Human chymase is a very important target for the treatment of cardiovascular diseases. Using a series of theoretical methods like pharmacophore modeling, database screening, molecular docking and Density Functional Theory (DFT) calculations, an investigation for identification of novel chymase inhibitors, and to specify the key factors crucial for the binding and interaction between chymase and inhibitors is performed. A highly correlating (r = 0.942) pharmacophore model (Hypo1) with two hydrogen bond acceptors, and three hydrophobic aromatic features is generated. After successfully validating “Hypo1”, it is further applied in database screening. Hit compounds are subjected to various drug-like filtrations and molecular docking studies. Finally, three structurally diverse compounds with high GOLD fitness scores and interactions with key active site amino acids are identified as potent chymase hits. Moreover, DFT study is performed which confirms very clear trends between electronic properties and inhibitory activity (IC50) data thus successfully validating “Hypo1” by DFT method. Therefore, this research exertion can be helpful in the development of new potent hits for chymase. In addition, the combinational use of docking, orbital energies and molecular electrostatic potential analysis is also demonstrated as a good endeavor to gain an insight into the interaction between chymase and inhibitors.

The characteristic fluorescence properties of quercetin-3-O-rhamnoside (QCRM) and quercetin-3-O-rutinoside (QCRT) were studied in CH3OH-H2O and CH3CN-H2O mixed solvents. Although QCRM and QCRT are known as nonfluorescent molecules, significant fluorescence emissions were discovered at 360 nm in CH3OH and CH3CN when they were promoted to the second excited state. The emission band is broad and structureless and the intensity decreases quickly as the H2O composition in the solvent increases. When the amount of H2O exceeds 60% in both mixed solvents, this emission disappears due to the formation of the distorted excited state. This state will be formed due to the strong intermolecular hydrogen bonding between the polar groups of solute and H2O. As the composition of CH3OH or CH3CN in solvent becomes large, the number of molecules having several intramolecular hydrogen bonding increases. Some of these molecules will be changed to a fluorescent species during the decay process, after excitation. The theoretical calculation further supports these results. The change of the lifetimes, quantum yields, and radiative and nonradiative rate constants of molecules was also examined as a function of solvatochromic parameters for CH3OH-H2O and CH3CN-H2O.

This work describes acylation reactions facilitated by at ype of heterocycle-based acyl transfer agent, 2-acyloxypyridazinone.R eactions of 2-acyloxypyridazinone with carboxylic acids yield mixed carbonic anhydride intermediates,w hich are reactive and couldb ec oupled with aw ide range of substrates including acids,a mines,a lcohols,a nd thiols.T he wide substrate scope,e ase of operation (no additive or catalyst), storage and handling stability,a nd atom-efficiency from recycling the heterocycle carrierm ake the reported acylating agent attractive for acylation-basedcoupling reactions.Keywords: 2-alkoxycarbonylpyridazin-3(2H)-ones; acylating agents;c oupling reactions;h eterocycles; mixed carbonic anhydrides Acylation is one of the most widelyu seds ynthetic processesf or functional group transformation,e .g.,t o produce amides from amines and esters from alcohols.[1] Owing to the widespread use of acylation in various areas, including pharmaceuticals, [2] synthetic polymers, [3] and functional molecular materials, [4] significante ffort has gone into developing acylating agents suitable for individual applications.[5] Although there have been advances in acylation processes, existing methods [5b] have inherentl imits in termso fs ubstrate scope,a tom-efficiency,h arsh reactionc onditions,a nd/or the necessityo fcatalysts or additives. Thedevelopment of an acylation systemwith easy operationa nd universal substrate scope remains challenging.An optimum acylation systemm ust meet at least the following criteria:( i) ab road substrate scope,i .e., an acylating agent not limited to primary amines,o ne of the most widelys tudied functional groups in acylation, but one applicable to aw ide range of functional groups including alcohols andt hiols;( ii)t he ability to operate without catalysts and/or additives;( iii)t he ability to enhance atomicefficiency by recycling of reagents;a nd (iv) ease of handling and storage under ambient conditions.H erein, we report an acylating agent based on ah eterocycle,4 ,5-dichloropyridazin-3(2H)-one (DCPN), that meets the abovefourcriteria (Figure 1). Thep yridazinone-based acylating agent facilitated coupling reactions via acylation under neutral conditions without catalysts anda dditives,a nd more interestingly,e xhibited aw ide substrate scope (amines,a lcohols,c arboxylica cids andt hiols). The coupling reactions proceeded throught he formation of an asymmetric carbonic anhydride,w hich was ar eactive intermediate,f ollowed by addition of the substrate to one of the carbonyl carbons in the anhydride.T he pyridazinone carrier, ab y-product formed upon completion of the reaction, is quantitatively isolable through extraction with basic aqueous solution (20 wt% NaOH) or, at least in part, through recrystallization after completion of the reaction. Thee ase and simplicity of isolatingt he by-product from the reaction solution maket he acyloxypyridazinonea na ttractivea cylating agent for av ariety of synthetic applications.Ac entral idea of this work was to utilize 2-acyl...

Abstract:The geometric structures of Pd-complexes {Pd ([9]aneB 2 A)L 2 and Pd ([9]aneBAB)L 2 where A = P, S; B = N; L = PH 3 , P(CH 3 ) 3 , Cl − }, their selective orbital interaction towards equatorial or axial (soft A…Pd) coordination of macrocyclic [9]aneB 2 A tridentate to PdL 2 , and electron density transfer from the electron-rich trans L-ligand to the low-lying unfilled a 1g (5s)-orbital of PdL 2 were investigated using B3P86/lanl2DZ for Pd and 6-311+G** for other atoms. The pentacoordinate endo- [Pd([9]complex with an axial (soft A--Pd) quasi-bond was optimized for stability. The fifth (soft A--Pd) quasi-bond between the σ-donor of soft A and the partially unfilled a 1g (5s)-orbital of PdL 2 was formed. The pentacoordinate endo-Pd ([9]aneB 2 A)(L-donor) 2 ] 2+ complex has been found to be more stable than the corresponding tetracoordinate endo-Pd complexes. Except for the endo-Pd pentacoordinates, the tetracoordinate Pd([9]aneBAB)L 2 complex with one equatorial (soft A-Pd) bond is found to be more stable than the Pd([9]aneB 2 A)L 2 isomer without the equatorial (A-Pd) bond. In particular, the geometric configuration of endo- [Pd([9]anePNP)(L-donor) 2 ] 2+ could not be optimized.

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