Structural Isomerism and Enhanced Lipophilicity of Pyrithione Ligands of Organoruthenium(II) Complexes Increase Inhibition on AChE and BuChE

The increasing number of Alzheimer’s disease (AD) cases requires the development of new improved drug candidates, possessing the ability of more efficient treatment as well as less unwanted side effects. Cholinesterase enzymes are highly associated with the development of AD and thus represent important druggable targets. Therefore, we have synthesized eight organoruthenium(II) chlorido complexes 1a–h with pyrithione-type ligands (pyrithione = 1-hydroxypyridine-2(1H)-thione, a), bearing either pyrithione a, its methyl (b-e) or bicyclic aromatic analogues (f–h) and tested them for their inhibition towards electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBuChE). The experimental results have shown that the novel complex 1g with the ligand 1-hydroxyquinoline-2-(1H)-thione (g) improves the inhibition towards eeAChE (IC50 = 4.9 μM) and even more potently towards hsBuChE (IC50 = 0.2 μM) in comparison with the referenced 1a. Moreover, computational studies on Torpedo californica AChE have supported the experimental outcomes for 1g, possessing the lowest energy value among all tested complexes and have also predicted several interactions of 1g with the target protein. Consequently, we have shown that the aromatic ring extension of the ligand a, though only at the appropriate position, is a viable strategy to enhance the activity against cholinesterases.

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Recent Advances and Computational Approaches in Peptide Drug Discovery

Current Pharmaceutical Design ◽

10.2174/1381612825666190911161106 ◽

2019 ◽

Vol 25 (31) ◽

pp. 3358-3366 ◽

Cited By ~ 2

Author(s):

Neha S. Maurya ◽

Sandeep Kushwaha ◽

Ashutosh Mani

Keyword(s):

Docking Studies ◽

Computational Approaches ◽

Simulation Tools ◽

Drug Candidates ◽

Recent Advances ◽

Long Duration ◽

Stability Of Complexes ◽

Therapeutic Peptides ◽

Target Binding ◽

Druggable Targets

Background: Drug design and development is a vast field that requires huge investment along with a long duration for providing approval to suitable drug candidates. With the advancement in the field of genomics, the information about druggable targets is being updated at a fast rate which is helpful in finding a cure for various diseases. Methods: There are certain biochemicals as well as physiological advantages of using peptide-based therapeutics. Additionally, the limitations of peptide-based drugs can be overcome by modulating the properties of peptide molecules through various biomolecular engineering techniques. Recent advances in computational approaches have been helpful in studying the effect of peptide drugs on the biomolecular targets. Receptor – ligand-based molecular docking studies have made it easy to screen compatible inhibitors against a target.Furthermore, there are simulation tools available to evaluate stability of complexes at the molecular level. Machine learning methods have added a new edge by enabling accurate prediction of therapeutic peptides. Results: Peptide-based drugs are expected to take over many popular drugs in the near future due to their biosafety, lower off-target binding chances and multifunctional properties. Conclusion: This article summarises the latest developments in the field of peptide-based therapeutics related to their usage, tools, and databases.

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Identification of novel transmembrane Protease Serine Type 2 drug candidates for COVID-19 using computational studies

Informatics in Medicine Unlocked ◽

10.1016/j.imu.2021.100725 ◽

2021 ◽

pp. 100725

Author(s):

Fatima A. Elbadwi ◽

Elaf A. khairy ◽

Fatima O. Alsamani ◽

Mariam A. Mahadi ◽

Segood E. Abdalrahman ◽

...

Keyword(s):

Computational Studies ◽

Drug Candidates

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The Novel Complex[LRuIV(μ-O)3RuIVL][PF6]2·H2O–a Molecular Section of the Structures of BaRuIVO3(High-Pressure Phase) and Ba5/6Sr1/6RuIVO3

Angewandte Chemie International Edition in English ◽

10.1002/anie.198907631 ◽

1989 ◽

Vol 28 (6) ◽

pp. 763-765 ◽

Cited By ~ 7

Author(s):

Peter Neubold ◽

Beatriz S. P. C. Della Vedova ◽

Karl Wieghardt ◽

Bernd Nuber ◽

Johannes Weiss

Keyword(s):

High Pressure ◽

High Pressure Phase ◽

The Novel ◽

Novel Complex ◽

Pressure Phase

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ChemInform Abstract: Synthesis and Reaction of the Novel Complex [AsPh4][OsCl5(H2O)]. X-Ray Structure Analysis of [AsPh4][OsCl5(H2O)]×2EtOH and [AsPh4][OsCl5(EtOH)]×EtOH.

