Parallel Solid-Phase Synthesis of disubstituted 3-(1H-benzo[d]imidazol-2-yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones

A multistep approach to construct novel 3-(1H-benzo[d]imidazol-2-yl)imidazolidine-2,4-diones and 3-(1H-benzo[d]imidazol-2-yl)-2-thioxoimidazolidin-4-ones from commercially available amino acids, amines, and carboxylic acids is described. Coupling of Fmoc-amino acid to resin-bound aminobenzimidazole provided following Fmoc elimination free amine. Treatment of the free amine with 1,1′-carbonyldiimidazole or 1,1′-thiocarbonyldiimidazole furnished the corresponding hydantoins and thiohydantoins via intramolecular cyclization. The desired aminobenzimidazole tethered hydantoins or thiohydantoins were isolated in good yields.     

Synthesis,characterization and cytotoxic activity of diorganotin (IV) complexes with 4H-pyrido[1,2-a]pyrimidin-4-one derivatives

The coordination behaviour of the diorganotin (IV) compounds R₂SnCl₂ (where R = Me, Ph) with 4H-pyrido [1,2-a] pyrimidin-4-one derivatives (L) has been described. The complexes R₂SnCl₂ · L obtained have been characterized physicochemically and spectroscopically. The pyrimidin-4-one ligands were found to coordinate with R₂SnCl₂ species in a monodentate fashion, mainly via the oxygen atom of the 4-one group or possibly via the nitrogen atom of the (SINGLE BOND)C(DOUBLE BOND)N linkage (the less sterically hindered nitrogen of the pyrimidine derivative) to give pentacoordinate tin complexes. Of the complexes selected to be screened against five tumour cell lines, some exhibited significant in vitro activity.     

Derivatives of benzo[4,5]cyclohepta[1,2-b]thiophene. 4. Synthesis of 1-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)-3-alkylaminoazetidines

Thirteen 1-(9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-yl)-3-alkylaminoazetidines 11 have been synthesized in three steps from 4-amino-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene ( 6 ), which was obtained from the reduction of either 4-azido 4 or 4-hydroxyimino 5 derivatives. All the compounds have been evaluated as potential antidepressive agents.     

达比加群酯中间体3-【【【2-{[(4-氰基苯基)氨基]甲基}-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯的合成

以对氨基苯腈为起始原料,经胺化反应制得N-(4-氰基苯基)甘氨酸(4);4与N-[3-氨基-4-(甲基氨基)苯甲酰基]-N-2-吡啶-β-丙氨酸乙酯(5)经酰胺化后经闭环反应,合成了达比加群酯的关键中间体——3-【【【2-{[(4-氰基苯基)氨基]甲基}-1-甲基-1H-苯并咪唑-5-基】羰基】(吡啶-2-基)氨基】丙酸乙酯,总收率79.6%,其结构经~1H NMR和ESI-MS确证。     

Polyethylene glycol (PEG-400): an efficient green reaction medium for the synthesis of benzo[4,5]imidazo[1,2-a]-pyrimido[4,5-d]pyrimidin-4(1H)-ones under catalyst-free conditions

A simple and an efficient eco-friendly methodology has been developed for the synthesis of benzo[4,5]imidazo[1,2-a]-pyrimido[4,5-d]pyrimidin-4(1H)-ones in excellent yields under catalyst-free-conditions using inexpensive and non-toxic polyethylene glycol (PEG-400) medium. This new protocol offers an environmental acceptability, shorter reaction time, room temperature, low cost, high yields, and recyclability of the PEG-400 medium are the important features. This method provides a green and much improved protocol over the existing methods.     

Synthesis,Crystal Structure and Luminescent Property of Cadmium Complex Based on 2-（2-（1Hbenzo[d]imidazol-2-yl）benzyl）-1H-benzo[d]-imidazole

The complex [Cd(bbb)Cl2]·DMF·H2O, where bbb is 2-(2-(1H-benzo[d]imidazol-2-yl)benzyl)-1H-benzo[d]imidazole, was synthesized and characterized by X-ray single-crystal structure analyses. For the complex: C24H25Cl2CdN5O2, Mr = 598.77, crystal system, triclinic, space group P1, a = 9.9878(12), b = 10.0008(12), c = 13.2217(15) , α = 80.674(2), β = 72.158(2), γ = 86.776(2)°, V = 1240.5(3) 3, Z = 2, Dc = 1.598 g/cm3, λ = 0.71073, μ(MoKα) = 1.127 mm–1, F(000) = 600, S = 1.04, R = 0.0905 and wR = 0.3088 for 4805 observed reflections with I 2σ(I). It is a neutral complex. The distorted tetrahedral geometry of cadmium ion is coordinated by two nitrogen atoms of ligand and two chloride ions. The complex emits blue green luminescence with emission peaks at 480 nm in DMF solution.     

