Ethyl Chloroacetate Research Articles

Synthesis of some novel 3,4,5-trisubstituted triazole derivatives bearing quinoline ring and evaluation of their antimicrobial activity

Some new 3,4,5-trisubstituted 1,2,4-triazole derivatives were synthesized and studied for their antimicrobial activity. The lead compounds were obtained starting from 8-hydroxyquinoline and ethyl 2-chloroacetate. The obtained ester compound (1) first reacted with hydrazine hydrate (2) then with phenyl isothiocyanate (3). Ring closure by KOH led to 3-mercapto-1,2,4-triazole derivative (4). Lastly, it reacted with 2-chloro-N-(substituted (benzo)/thiazole)acetamide derivatives to obtain the final compounds (5a–j). The structural elucidation of the compounds was performed by 1H NMR and 13C NMR spectroscopy and high resolution mass spectrometry techniques and elemental analysis. The synthesized compounds were investigated for their antimicrobial activities against seven bacteria and four fungi. As a result of the activity studies, it was observed that compounds N-(6-nitrobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5a) and N-(6-fluorobenzothiazol-2-yl)-2-[[4-phenyl-5-((quinolin-8-yloxy)methyl)-4H-1,2,4-triazol-3-yl]thio]acetamide (5d) were the most active molecules. Also, the antifungal activity of the compounds was found to be higher than their antibacterial activity although lower than the standard drug’s potential. Additionally, the physicochemical properties of the compounds were calculated which were evaluated to be at a suitable range for oral administration.

Synthesis and structure of ethyl 2-[(4-oxo-3-phenyl-3,4-di-hydro-quinazolin-2-yl)sulfan-yl]acetate.

The title compound, C18H16N2O3S, was synthesized by reaction of 2-mercapto-3-phenyl-quinazolin-4(3H)-one with ethyl chloro-acetate. The quinazoline ring forms a dihedral angle of 86.83 (5)° with the phenyl ring. The terminal methyl group is disordered by a rotation of about 60° in a 0.531 (13): 0.469 (13) ratio. In the crystal, C-H⋯O hydrogen-bonding inter-actions result in the formation of columns running in the [010] direction. Two parallel columns further inter-act by C-H⋯O hydrogen bonds. The most important contributions to the surface contacts are from H⋯H (48.4%), C⋯H/H⋯C (21.5%) and O⋯H/H⋯O (18.7%) inter-actions, as concluded from a Hirshfeld analysis.

Design, synthesis, characterization and biological evaluation of Thieno[2,3−b]pyridines−chitosan nanocomposites as drug delivery systems for colon targeting

Thieno[2,3−b]pyridine derivatives DATPa−c have been synthesized based on Thorpe−Ziegler Cyclization. The reaction of arylidene malononitrile derivatives (Ia−c) with thiocyanoacetamide (II) in basic medium (piperidine) followed by alkylation using ethyl chloroacetate and finally, cyclization in sodium ethoxide yielded DATPa−c. Thieno[2,3−b]pyridine−chitosan nanocomposites CS−DATPa−c were prepared from the DATPa−c and CS nanoparticles using sodium tripolyphosphate (TPP). CS−DATPa−c nanocomposites were characterized using FTIR, TEM and XRD techniques and showed a relatively narrow size distribution of monodispersed nanoparticles with the average size of 14–78 nm. The in vitro release studies of CS−DAΤPa−c nanocomposites were investigated and showed that the drug release rate is pH-dependent and the trend is as follows: basic > neutral > acidic. The faster release rate in basic medium effectively prolongs drug delivery in gastric pH. Additionally, the antibacterial investigation showed that DATPa−c and CS−DATPa−c nanocomposites exhibited antibacterial activity against both Gram-positive and Gram-negative bacteria but CS−DATPa−c nanocomposites showed much higher antibacterial activity compared to the DATPa−c, which in agreement with the particle size measurements as DATPa−c are in the bulky structure whereas, CS−DATPa−c are in the nanostructure. The results may have applications of drug design for colon targeting.

Synthesis, Molecular Modeling of Novel Substituted Pyridazinones and their Vasorelaxant Activities.

Hypertension, one of the most common cardiovascular diseases that can cause coronary disease, stroke, myocardial infarction, and sudden death, it is the major contributor to cardiac failure as well as renal insufficiency. As there are many cardio-active pyridazinone-base derivatives in clinical use, therefore, we aimed to synthesize a new series of pyridazin-3-ones and evaluate their vasorelaxant activity. A new series of synthesized compounds were carried out first by the synthesis of 6- flouroarylpyridazinones by cyclization of 3-(4-flourobenzoyl) propionic acid with hydrazine hydrate or arylhydrazines to provide the corresponding pyridazinone derivatives 2a-d. Mannich reaction was performed using morpholine or piperidine formaldehyde to obtain compounds 3a,b. On the other hand, reaction of 2a with various chloroacetamide intermediates, in dimethylformamide and potassium carbonate as a catalyst, afforded the target compounds 5a-c. The aromatic acid hydrazide intermediates 6a-g were prepared in 50-90% yield, by reacting to the prepared esters with hydrazine hydrate under reflux in ethanol. The two compounds 8a,b were prepared via condensation of 7a,b with ethyl chloroacetate in dry acetone. Finally, the target 2,4,6-trisubstituted pyridazinones 9a-c derivatives were obtained by the reaction of 7a with the appropriate aromatic aldehyde or substituted acetophenones. The new compounds were then evaluated for their vasorelaxant properties using isolated thoracic rat aortic rings. In addition, a homology model was built and molecular modeling simulation of these compounds into the active sites of the newly created α1a-adrenoceptor model was performed in order to predict and rationalize their affinities toward this receptor. Among these compounds; 5a was the most potent, it exhibited approximately two-times the activity of prazosin (IC50 = 0.250, 0.487 mmol, respectively) also, fourteen compounds were more potent than prazosin.

