Q-Tube®-Assisted Alkylation and Arylation of Xanthines and Other N-H-Containing Heterocycles in Water

Scimmi, Cecilia; Cardinali, Marta; Abenante, Laura; Amatista, Marina; Nacca, Francesca Giulia; Lenardão, Eder J.; Sancineto, Luca; Santi, Claudio

doi:10.3390/chemistry3040082

Cited by 4 publications

(3 citation statements)

References 31 publications

(82 reference statements)

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“…A novel technique used the Q-tube system in which reactions were carried out under high pressure, overcoming the solvent boiling point. Consequently, there was a significant increase in the pressure and temperature, leading to a decreased reaction time [ 95 ]. Water was used as a green solvent, and the target compounds were achieved generally in good yields.…”

Section: Modulation Of Calcium Signaling and Homeostasis By Heterocyc...mentioning

confidence: 99%

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

et al. 2023

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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in the elderly. The key histopathological features of these diseases are the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), along with a depleted antioxidant system, mitochondrial dysfunction, and intracellular Ca2+ dyshomeostasis, plays a vital role in the pathophysiology of these neurological disorders. Due to an improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. However, there is no effective protective treatment or therapy available but rather only very limited palliative treatment. Therefore, there is an urgent need for the development of preventive strategies and disease-modifying therapies to treat AD/PD. Because dysregulated Ca2+ metabolism drives oxidative damage and neuropathology in these diseases, the identification or development of compounds capable of restoring Ca2+ homeostasis and signaling may provide a neuroprotective avenue for the treatment of neurodegenerative diseases. In addition, a set of strategies to control mitochondrial Ca2+ homeostasis and signaling has been reported, including decreased Ca2+ uptake through voltage-operated Ca2+ channels (VOCCs). In this article, we review the modulatory effects of several heterocyclic compounds on Ca2+ homeostasis and trafficking, as well as their ability to regulate compromised mitochondrial function and associated free-radical production during the onset and progression of AD or PD. This comprehensive review also describes the chemical synthesis of the heterocycles and summarizes the clinical trial outcomes.

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Section: Modulation Of Calcium Signaling and Homeostasis By Heterocyc...mentioning

confidence: 99%

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

et al. 2023

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“…236～238 ℃ (lit. [30] 234～ 236 ℃); 1 H NMR (400 MHz, CDCl 3 ) δ: 7.49 (s, 1H, N-H), 3.97 (s, 3H, N-CH 3 ), 3.55 (s, 3H, N-CH 3 ), 3.37 (s, 3H, N-CH 3 ); 13 [25] , 白色固体, 产率 25.2%. m.p.…”

Section: -氨基-N-(4-溴苄基)苯甲酰胺(2h): 白色固体产mentioning

confidence: 99%

Studies on the Synthesis and Biological Activities of Novel Dihydroquinazolinone-Containing Caffeine Derivatives

Wang¹,

Yu²,

Yang³

et al. 2023

Chinese Journal of Organic Chemistry

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Based on the strategy of introducing the "dihydroquinazolinone" bioactive group into 8-position of caffeine, thirteen novel caffeine derivatives containing dihydroquinazolinone moiety have been synthesized using theophylline and isatoic anhydride/5-bromoisatoic anhydride as materials, via multi-step reactions such as N-methylation, palladium-catalyzed coupling, nucleophilic addition-elimination and condensation, etc. The bioassay results showed that most of the compounds possess favourable insecticidal activity against Plutella xylostella L., among which 1,3,7-trimethyl-8-(4-(4-oxo-3-propyl-1,2,3,4tetrahydroquinazolin-2-yl)phenyl)-3,7-dihydro-1H-purine-2,6-dione (Ia) and 8-(4-(6-bromo-3-(4-fluorobenzyl)-4-oxo-1,2,3,4tetrahydroquinazolin-2-yl)phenyl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (Im) held lethality rate of 50% and 43% respectively at a test concentration of 50 mg•L -1 , especially Ia still had 20% lethality rate at 10 mg•L -1 . Partial compounds also showed good herbicidal activities. In particular, Ia held an growth inhibition rate of 96.6% against root of Brassica campestris L. at a test concentration of 100 mg•L -1 , which was better than that of the control chlorsulfuron. In addition, partial compounds possessed ＞50% fungicidal activities at 50 mg•L -1 against Sclerotinia sclerotiorum, Phytophthora capsicum, Physalospora piricola, etc. The inhibitory activity of Ia against Phytophthora capsicum reached 80.6%, which greatly exceeded that of the contrast caffeine. Compounds Ia exhibited good biological activities in almost all the insecticidal, herbicidal and fungicidal bioassays, and could be considered as a novel pesticide lead compound to carry out further structural optimizations. The results of this study provide useful reference for the design of new pesticidal agents based on the structure of natural products.

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“…A novel technique uses the Q-tube apparatus in water at over boiling temperature as a green solvent. [244] In a different study, Schnürch's group optimized the employment of quaternary ammonium salts as monoselective N-methylation reagents (Scheme 3). [245] Scheme 3.…”

Section: Scheme 2 Synthesis Of Caffeine 2 Reported By Narayan In 2003...mentioning

confidence: 99%

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

Tapias¹,

González-Andrés²,

Peña³

et al. 2023

Preprint

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The brain is a complex organ that controls body functions and homeostasis through the action of neuronal and glial cells. Neuronal activity is highly energy-dependent and requires large numbers of functional mitochondria to provide substantial amount of energy via mitochondrial oxidative phosphorylation (OXPHOS), the most efficient metabolic process to generate adenosine triphosphate (ATP). Under stress conditions, neurons are particularly vulnerable to mitochondrial dysfunction, leading to decreased ATP synthesis, excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and intracellular Ca2+ dyshomeostasis, although not necessarily in this order. Alzheimer's disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in elderly and are characterized by the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that compromised mitochondrial energy metabolism along with a depleted antioxidant system play a vital role in the pathophysiology of these neurological disorders. Toxic accumulation of proteins such as amyloid β peptides (Aβ) or amyloid precursor protein (APP) in AD and α-synuclein (α-syn) or leucine-rich repeat kinase 2 (LRRK2) in PD cause mitochondrial deficits through direct inhibition of electron transport chain (ETC) assembly and function, thereby resulting in further generation of ROS/RNS and disturbance of Ca2+ influx. Due to the improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. There is no effective protective treatment or therapy available but rather only very limited palliative treatment. There is an urgent need for the development of preventive strategies and disease-modifying therapies (both neuroprotective and neurorestorative interventions) to treat AD/PD. Here, we review the capability of some heterocyclic compounds to modulate Ca2+ homeostasis and signaling with a potential role in regulating mitochondrial function and associated free radical production during the development and onset of AD or PD. Moreover, we have included the chemical synthesis of a series of heterocycles and their derivatives.

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Q-Tube®-Assisted Alkylation and Arylation of Xanthines and Other N-H-Containing Heterocycles in Water

Cited by 4 publications

References 31 publications

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

Studies on the Synthesis and Biological Activities of Novel Dihydroquinazolinone-Containing Caffeine Derivatives

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

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