Novel multi-target directed ligands based on annelated xanthine scaffold with aromatic substituents acting on adenosine receptor and monoamine oxidase B. Synthesis, in vitro and in silico studies

Załuski, Michał; Schabikowski, Jakub; Schlenk, Miriam; Olejarz-Maciej, Agnieszka; Kubas, Bartłomiej; Karcz, Tadeusz; Kuder, Kamil; Latacz, Gniewomir; Zygmunt, Małgorzata; Synak, David; Hinz, Sonja; Müller, Christa E.; Kieć‐Kononowicz, Katarzyna

doi:10.1016/j.bmc.2019.02.004

Cited by 18 publications

(17 citation statements)

References 49 publications

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“…CAF has been also investigated for synthetic applications in the sustainable pharmaceutical chemistry. In fact, the xanthine structural core of CAF represents a useful natural renewable starting material in the synthesis of known and/or new drugs, especially addressed to diseases related to material in the synthesis of known and/or new drugs, especially addressed to diseases related to oxidative stress [13][14][15][16]. Because of its high chemical stability, CAF needs drastic conditions to react, while an easier reactivity is shown by electrochemical route.…”

Section: Introductionmentioning

confidence: 99%

An Insight into the Reactivity of the Electrogenerated Radical Cation of Caffeine

et al. 2020

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Controlled potential electrolyses of caffeine (CAF) were carried out at a Pt electrode in undried acetonitrile (ACN) and ACN-H2O and the products of the anodic oxidation were analyzed by HPLC-PDA-ESI-MS/MS. A higher current efficiency occurred in ACN-H2O, but an analogous chromatographic outline was found in both media, evidencing a reactive pathway of the electrogenerated radical cation CAF•+ with water, added or in trace, as nucleophile. No dimeric forms were evidenced, excluding any coupling reactions. Neither was 1,3,7-trimethyluric acid found, reported in the literature as the main oxidative route for CAF in water. Four main chromatographic peaks were evidenced, assigned to four proposed structures on the base of chromatographic and spectral data: a 4,5-diol derivative and an oxazolidin-2-one derivative were assigned as principal oxidation products, supporting a mechanism proposed in a previous work for the primary anodic oxidation of the methylxanthines olefinic C4 = C5 bond. Two highly polar degradation products were also tentatively assigned, that seemed generating along two different pathways, one opening the imidazolic moiety and another one opening the purinic one.

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Section: Introductionmentioning

confidence: 99%

An Insight into the Reactivity of the Electrogenerated Radical Cation of Caffeine

et al. 2020

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“…Interestingly, the compounds with a higher in vitro inhibitory activity, 12 and 13 (Figure 15) were also the molecules with the highest affinity towards the catalytic site of MAO-B, interacting with the main amino acids of the active site (Tyr60, Leu171, Ile198, Tyr 398, and Tyr435) [110]. Similar strategies were carried out by other researchers to study the drug potential of garcinol (PDB#3PO7) [111], tricyclic molecules with xanthine scaffolds (PDB#2V5Z) [112], benzothiazoles and benzoxazoles (PDB#2V5Z) [113], rutamarin (PDB#2V60) [114], isoxazole carbohydrazides (PDB#2V60) [115], eugenol derivatives [116], and 4-(3-nitrophenyl)thiazol-2-yl hydrazone derivatives (PDB#6FW0) [117] in PD, as summarized in Figure 15. Moreover, the Chaurasiya research team also studied the affinity of several acacetin derivatives (Figure 16) by molecular docking and combined this analysis with molecular dynamics simulations to evaluate the compounds' binding modes and selectivity towards both MAO-A (PDB ID: 2Z5X) and MAO-B (PDB#4A79) isoforms [118].…”

Section: Monoamine Oxidase Type B Inhibitorsmentioning

confidence: 86%

“…Interestingly, compounds 23 and 24 (Figure 21) showed the highest affinity for A 1 receptor, and compound 25 displayed a higher affinity against all tested macromolecular targets, being considered a potential novel adenosine receptor antagonist with affinity for multiple receptors [134]. Załuski and co-workers designed new N9-benzyl-substituted imidazo-, pyrimido-and 1,3-diazepino[2,1-f ]purinediones derivatives and evaluated their potential adenosine A 2A receptors antagonistic activity with in vitro and in silico approaches [112]. Thus, thirty-seven novel derivatives were studied by molecular docking to evaluate their affinity towards the target (PDB#3REY) [112].…”

Section: Adenosine Receptors Antagonistsmentioning

confidence: 99%

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

et al. 2021

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Neurodegenerative diseases (ND), including Alzheimer’s (AD) and Parkinson’s Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.

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“…The compounds were synthesized by oxidative bromination of theophylline followed by N7‐alkylation under phase transfer catalytic conditions and finally condensing the corresponding intermediate with various amines to obtain the final tricyclic xanthine derivatives as shown in Scheme 5a. The pyrimido and diazepino based compounds, particularly substituted with bromobenzyl ( 42 a ) and dichlorobenzyl ( 42 b ) groups have shown maximum potency [166,167] …”

Section: Synthetic Approaches and Design Aspects Of Various Classes Omentioning

confidence: 99%

An Update of Synthetic Approaches and Structure‐Activity Relationships of Various Classes of Human MAO‐B Inhibitors

2021

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The selective MAO‐B inhibition is greatly influenced by the degradation pathways of various biogenic amines. So the design and development of diverse class of MAO‐B inhibitors are considered as an effective adjuvant therapy of various neurodegenerative disorders. Recent studies documented that introduction of an electron rich linker between two aryl or heteroaryl rings explored as a promising structural framework of the inhibition of MAO‐B. The electrophilicity and flexibility character of the linker can anchor different orientation of binding mode in both entrance and substrate cavity of MAO‐B. The current review focus on the design aspect, synthetic route and structure activity relationships (SARs) various class of selective MAO‐B inhibitors like chalcones, coumarins, chromones, pyrazolines, xanthines, isatins, FDA approved analogs etc.

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Novel multi-target directed ligands based on annelated xanthine scaffold with aromatic substituents acting on adenosine receptor and monoamine oxidase B. Synthesis, in vitro and in silico studies

Cited by 18 publications

References 49 publications

An Insight into the Reactivity of the Electrogenerated Radical Cation of Caffeine

An Insight into the Reactivity of the Electrogenerated Radical Cation of Caffeine

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

An Update of Synthetic Approaches and Structure‐Activity Relationships of Various Classes of Human MAO‐B Inhibitors

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