ChemInform ◽

10.1002/chin.200112019 ◽

2001 ◽

Vol 32 (12) ◽

pp. no-no

Author(s):

Andrei Maiboroda ◽

Gerd Rheinwald ◽

Heinrich Lang

Keyword(s):

Structure Analysis ◽

The Novel ◽

X Ray ◽

Novel Complex

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Preparation and Chemical and Biological Studies of the Novel Complex μ-1,4,5-triphenyl-1,3,4-triazole-2-thiolate-bis[dichlorotriethylphosphineplatinum(II)]a

Transition Metal Chemistry ◽

10.1007/s11243-005-6260-z ◽

2005 ◽

Vol 30 (6) ◽

pp. 733-737

Author(s):

Wagner M. Teles ◽

Flávia C. Machado ◽

Carlos A. Montanari ◽

Carlos A. L. Filgueiras ◽

Terence C. Jenkins

Keyword(s):

The Novel ◽

Biological Studies ◽

Novel Complex

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A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin

Scientific Reports ◽

10.1038/s41598-019-52254-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Jong Bong Lee ◽

Masar Radhi ◽

Elena Cipolla ◽

Raj D. Gandhi ◽

Sarir Sarmad ◽

...

Keyword(s):

Oral Administration ◽

Metabolic Pathway ◽

Oral Absorption ◽

Therapeutic Effects ◽

The Novel ◽

Drug Candidates ◽

Biopharmaceutical Properties

Abstract Although adenosine and its analogues have been assessed in the past as potential drug candidates due to the important role of adenosine in physiology, only little is known about their absorption following oral administration. In this work, we have studied the oral absorption and disposition pathways of cordycepin, an adenosine analogue. In vitro biopharmaceutical properties and in vivo oral absorption and disposition of cordycepin were assessed in rats. Despite the fact that numerous studies showed efficacy following oral dosing of cordycepin, we found that intact cordycepin was not absorbed following oral administration to rats. However, 3′-deoxyinosine, a metabolite of cordycepin previously considered to be inactive, was absorbed into the systemic blood circulation. Further investigation was performed to study the conversion of 3′-deoxyinosine to cordycepin 5′-triphosphate in vitro using macrophage-like RAW264.7 cells. It demonstrated that cordycepin 5′-triphosphate, the active metabolite of cordycepin, can be formed not only from cordycepin, but also from 3′-deoxyinosine. The novel nucleoside rescue metabolic pathway proposed in this study could be responsible for therapeutic effects of adenosine and other analogues of adenosine following oral administration. These findings may have importance in understanding the physiology and pathophysiology associated with adenosine, as well as drug discovery and development utilising adenosine analogues.

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Full-length and C-terminal neurogranin in Alzheimer’s disease cerebrospinal fluid analyzed by novel ultrasensitive immunoassays

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00748-6 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Annika Öhrfelt ◽

Julien Dumurgier ◽

Henrik Zetterberg ◽

Agathe Vrillon ◽

Nicholas J. Ashton ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Single Molecule ◽

Full Length ◽

The Novel ◽

Drug Candidates ◽

Postsynaptic Protein ◽

Coefficients Of Variation ◽

Assay Precision ◽

Novel Drug

Abstract Background Neurogranin (Ng) is a neuron-specific and postsynaptic protein that is abundantly expressed in the brain, particularly in the dendritic spine of the hippocampus and cerebral cortex. The enzymatic cleavage of Ng produces fragments that are released into cerebrospinal (CSF), which have been shown to be elevated in Alzheimer’s disease (AD) patients and predict cognitive decline. Thus, quantification of distinctive cleavage products of Ng could elucidate different features of the disease. Methods In this study, we developed novel ultrasensitive single molecule array (Simoa) assays for measurement of full-length neurogranin (FL-Ng) and C-terminal neurogranin (CT-Ng) fragments in CSF. The Ng Simoa assays were evaluated in CSF samples from AD patients (N = 23), mild cognitive impairment due to AD (MCI-AD) (N = 18), and from neurological controls (N = 26). Results The intra-assay repeatability and inter-assay precision of the novel methods had coefficients of variation below 7% and 14%, respectively. CSF FL-Ng and CSF CT-Ng median concentrations were increased in AD patients (6.02 ng/L, P < 0.00001 and 452 ng/L, P = 0.00001, respectively) and in patients with MCI-AD (5.69 ng/L, P < 0.00001 and 566 ng/L, P < 0.00001) compared to neurological controls (0.644 ng/L and 145 ng/L). The median CSF ratio of CT-Ng/FL-Ng were decreased in AD patients (ratio = 101, P = 0.008) and in patients with MCI-AD (ratio = 115, P = 0.016) compared to neurological controls (ratio = 180). CSF of FL-Ng, CT-Ng, and ratio of CT-Ng/FL-Ng could each significantly differentiate AD patients from controls (FL-Ng, AUC = 0.907; CT-Ng, AUC = 0.913; CT-Ng/FL-Ng, AUC = 0.775) and patients with MCI-AD from controls (FL-Ng, AUC = 0.937; CT-Ng, AUC = 0.963; CT-Ng/FL-Ng, AUC = 0.785). Conclusions Assessments of the FL-Ng and CT-Ng levels in CSF with the novel sensitive immunoassays provide a high separation of AD from controls, even in early phase of the disease. The novel Ng assays are robust and highly sensitive and may be valuable tools to study synaptic alteration in AD, as well as to monitor the effect on synaptic integrity of novel drug candidates in clinical trials.

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