Theophylline-based hybrids as acetylcholinesterase inhibitors endowed with anti-inflammatory activity: synthesis, bioevaluation,<i>in silico</i>and preliminary kinetic studies

Elgazar, Abdullah A.; El-Domany, Ramadan A.; Eldehna, Wagdy M.; Badria, Farid A.

doi:10.1039/d3ra04867e

Cited by 8 publications

(5 citation statements)

References 75 publications

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“…Acetyl derivatives were prepared using the previously reported method 27 to obtain compounds ( 4a – d )…”

Section: Methodsmentioning

confidence: 99%

“…Acetyl derivatives were prepared using the previously reported method 27 to obtain compounds (4a−d) 4.1.5. Synthesis of the AKBA Hybrid Acetyl Linker Derivative (5a−d).…”

Section: Synthesis Of Bromoacetyl Derivatives (4a−d)mentioning

confidence: 99%

“…In our lab, we attempted new approaches to explore and modify bioactive natural products using molecular biology tools, in silico investigations, derivatization strategies, and pharmaceutical formulations. − So, the successful stories of hybridization of boswellic acids as anti-inflammatory, cytotoxic agents, and antidiabetic agents − encouraged us to pursue novel new hybrids based on AKBA and other anti-inflammatory and antioxidant natural products; these hybrids will be evaluated for their ability to mitigate APAP toxicity in vitro . Furthermore, gene enrichment for the elucidation of potential targets of the compounds would be addressed and supported by molecular docking studies.…”

Section: Introductionmentioning

confidence: 99%

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3-Acetyl-11-keto-β-boswellic Acid-Based Hybrids Alleviate Acetaminophen-Induced Hepatotoxicity in HepG2 by the Regulation of Inflammatory and Oxidative Stress Pathways: An Integrated Approach

Elgazar,

El-Domany,

Eldehna

et al. 2023

ACS Omega

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In an effort to develop new compounds for managing drug-induced liver injury, we prepared 23 novel hybrids based on 3-acetyl-11-keto-β-boswellic acid (AKBA) using various biocompatible linkers. A bioguided approach was employed to identify the most promising hybrid. Eight compounds exhibited superior anti-inflammatory activity compared to the parent compound. Two of these hybrids (5b and 18) were able to reduce gene expression of TNF-α in LPS-induced inflammation in RAW 264.7 cells, similar to dexamethasone. Subsequently, the hepatoprotective potential of these hybrids was evaluated against acetaminophen (APAP) toxicity in HepG2 cells at doses of 1 and 10 μM. Both hybrids effectively restored cytokine levels, which had been elevated by APAP, to normal levels. Furthermore, they normalized depleted superoxide dismutase and reduced glutathione levels while significantly reducing malondialdehyde (MDA) levels. Network pharmacology analysis suggested that AKBA-based hybrids exert their action by regulating PI3K and EGFR pathways, activating anti-inflammatory mechanisms, and initiating tissue repair and regeneration. Molecular docking studies provided insights into the interaction of the hybrids with PI3K. Additionally, the hybrids demonstrated good stability at different pH levels, following first-order kinetics, with relatively long half-lives, suggesting potential for absorption into circulation without significant degradation.

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“…Acetyl derivatives were prepared using the previously reported method 27 to obtain compounds ( 4a – d )…”

Section: Methodsmentioning

confidence: 99%

“…Acetyl derivatives were prepared using the previously reported method 27 to obtain compounds (4a−d) 4.1.5. Synthesis of the AKBA Hybrid Acetyl Linker Derivative (5a−d).…”

Section: Synthesis Of Bromoacetyl Derivatives (4a−d)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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3-Acetyl-11-keto-β-boswellic Acid-Based Hybrids Alleviate Acetaminophen-Induced Hepatotoxicity in HepG2 by the Regulation of Inflammatory and Oxidative Stress Pathways: An Integrated Approach

Elgazar,

El-Domany,

Eldehna

et al. 2023

ACS Omega

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“…csic.es/tools/venny/) (accessed on 1 January 2024). Gene ontology and pathway analysis were performed as described previously [60] to highlight enriched genes responsible for biological processes, molecular functions, cellular processes, and the KEGG pathways related to nephrotoxicity. Molecular docking was applied to obtain insights about PV-MAPK1 interaction.…”

Section: Network Pharmacology and In Silico Prediction Of Pv Targetsmentioning

confidence: 99%

Unraveling the Nephroprotective Potential of Papaverine against Cisplatin Toxicity through Mitigating Oxidative Stress and Inflammation: Insights from In Silico, In Vitro, and In Vivo Investigations

