘pain and psychological (9.1%), and ‘musculoskeletal’ (32.4%). The non-OA group had similar patterns except that the ‘pain+ psychological’ cluster was replaced by ‘thyroid and psychological’. (Figure 1) Among people with OA, ‘CVD+MSK’ and metabolic syndrome clusters were strongly associated with obesity with a relative risk ratio (RRR) of 2.04 (95% CI 1.95-2.13) and 2.10 (95% CI 2.03-2.17), respectively. Women had four times higher risk of being in the ‘pain+ psychological’ cluster than men when compared to the gender ratio in the healthy cluster, (RRR 4.28; 95% CI 4.09-4.48). In the non-OA group, obesity was significantly associated with all the clusters.Figure 1: Posterior probability distribution of chronic conditions across the clusters in Osteoarthritis (OA, n=221922) and Non-Osteoarthritis (Non-OA, n=221900) group. COPD- Chronic Obstructive Pulmonary Disease; CVD- Cardiovascular; MSK- MusculoskeletalOA (n=24139) and non-OA (n=24144) groups had five and four multimorbidity trajectory clusters, respectively. Among the OA population, 2.7% had rapid onset of multimorbidity, 9.5% had gradual onset and 11.6% had slow onset, whereas among the non-OA population, there was no rapid onset cluster, 4.6% had gradual onset and 14.3% had slow onset of multimorbidity. (Figure 2)Figure 2: Clusters of multimorbidity trajectories after index date in OA (n=24139) and Non-OA (n=24144)Conclusion:Distinct identified groups in OA and non-OA suggests further research for possible biological linkage within each cluster. The rapid onset of multimorbidity in OA should be considered for chronic disease management.Supported by:Acknowledgments:We would like to thank the University of Nottingham, UK, Beijing Joint Care Foundation, China and Foundation for Research in Rheumatology (FOREUM) for supporting the study.Disclosure of Interests:Subhashisa Swain: None declared, Carol Coupland: None declared, Victoria Strauss: None declared, Christian Mallen Grant/research support from: My department has received financial grants from BMS for a cardiology trial., Chang-Fu Kuo: None declared, Aliya Sarmanova: None declared, Michael Doherty Grant/research support from: AstraZeneca funded the Nottingham Sons of Gout study, Consultant of: Advisory borads on gout for Grunenthal and Mallinckrodt, Weiya Zhang Consultant of: Grunenthal for advice on gout management, Speakers bureau: Bioiberica as an invited speaker for EULAR 2016 satellite symposium


2021 ◽  
Vol 50 ◽  
pp. 260-271
Author(s):  
Kerry W Bowman ◽  
Samuel A Dale ◽  
Sumana Dhanani ◽  
Jevithen Nehru ◽  
Benjamin T Rabishaw

Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 162
Author(s):  
Ahmed Ragab ◽  
Sawsan A. Fouad ◽  
Ola A. Abu Ali ◽  
Entsar M. Ahmed ◽  
Abeer M. Ali ◽  
...  

Herein, a series of novel hybrid sulfaguanidine moieties, bearing 2-cyanoacrylamide 2a–d, pyridine-2-one 3–10, and 2-imino-2H-chromene-3-carboxamide 11, 12 derivatives, were synthesized, and their structure confirmed by spectral data and elemental analysis. All the synthesized compounds showed moderate to good antimicrobial activity against eight pathogens. The most promising six derivatives, 2a, 2b, 2d, 3a, 8, and 11, revealed to be best in inhibiting bacterial and fungal growth, thus showing bactericidal and fungicidal activity. These derivatives exhibited moderate to potent inhibition against DNA gyrase and DHFR enzymes, with three derivatives 2d, 3a, and 2a demonstrating inhibition of DNA gyrase, with IC50 values of 18.17–23.87 µM, and of DHFR, with IC50 values of 4.33–5.54 µM; their potency is near to that of the positive controls. Further, the six derivatives exhibited immunomodulatory potential and three derivatives, 2d, 8, and 11, were selected for further study and displayed an increase in spleen and thymus weight and enhanced the activation of CD4+ and CD8+ T lymphocytes. Finally, molecular docking and some AMED studies were performed.


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