202191-53-5Relevant academic research and scientific papers
Hydrazone exchange: a viable route for the solid-tethered synthesis of [2]rotaxanes
Da Silva Rodrigues, Rafael,Luis, Ena T.,Marshall, David L.,McMurtrie, John C.,Mullen, Kathleen M.
, p. 4414 - 4421 (2021)
Controlled and complete assembly of supramolecular systems on solid supports is a challenge that would elevate the function of interlocked architectures. Building on the success of other dynamic covalent synthetic methods, we present hydrazone exchange as a strategy to improve the formation of rotaxanes in solution and on solid surfaces. Solution-state analogues containing naphthalenediimide (NDI) or bipyridinium motifs and 1,5-dinaphtho[38]crown-10 were initially prepared to establish ideal conditions for maintaining thermal equilibrium throughout the exchange reaction. Solid-state rotaxanes were synthesised on hydrazide-functionalised TentaGel polymer resins and analysed with HR MAS1H NMR spectroscopy. Surface rotaxane functionalisation of 80% was achieved for the NDI rotaxane, which is significantly higher than previously reported with either dynamic covalent or traditional irreversible synthetic strategies.
Controlled Reduction of Nitriles by Sodium Hydride and Zinc Chloride
Chiba, Shunsuke,Ong, Derek Yiren
, p. 1369 - 1378 (2020/04/27)
A new protocol for the controlled reduction of nitriles to aldehydes was developed using a combination of sodium hydride and zinc chloride. The iminyl zinc intermediates derived from aromatic nitriles could be further functionalized with allylmetal nucleophiles to afford homoallylamines. As the method allows the reduction of various aliphatic and aromatic nitriles with a concise procedure under milder reaction conditions and exhibits wide functional group compatibility, it is well suited for use in various opportunities in chemical synthesis.
Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling
Bembenek, Scott D.,Keith, John M.,Letavic, Michael A.,Apodaca, Richard,Barbier, Ann J.,Dvorak, Lisa,Aluisio, Leah,Miller, Kirsten L.,Lovenberg, Timothy W.,Carruthers, Nicholas I.
, p. 2968 - 2973 (2008/09/20)
Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H3 receptor antagonist. Both histamine H3 receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H3 antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs 2004, 18, 827]. Further, recent studies2 indicate the peripheral anionic site (PAS) of AChE interacts with the β-amyloid (βA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of βA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H3 receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.
Target Guided Synthesis of 5-Benzyl-2,4-diamonopyrimidines: Their Antimalarial Activities and Binding Affinities to Wild Type and Mutant Dihydrofolate Reductases from Plasmodium falciparum
Sirichaiwat, Chawanee,Intaraudom, Chakapong,Kamchonwongpaisan, Sumalee,Vanichtanankul, Jarunee,Thebtaranonth, Yodhathai,Yuthavong, Yongyuth
, p. 345 - 354 (2007/10/03)
The resistance to pyrimethamine (PYR) of Plasmodium falciparum arising from mutation at position 108 of dihydrofolate reductase (pfDHFR) from serine to asparagine (S108N) is due to steric interaction between the bulky side chain of N108 and C1 atom of the 5-p-C1 aryl group of PYR, which consequently resulted in the reduction in binding affinity between the enzyme and inhibitor. Molecular modeling suggested that the flexible antifolate, such as trimethoprim (TMP) derivatives, could avoid this steric constraint and should be considered as new, potentially effective compounds. The hydrophobic interaction between the side chain of inhibitor and the active site of the enzyme around position 108 was enhanced by the introduction of a longer and more hydrophobic side chain on TMP's 5-benzyl moiety. The prepared compounds, especially those bearing aromatic substituents, exhibited better binding affinities to both wild type and mutant enzymes than the parent compound. Binding affinities of these compounds correlated well with their antimalarial activities against both wild type and resistant parasites. Molecular modeling of the binding of such compounds with pfDHFR also supported the experimental data and clearly showed that aromatic substituents play an important role in enhancing binding affinity. In addition, some compounds with 6-alkyl substituents showed relatively less decrease in binding constants with the mutant enzymes and relatively good antimalarial activities against the parasites bearing the mutant enzymes.