Abass,

Elgazar,

El-kholy

et al. 2024

Molecules

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Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether papaverine could mitigate cisplatin-induced kidney damage while preserving its chemotherapeutic efficacy. Integrative bioinformatics analysis predicted papaverine modulation of the mechanistic pathways related to cisplatin renal toxicity; notably, mitogen-activated protein kinase 1 (MAPK1) signaling. We validated protective effects in normal kidney cells without interfering with cisplatin cytotoxicity on a cancer cell line. Concurrent in vivo administration of papaverine alongside cisplatin in rats prevented elevations in nephrotoxicity markers, including serum creatinine, blood urea nitrogen, and renal oxidative stress markers (malondialdehyde, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines), as tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6). Papaverine also reduced apoptosis markers such as Bcl2 and Bcl-2–associated X protein (Bax) and kidney injury molecule-1 (KIM-1), and histological damage. In addition, it upregulates antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) while boosting anti-inflammatory signaling interleukin-10 (IL-10). These effects were underlined by the ability of Papaverine to downregulate MAPK-1 expression. Overall, these findings show papaverine could protect against cisplatin kidney damage without reducing its cytotoxic activity. Further research would allow the transition of these results to clinical practice.

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“…Furthermore, whereas analogues with a linker of 5 C atoms showed nAChR activation and also receptor desensitization, those analogues with a linker of 7 C atoms did not cause nAChR desensitization . Recently, compounds derived from caffeine, achieved through chemical modifications of theophylline, theobromine, or acefylline, have also been identified as inhibitors of the acetylcholinesterase enzyme. − This strategy, involving the combination of diverse pharmacophores or functional groups derived from theophylline and its derivatives, has proven effective in enhancing the activity of the original pharmacological compounds, as demonstrated in our previously synthesized series of caffeine derivatives . However, these reports evaluated only the effect on AChE and not on nAChR.…”

Section: Introductionmentioning

confidence: 99%

New Multitarget Molecules Derived from Caffeine as Potentiators of the Cholinergic System

Munafó,

Biscussi,

Obiol

et al. 2024

ACS Chem. Neurosci.

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Cholinergic deficit is a characteristic factor of several pathologies, such as myasthenia gravis, some types of congenital myasthenic syndromes, and Alzheimer's Disease. Two molecular targets for its treatment are acetylcholinesterase (AChE) and nicotinic acetylcholine receptor (nAChR). In previous studies, we found that caffeine behaves as a partial nAChR agonist and confirmed that it inhibits AChE. Here, we present new bifunctional caffeine derivatives consisting of a theophylline ring connected to amino groups by different linkers. All of them were more potent AChE inhibitors than caffeine. Furthermore, although some of them also activated muscle nAChR as partial agonists, not all of them stabilized nAChR in its desensitized conformation. To understand the molecular mechanism underlying these results, we performed docking studies on AChE and nAChR. The nAChR agonist behavior of the compounds depends on their accessory group, whereas their ability to stabilize the receptor in a desensitized state depends on the interactions of the linker at the binding site. Our results show that the new compounds can inhibit AChE and activate nAChR with greater potency than caffeine and provide further information on the modulation mechanisms of pharmacological targets for the design of novel therapeutic interventions in cholinergic deficit.

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Theophylline-based hybrids as acetylcholinesterase inhibitors endowed with anti-inflammatory activity: synthesis, bioevaluation,in silicoand preliminary kinetic studies

Abstract: In this study, conjugation of theophylline with different compounds of natural origin led to new hybrids with dual activity against cholinergic and inflammatory pathways as potential agents for management of Alzheimer's disease (AD).

Cited by 8 publications

References 75 publications

3-Acetyl-11-keto-β-boswellic Acid-Based Hybrids Alleviate Acetaminophen-Induced Hepatotoxicity in HepG2 by the Regulation of Inflammatory and Oxidative Stress Pathways: An Integrated Approach

3-Acetyl-11-keto-β-boswellic Acid-Based Hybrids Alleviate Acetaminophen-Induced Hepatotoxicity in HepG2 by the Regulation of Inflammatory and Oxidative Stress Pathways: An Integrated Approach

Unraveling the Nephroprotective Potential of Papaverine against Cisplatin Toxicity through Mitigating Oxidative Stress and Inflammation: Insights from In Silico, In Vitro, and In Vivo Investigations

New Multitarget Molecules Derived from Caffeine as Potentiators of the Cholinergic System

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