Synthesis and herbicidal activity of novel 6-arylthio-3-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones

A series of pyrazolo[3,4-d]pyrimidine-4-one derivatives was conveniently synthesized via tandem aza-Wittig and annulation reactions of the corresponding iminophosphoranes, arylisocyanate, and substituted thiophenols. The structures of the target compounds were confirmed by IR, ¹H NMR, ¹³C NMR, LC-MS, and elemental analysis. The preliminary bioassay demonstrated that some title compounds such as 6-(3-chlorophenylthio)-1-phenyl-3-methylthio-5-(4-chlorophenyl)-1H-pyrazolo[3,4-d]-pyrimidin-4(5H)-one and 6-(4-fluorophenylthio)-1-phenyl-3-methylthio-5-(3-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one showed good inhibition activities against the root of Brassica napus (rape) and Echinochloa crusgalli (barnyard grass) at a dosage of 100 mg/L.     

Synthesis and Crystal Structure of 1-（4-Fluorophenyl）-2-hexylthiobenzo[4,5]-furo[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-5（1H）-one

The crystal structure of the title compound 1-(4-fluorophenyl) -2-hexylthio-benzo [4,5]furo[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidin-5(1H) -one(C23H21FN4O2S,Mr = 436.5) has been prepared and determined by single-crystal X-ray diffraction. The crystal is of monoclinic,space group P21/n with a = 13.9854(3) ,b = 17.2678(4) ,c = 18.1828(5) ,β = 99.364(2) °,V = 4332.58(18) 3,Z = 4,Dc = 1.338,F(000) =1824,μ = 0.185 mm-1,MoKa radiation(λ = 0.71073) ,R = 0.0538 and wR = 0.1162 for 4728 observed reflections with I > 2σ(I) . X-ray diffraction analysis reveals the fused rings of benzo[4,5]furo[3,2-d]-1,2,4-triazolo[1,5-a] pyrimidin-5(1H) -one system are nearly coplanar. The crystal packing is mainly stabilized by weak intermolecular C-H···O hydrogen bond and π-π interactions.     

Microwave-assisted one-pot synthesis of benzo[b][1,4]thiazin-3(4H)-ones via Smiles rearrangement

The synthesis of benzo[b][1,4]thiazin-3(4H)-one derivatives in a simple and efficient method from the one-pot reaction of substituted 2-chlorobenzenthiols, chloroacetyl chloride, and primary amines via Smiles rearrangement under microwave irradiation gave high yields (65-92%) of the products with short reaction time (15-20 min).     

Efficient Synthesis of 6-(1H-1,2,4-Triazol-1-yl)-thieno[2,3-d]pyrimidin-4(3H)-ones via an Iminophosphorane

Ethyl 2-amino-4-methyl-5-(1H-1,2,4-triazol-1-yl)thiophene-3-carboxylate 2, obtained from Gewald reaction of 1-(1H-1,2,4-triazol-1-yl)acetone 1 with ethyl cyanoacetate and sulfur, was transferred into iminophosphorane 3. Further reaction of 3 with aromatic isocyanates gave carbodiimides 4, which were treated subsequently with a secondary amine to give 6-(1H-1,2,4-triazol-1-yl)-thieno[2,3-d]pyrimidin-4(3H)-ones 6 in good yields in the presence of a catalytic amount of sodium ethoxide.     

Pd(II)-Catalyzed Benzimidazole-Assisted Annulation of 3-(1H-Benzo[d]imidazol-2-yl)-2H-chromen-2-one: Access to Imidazo[1,2-a]chromeno[3,4-c]pyridine

Palladium-catalyzed [4+2] oxidative annulation of coumarin-benzimidazoles with olefins for the synthesis of polycyclic aromatic hydrocarbons have been achieved. This synthetic protocol gives access to a wide range of structurally distinct imidazo[1,2-a]chromeno[3,4-c]pyridines in moderate to good yield with wide functional group tolerance. Further, photophysical properties of annulated scaffolds have been examined, which discloses their interesting solvatochromic emission behaviors.     

Condensed Isoquinolines. 16. Enamine Properties of Benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-one in Terms of Its Acylation Reactions

A study has shown that the acylation of benzo[4,5]imidazol[1,2-b]isoquinolin-11(5H)-one occurs at N₍₅₎ or at C₍₆₎ depending on the nature of the acylating reagent and the reaction conditions. It was found that principally C-acylation takes place in the absence of base. The reaction with -halo-substituted carboxylic acid chlorides leads to the formation of C-acylated products which are converted to derivatives of the novel heterocyclic system 7H-2a,6b-diazabenzo[b]cyclopenta[l,m]fluorene-1,7(2H)-dione in the presence of base.     

Synthesis of 1-benzyl-8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H)-one via palladium-catalyzed intramolecular arylation

The synthesis of a novel tetracyclic structure, 8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H)-one, has been achieved by a convergent pathway. Coupling of the weakly nucleophilic hindered aromatic amine with 1-benzylimidazole-4-carboxylic acid, 7, afforded the corresponding amide 9 using a DCP/DMF complex; subsequent Heck-type arylation leading to desired tetracyclic molecule imidazo[4,5-c]-pyrrolo[3,2-g]quinolin-4(5H)-one.     

