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Multi-Functional Monoamine Oxidase and Cholinesterase Inhibitors for the Treatment of Alzheimer’s Disease
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Ireen Denya, Sarel F. Malan, Jacques Joubert
Wang et al., 2014, reported on the synthesis, biochemical evaluation, ADME, toxicity and molecular modelling of novel multi-target directed hybrids of donepezil, selegiline and 8-hydroxyyquinoline for the potential prevention and treatment of AD. The most interesting derivative was racemic compound 21 (Fig. 11.17), an irreversible MAO-A/B inhibitor and mixed-type ChE inhibitor with metal-chelating properties. According to docking studies, both the enantiomers of 21 interact simultaneously with the CAS and PAS of eeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO-A. For MAO-B, the quinoline system was hosted at the entrance cavity whereas for MAO-A this system occupied the substrate cavity. In this disposition, the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. In addition, they established an essential role for the cyano group in properly positioning the ligand by hydrogen-bond formation with the amino acid residues of the binding sites of AChE, BuChE and MAO-A (Wang et al., 2014).
Additional Techniques for Designing and Representing Structures of Large Molecules
Published in Patrick E. McMahon, Rosemary F. McMahon, Bohdan B. Khomtchouk, Survival Guide to General Chemistry, 2019
Patrick E. McMahon, Rosemary F. McMahon, Bohdan B. Khomtchouk
Example: Construct isomers for the molecular formula C5H5NOClBr. Determine the number of multiple bonds required for this specific formula.Determine any valid Lewis structure for this formula.Construct a molecule from the same central atom connection pattern that contains no triple bonds.Construct a molecule from the same central atom connection pattern that contains a different C—C multiple bond pattern.Construct a molecule from a different central atom connection pattern that contains a cyano group; cyano represents an example of a C—N triple bond.Construct a molecule from a different central atom connection pattern that contains an example of a C—O double bond.
Pharmacology for venous and lymphatic diseases
Published in Ken Myers, Paul Hannah, Marcus Cremonese, Lourens Bester, Phil Bekhor, Attilio Cavezzi, Marianne de Maeseneer, Greg Goodman, David Jenkins, Herman Lee, Adrian Lim, David Mitchell, Nick Morrison, Andrew Nicolaides, Hugo Partsch, Tony Penington, Neil Piller, Stefania Roberts, Greg Seeley, Paul Thibault, Steve Yelland, Manual of Venous and Lymphatic Diseases, 2017
Ken Myers, Paul Hannah, Marcus Cremonese, Lourens Bester, Phil Bekhor, Attilio Cavezzi, Marianne de Maeseneer, Greg Goodman, David Jenkins, Herman Lee, Adrian Lim, David Mitchell, Nick Morrison, Andrew Nicolaides, Hugo Partsch, Tony Penington, Neil Piller, Stefania Roberts, Greg Seeley, Paul Thibault, Steve Yelland
The cyanoacrylate molecule has a two-carbon ethylene group, a B-carbon which has two hydrogens attached which contribute to its electric activity, and an A-carbon which has a cyano-group and an ester function called a carbonyl (Figure 5.5a). Various hydrocarbons perform the carbonyl function and provide its name, such as n-butyl cyanoacr ylate, ethyl2-cyanoacrylate, methyl 2-cyanoacrylate and 2-octyl cyanoacrylate.
Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A2A/A2B adenosine receptor antagonists
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zhi Li, Lijuan Kou, Xinzhen Fu, Zeping Xie, Maolei Xu, Lin Guo, Tiantian Lin, Shizhou Gong, Shumin Zhang, Ming Liu
The binding mode of hA2B AR was also analysed with the same docking protocols in Discovery Studio 2017 R2. The homology model of hA2B AR was developed using a hA2A AR crystal structure as the template (PDB ID: 6PS7) and has been checked using the Ramachandran plot application within Discovery Studio40,41. In the binding mode (Figure 4(b,d); for more details see Supporting information Figure S3), the pyridine scaffold is located at the entrance of the cavity getting close to residue Phe173 in the ECL2 segment, and the methylbenzonitrile moiety is located in the depth of the binding pocket by a π–π interaction with Trp247. In addition, the cyano group has a polar interaction with the amide function of Asn282. The binding mode shows the methylbenzonitrile structure is beneficial to obtaining potent inhibitory activity on A2B AR. Moreover, favourable interactions with the amide group and methyl group are established with the side chains of Ala64 and His280. Thus, the substituents on the pyridine ring may affect the compound affinity.
Clinical presentation of type 1 and type 2 pyrethroid poisoning in humans
Published in Clinical Toxicology, 2022
Manna Sera Jacob, Ramya Iyyadurai, Arun Jose, Jude Joseph Fleming, Grace Rebekah, Anand Zachariah, Samuel George Hansdak, Reginald Alex, Vignesh Kumar Chandiraseharan, Audrin Lenin, John Victor Peter
These clinical manifestations in pyrethroid poisoning can be explained by the primary action of pyrethroids on sodium channels of muscles and nerves causing a delay in the channel closure [3,7]. This allows continued and repetitive sodium influx, known as sodium “tail current” leading to hyperexcitability of these neurons, which clinically manifest as paraesthesia [3]. Similar action in insects leads to paralysis and death. Higher concentrations of pyrethroid act in addition to chloride channels, GABA gated chloride channels and peripheral benzodiazepine receptors causing hypersalivation and seizures [3,21]. In experimental studies in animals, type 1 pyrethroid poisoning manifests with fine tremors, paraesthesia and reflex hyperexcitability (tremor syndrome) and type 2 poisoning presents with profuse salivation, coarse tremors, choreoathetosis and seizures (choreoathetosis syndrome) [3]. The cyano group confers higher insecticidal activity to type 2 compounds.
Effect of 3-subsitution of quinolinehydroxamic acids on selectivity of histone deacetylase isoforms
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Samir Mehndiratta, Mei-Chuan Chen, Yuh-Hsuan Chao, Cheng-Hsin Lee, Jing-Ping Liou, Mei-Jung Lai, Hsueh-Yun Lee
All synthetic compounds (14–29) were tested for their anti-proliferative activity in A549 and HCT116 cells, with SAHA (N1-hydroxy-N8-phenyloctanediamide) or PXD101 ((E)-N-hydroxy-3–(3-(N-phenylsulfamoyl)phenyl)acrylamide) as reference compounds (Table 1)27. Cell line inhibitory results show that halogen-substituted or most aryl/heteroaryl-substituted compounds have similar cellular activity. However, the methoxyphenyl group in 19 and 20 and the 2-cyanophenyl group (21) result in diminished activity. Comparison of 21, 22, and 23 revealed that the cyano group is disfavoured at C2’ of the C3-phenyl group. Among compounds possessing a C3-heteroaryl group, compounds 25 and 26 with pyridine substituents showed improved antiproliferative activity against A549 and HCT116 cells. Compound 25 in particular, inhibits the growth of A549 and HCT116 cells with IC50 values of 1.29 and 1.61 µM, respectively.