Synthesis, DFT study, molecular docking and insecticidal evaluation of some pyrazole-based tetrahydropyrimidine derivatives

The building block synthon, 1-(4-(1,3-diphenyl-1H-pyrazol-4-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)ethan-1-one was efficiently synthesized by Biginelli reaction of 1,3-diphenyl-1H-pyrazole-4-carbaldehdye, acetylacetone, and thiourea and submitted to react with ethyl chloroacetate and chloroacetyl chloride under different conditions to afford some N-heterocycles integrated with pyrazole scaffold. Hydrazinolysis of the pyrimidinethione was studied under different conditions. The insecticidal activity for these compounds, DFT calculations, and docking were run and discussed. Some of them exhibited 100% mortality against Nilaparvata lugens and Mythimna separata.

Synthesis of new uracil derivatives and their sugar hydrazones with potent antimicrobial, antioxidant and anticancer activities

6-(4-Chloro-3-nitrophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (4) was prepared and was reacted with ethyl chloroacetate, hydrazine hydrate, 4-chloroaniline, formaldehyde, acetic anhydride, formic acid, carbon disulfide, 4-cyanobenzaldehyde, triethyl orthoformate, D-sugars, 4-aminoacetophenone, benzoyl choride and cyclohexanone to afford a series of new uracil derivatives (5–18). Examination of some of the prepared compounds for their antimicrobial, antioxidant and anticancer activities was conducted. Among the tested samples, compound 17 was the most active substance against the gram-positive bacteria and was more potent than the reference drug Cefoperazone. Moreover, the antibacterial activity of 17 was higher against gram-negative bacteria. Compounds 6 and 13 reached a higher scavenging ability toward DPPH radicals and are better candidates for antioxidant activity. Also, compounds 6 and 13 had no significant anticancer activity toward liver cancer (Hep G2) and breast cancer (MCF-7) cell lines.

Synthesis and fluorescent properties of some Furan‐tagged Thieno[2,3‐d]pyrimidines and Thieno[2,3‐d:4,5‐d']dipyrimidines

AbstractIntermolecular cyclization of pyrimidinethiol 1 with ethyl chloroacetate and chloroacetonitrile furnished thieno[2,3‐d]pyrimidines 2a,b. Hydrazinolysis of o‐aminoester 2a gave acid hydrazide 3, which was cyclized with various electrophilic reagents including formic acid, triethyl orthoformate, acetic anhydride, p‐chlorobenzaldehyde then triethyl orthoformate, carbon disulfide, and acetylacetone affording thienopyrimidine derivatives 4 to 10. Another thienopyrimidine series could be obtained via treatment of o‐aminocarbonitrile 2b with a variety of reagents giving derivatives 11 to 17. The fluorescent measurements for a group of the synthesized compounds at room temperature demonstrated high fluorescent properties.

Discovery of hydrazide-based pyridazino[4,5-b]indole scaffold as a new phosphoinositide 3-kinase (PI3K) inhibitor for breast cancer therapy.

Herein, the mono and dialkylation of pyridazino[4,5-b]indole were achieved with a set of alkylating agents, including amyl bromide, allyl bromide, benzyl bromide and ethyl chloroacetate in the presence of K2CO3/acetone or KOH/DMSO. The hydrazinolysis of mono and di-esters 10 and 11 gave the target hydrazides 12 and 13, which displayed promising, potent, and significant cytotoxic activity against the MCF-7 cell line with IC50 values of 4.25 and 5.35 μm compared to that of the standard drug 5-FU (IC50 6.98 μm), respectively. RT-PCR analysis of the most active compound 12 was performed to determine its mode of action through the up-regulation of pro-apoptotic genes and inhibition of anti-apoptotic and PI3K/AKT/mTOR genes. The findings were consistent with the proposed mechanism illustrated in the in silico study. Further, the in vivo analysis exhibited its potent anti-cancer activity through the prolongation of survival parameters, and inhibition of ascetic fluid parameters in EAC-bearing mice.