Mass Spectrometry of 2a, 4-Disubstituted 5-Benzoyl-2a, 3,4,5-tetrahydro-2-phenoxy-azeto [ 1,2-a ] [1,5 ] benzodiazepin - 1 （2H）-ones Under Electron Impact Ionization Conditions

The mass spectrometric fragmentation of 2a, 4-disubstituted 5-benzoyl-2a, 3,4, 5-tetrahydro-2-phenoxy-azeto[1,2-α] [ 1,5 ] benzodiazepin-I (2H)-ones has been investigated by means of mass-analyzed ion kinetic energy spectrometry under electron impact ionization conditions. All compounds tend to lose different moieties, such as phenoxy, phenoxy and H, and phenoxyketene. Both [ M^ - PhO ] and [ M^ - PhOH ] ions could further lose CO, and the [ M^ - PhOCH = C = O] ions could lose propene or styrene, PhCON, PhCOHN, and other fragments.     

Highly sensitive and selective determination of Hg2+ by using 3-((2-(1H-benzo[d]imidazol-2-yl)phenylimino)methyl)benzene-1,2-diol as fluorescent chemosensor and its application in real water sample

A new receptor 3-((2-(1H-benzo[d]imidazol-2-yl)phenylimino)methyl)benzene-1,2-diol (1) was synthesised and developed as a highly selective fluorescent chemosensor for the detection of Hg²⁺ in semi-aqueous media. The fluorescence of receptor 1 was dramatically and selectively quenched on complexation with Hg²⁺ ion with the detection limit down to 0.20 μM. The developed sensor was successfully applied for the determination of Hg²⁺ content in water samples. Density Functional Theory (DFT) calculations were performed to study the mechanistic behaviour behind the binding of Hg²⁺ with receptor 1.     

4-氟苯甲醛、β-萘胺和Meldrum酸一锅反应生成1-(4-氟苯基)-1,2-二氢苯并[f]喹啉-3(4H)-酮的反应机理理论研究

采用密度泛函理论(DFT)研究了4-氟苯甲醛、β-萘胺和Meldrum酸一锅反应生成1-(4-氟苯基)-1,2-二氢苯并[f]喹啉-3(4H)-酮的微观反应机理.在B3LYP/6-311G*基组水平上优化了反应物、过渡态、中间体及产物的几何构型,通过振动分析确认了过渡态的结构,并用内禀反应坐标(IRC)确认反应途径.应用分子中的原子理论(AIM)分析了这些物质的成键特征.采用SCRF(PCM)方法研究了反应体系的溶剂化效应.报道了可能的反应路径,其中Re→TS1→IM1→TS2→IM2→TS3→IM3→TS4→IM5→TS7→IM9→TS13→IM10→TS14→P3具有相对较低的活化能,是反应的主要通道,理论预测的主要产物与实验吻合.     

Atomistic insights into the selective therapeutic activity of 6-(2,4-difluorophenoxy)-5-((ethylmethyl)pyridine-3-yl)-8-methylpyrrolo[1,2-a]pyrazin-1(2H)-one towards bromodomain-containing proteins

Cross-target effect has been one of the major mechanisms of drug toxicity, this has necessitated the design of inhibitors that are specifically tailored to target particular biomolecules. 6-(2,4-difluorophenoxy)-5-((ethylmethyl)pyridine-3-yl)-8-methylpyrrolo[1,2-a] pyrazin-1(2H)-one (Cpd38) is an inhibitor possessing high inhibition rate and tailored specificity towards bromodomain-containing protein 4 (BRD4). In this research, we used an array of computational techniques to provide insight at the atomistic level the specific targeting of BRD4 by Cpd38 relative to the binding of Cpd38 with E1A binding protein P300 (EP300); another bromodomain-containing protein (BCP). Comparatively, binding of Cpd38 improved the conformational stability and compactness of BRD4 protein when compared to the Cpd38 bound EP300. Also, Cpd38 induced a conformational change in the active site of BRD4 that facilitated a complementary pose between Cpd38 and BRD4 suitable for effective atomistic interactions. Expectedly, thermodynamic calculations revealed that the Cpd38-BRD4 system had higher binding energy (−36.11 Kcal/mol) than the Cpd38-EP300 system with a free binding energy of −15.86 Kcal/mol. Noteworthy is the opposing role Trp81 (acting as hydrogen bond acceptor) and Pro1074 (acting as hydrogen bond donor) found on the WPF and LPF loops respectively play in maintaining Cpd38 stability. Furthermore, the hydrogen bond acceptor/donator ratio was approximately 4:1 in Cpd38-BRD4 system compared with 2:1 in Cpd38-EP300 system. Taken together, atomistic insights and structural perspectives detailed in this report supplements the experimental report supporting the improved selectivity of Cpd38 for BRD4 ahead of other BCPs while providing leeway for the future design of BET selective agents with better pharmacological profile.