29277-45-0Relevant academic research and scientific papers
Contribution of Solvents to Geometrical Preference in the Z/ E Equilibrium of N-Phenylthioacetamide
Song, Shuyi,Hyodo, Tadashi,Ikeda, Hirotaka,Vu, Kim Anh L.,Tang, Yulan,Chan, Erika S.,Otani, Yuko,Inagaki, Satoshi,Yamaguchi, Kentaro,Ohwada, Tomohiko
, p. 1641 - 1660 (2021/06/28)
We studied the Z/E preference of N-phenylthioacetamide (thioacetanilide) derivatives in various solvents by means of 1H NMR spectroscopy, as well as molecular dynamics (MD) and other computational analyses. Our experimental results indicate that the Z/E isomer preference of secondary (NH)thioamides of N-phenylthioacetamides shows substantial solvent dependency, whereas the corresponding amides do not show solvent dependency of the Z/E isomer ratios. Detailed study of the solvent effects based on molecular dynamics simulations revealed that there are two main modes of hydrogen (H)-bond formation between solvent and (NH)thioacetamide, which influence the Z/E isomer preference of (NH)thioamides. DFT calculations of NH-thioamide in the presence of one or two explicit solvent molecules in the continuum solvent model can effectively mimic the solvation by multiple solvent molecules surrounding the thioamide in MD simulations and shed light on the precise nature of the interactions between thioamide and solvent. Orbital interaction analysis showed that, counterintuitively, the Z/E preference of NH-thioacetamides is mainly determined by steric repulsion, while that of sterically congested N-methylthioacetamides is mainly determined by thioamide conjugation.
1,4-Dihydropyridines as Antagonists of Platelet Activating Factor. 1. Synthesis and Structure-Activity Relationships of 2-(4-Heterocyclyl)phenyl Derivatives
Cooper, Kelvin,Fray, M. Jonathan,Parry, M. John,Richardson, Kenneth,Steele, John
, p. 3115 - 3129 (2007/10/02)
A novel class of 2-(4-heterocyclylphenyl)-1,4-dihydropyridines (2-38) possessing antagonist activity against platelet activating factor (PAF) was prepared by the Hantzsch synthesis from a variety of ethyl 4'-heterocyclic-substituted benzoylacetates, aryl or heteroaryl aldehydes, and substituted 3-aminocrotonamides or 3-aminocrotonate esters.Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit the PAF-induced aggregation of rabbit washed platelets,and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF.The nature of the substituent at the dihydropyridine 2-position was found to be important for both in vitro and in vivo activity, whereas there was greater flexibility for structural variation at the 4- and 5-positions.The most potent compound was 4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl-2-pyrid-1-yl)phenyl>-5-pyridine (17, UK-74,505), IC50 = 4.3 nM, ED50 = 0.26 mg/kg po, which was found to be approximately 33 times more potent in vitro (rabbit platelet aggregation) and about 8 times more potent in vivo (murine lethality) than WEB2086.Compound 17 also exhibited a long duration of action in the dog (inhibition of PAF-induced whole blood aggregation ex vivo was maintained for > 24 h following a single oral dose of 75 μg/kg) and was highly selective as a PAF antagonist, showing only weak affinity (IC50 = 6600 nM) for the nitrendipine binding site.As a result of its high oral potency, selectivity, and duration of action, UK-74,505 has been selected for clinical evaluation.
