SnAP Reagents for the Synthesis of Piperazines and Morpholines

Luescher, Michael U.; Vo, Cam‐Van T.; Bode, Jeffrey W.

doi:10.1021/ol500210z

Cited by 84 publications

(58 citation statements)

References 24 publications

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“…After 30 min stirring at room temperature, tert -butyl (2-bromoethyl)carbamate [42] (6.3 mmol, 1.4 g) was added. The reaction mixture was heated at 60 °C for 24 h. After cooling, the mixture was poured into ice-water and extracted with ethyl acetate (3 × 20 mL).…”

Section: Methodsmentioning

confidence: 99%

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation

et al. 2018

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New thiazole nortopsentin analogues were conveniently synthesized and evaluated for their activity as inhibitors of biofilm formation of relevant Gram-positive and Gram-negative pathogens. All compounds were able to interfere with the first step of biofilm formation in a dose-dependent manner, showing a selectivity against the staphylococcal strains. The most active derivatives elicited IC50 values against Staphylococcus aureus ATCC 25923, ranging from 0.40–2.03 µM. The new compounds showed a typical anti-virulence profile, being able to inhibit the biofilm formation without affecting the microbial growth in the planktonic form.

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Section: Methodsmentioning

confidence: 99%

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation

et al. 2018

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“… The SnAP protocol. Reagents and conditions : a) 4 Å MS, DCM (0.2 M), rt, 2 h; b) Cu(OTf) 2 (1.0 equiv), 2,6‐lutidine (1.0 equiv), 4 : 1 CH 2 Cl 2 /HFIP (0.05 M), rt, 12 h (overall yield: 5–94 %) . (MS: molecular sieves, OTf: triflate, HFIP: hexafluoroisopropanol).…”

Section: Synthesis Of Morpholinesmentioning

confidence: 99%

“…Their physicochemical properties, as well as the variety of substituents’ positions, renders them of great research interest . Minor modifications to the previously published protocol led to 4‐, 6‐ and 7‐ membered spirocycles (Scheme ). Moreover, α ‐trifluoromethyl substituted morpholines were synthesized with the use of an azido SnAP reagent, serving well the recent interest in introducing fluorine substitution, which is considered to improve the biological profile of a compound …”

Section: Synthesis Of Morpholinesmentioning

confidence: 99%

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

2020

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Morpholine is a frequently used heterocycle in medicinal chemistry and a privileged structural component of bioactive molecules. This is mainly due to its contribution to a plethora of biological activities as well as to an improved pharmacokinetic profile of such bioactive molecules. The synthesis of morpholines is a subject of much study due to their biological and pharmacological importance, with the last such review being published in 2013. Here, an overview of the main approaches toward morpholine synthesis or functionalization is presented, emphasizing on novel work which has not been reviewed so far. This review is an update on synthetic strategies leading to easily accessible libraries of bioactives which are of interest for drug discovery projects.

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“…The synthesis of hybrid 2 featured, as first step, the protection of 2-bromoethylamine hydrobromide to afford the tert-butyl (2-bromoethyl)carbamate, 37 which was reacted with 6 under basic conditions to afford the diamine 7 in 39% yield 38 (Scheme 2). Removal of the protection group with trifluoroacetic acid (TFA) furnished 8 as trifluoroacetate salt in quantitative yield.…”

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confidence: 99%

Two Novel Donepezil-Lipoic Acid Hybrids: Synthesis, Anticholinesterase and Antioxidant Activities and Theoretical Studies

Terra¹,

Silva²,

Tramarin³

et al. 2017

J. Braz. Chem. Soc.

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Alzheimer disease (AD) is a complex disease related to multiple pathogenic mechanisms. A strategy to develop effective drugs is based on the so-called multi-target directed ligands (MTDL) by using hybrid compounds. So, in the present study, we have designed and synthesized two hybrids, containing the indanone-piperidine moiety of donepezil, a drug approved for the treatment of AD, and the lipoic acid scaffold, an antioxidant compound endowed with neuroprotective effects. One hybrid was synthesized in four steps with 42% global yield, and the other hybrid in six steps with 19% global yield. The latter hybrid displayed moderate inhibitory activity against human acetylcholinesterase (hAChE) and greater activity against human butyrylcholinesterases (hBuChE). The selectivity for hBuChE was further rationalized by theoretical study. Importantly, the second hybrid showed a good antioxidant activity, exhibiting better ability in scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals than lipoic acid. Keywords: donepezil-lipoic acid hybrids, Alzheimer disease, multi-target directed ligands IntroductionAlzheimer disease (AD) is the most common cause of dementia in aging population. It was estimated that, in 2010, about 35.6 millions of people suffered from dementia worldwide, and it is expected that this number might triplicate in the next 40 years.1 Patients affected by AD experience progressive cognitive impairment, such as a decline in short-term memory, loss of speech, language and motor coordination. 2,3 AD is pathologically characterized by an extracellular deposition of β-amyloid (Aβ) peptide into senile plaques, intracellular formation of neurofibrillary tangles (NFTs) containing a hyperphosphorylated form of Tau protein, oxidative stress, mitochondrial abnormality, neuroinflammatory processes and neuronal loss, mainly affecting the frontal cortex and hippocampus. 4,5 AD is also characterized by a reduction of acetylcholine (ACh) levels, which is correlated with the cognitive symptoms. 6 The "cholinergic hypothesis", proposed in 1982 by Bartus et al.,7 postulated that the cognitive decline experienced by patients with AD resulted from a deficiency of acetylcholine or cholinergic neurotransmission. In humans, acetylcholine is degraded in the synaptic cleft by two main classes of cholinesterase enzymes: acetyl-(AChE) and butyryl- (BuChE) 8 cholinesterases. Near the amyloid plaques and neurofibrillary tangles, an extensive oxidative stress has been observed 9 which is a result of an altered balance of formation of reactive oxygen species (ROS) versus scavenging activity. 5,10 The production of ROS is also related to calcium homeostasis; the misbalance of calcium influx affects the mitochondrial Terra et al. 739 Vol. 29, No. 4, 2018 enzymes and ROS production is a normal part of the electron transport chain. However, excessive levels of these species damage proteins, lipids and nucleic acids. 9AD is a complex disease related to multiple pathogenic mechanisms involving different molecular targets. All the dru...

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SnAP Reagents for the Synthesis of Piperazines and Morpholines

Cited by 84 publications

References 24 publications

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation

New Thiazole Nortopsentin Analogues Inhibit Bacterial Biofilm Formation

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

Two Novel Donepezil-Lipoic Acid Hybrids: Synthesis, Anticholinesterase and Antioxidant Activities and Theoretical Studies

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