Reaction of a 3-aryilidene-2-thiohydantoin derivative with polymeric trans-[CuCl2(DMSO)2]n complex: Unexpected isomerization to dinuclear cis-[{CuCl(DMSO)2}(μ-Cl)

The 3-arylidene-2-thiohydantoin derivative, 3-[(2-hydroxybenzylidene) amino]-2-thioxoimidazolidin-4-one, was synthesized in a two-step condensation reaction of 2-hydroxybenzaldehyde, thiosemicarbazide and ethyl chloroacetate. The ligand was structurally characterized by NMR and IR spectroscopy, as well as by elemental analysis. In the reaction of the well-known polymeric trans-[CuCl2(DMSO)2]n complex with the polydentate thiohydantoin type ligand, instead of the corresponding copper thiohydantoin complex, unexpectedly, the dinuclear cis-[{CuCl(DMSO)2}(?-Cl)]2 complex (1) was formed predominantly as the final stable product. The structure of the complex 1 was confirmed by single crystal X-ray diffraction analysis. The cis-complex is obtained through assisted isomerization of the trans-form, in which the thiohydantoin derivative has a crucial role.

Synthesis, antioxidant, anticoagulant, and fibrinolytic activities of new isatin derivative

Background Isatin as a product was first obtained from the oxidation of indigo dye by nitric acid and chromic acids by Otto Linne Erdman and Auguste Laurent in 1841. Objective This study presents the synthesis of some new isatin derivatives and examines their biological activities. Materials and methods 2-Cyano-N’-(5-nitro-2-oxoindolin-3-ylidene)acetohydrazide (2) reacted with some reagents, namely, salicylaldehyde, phenyl isothiocyanate, ethyl chloroacetate, ethyl iodide, ethyl cyanoacetate, thioglycolic acid, phenyl isothiocyanate, malononitrile, and hydrazine hydrate to produce compounds 3, 4, 5, 6, 8, 9, 10, 11, and 12, respectively. Moreover, compound 6 reacted with hydrazine hydrate to produce compound 7. Antimicrobial activities of some newly synthesized compounds were studied. Results Antioxidant, anticoagulant, and fibrinolytic activities of the new synthesized compounds (1–12) were studied. Compound 10 exhibited highest fibrinolytic activity. On the contrary, compound 12 exhibited highest anticoagulant activities. Moreover, it was noticed that compound 9 exhibited highest antioxidant activity. Conclusion In summary, 14 novel isatin derivatives were synthesized and screened for their antioxidant, anticoagulant, and fibrinolytic activities. Some compounds displayed moderate-to-excellent activities such as antioxidant, anticoagulant, and fibrinolytic agents.

2-Mercaptobenzimidazole Derivatives as Novel Butyrylcholinesterase Inhibitors: Biology-Oriented Drug Synthesis (BIODS), In-Vitro and In-Silico Evaluation

Schiff bases gaining remarkable importance day by day in the current situation Schiff bases are found to be a valuable pharmacophore for the synthesis and development of various biologically active heterocyclic compounds. In recent past, we have reported various classes of compounds as enzyme inhibitors, in continuation; A series of 2-Mercaptobenzimidazole hydrazone derivatives (9-42) were synthesized through multistep reactions in high yields and evaluated for butyrylcholinesterase inhibition. In present study, 2-ethylthio benzimidazole was formed by the reaction of 2-Mercaptobenzimidazole with bromoethane. In the second step (2-(2-(ethylthio)benzimidazolyl)acetate) obtained by the reaction of 2-ethylthio benzimidazole with ethyl chloroacetate. In the third step, 2-(2-(ethylthio)benzimidazolyl)acetate was refluxed in methanol with hydrazine hydrate and get 2-((ethylthio)benzimidazolyl)acetohyrazide. In the last step, 2-((ethylthio)benzimidazolyl)acetohyrazide was reacted with different aldehydes in the presence of glacial acetic acid (catalyst) to get a series of 2-Mercaptobenzimidazole hydrazone derivatives. Product was characterized by 1H NMR and 13C NMR. These newly synthesized compounds showed varying degree of butyrylcholinesterase inhibition. Compound no. 15 with (IC50 = 25.10 and#177; 0.90 and#181;M) was found to be most active in the whole series. Similarly, compounds 42, 12, 40, 17, 22, 28 and 09 exhibited excellent activity with IC50 values are (IC50 = 25.36 and#177; 0.57 and#181;M, IC50 = 27.30 and#177; 0.52 and#181;M, IC50 = 34.31 and#177; 0.59 and#181;M, IC50 = 51.29 and#177; 0.64 and#181;M, IC50 = 54.52 and#177; 0.95 and#181;M, IC50 = 57.90 and#177; 0.45 and#181;M and IC50 = 60.93 and#177;0.67 and#181;M) respectively as compared to standard galantamine 18.13and#177;0.20 and#181;M. Molecular docking helped to find interactions between butyrylcholinesterase enzyme and test compounds. This study results that Schiff bases have been discovered a new class of butyrylcholinesterase inhibitors which have not been discovered earlier.

Synthesis and Antimicrobial Activity of Novel Piperidinyl Tetrahydrothieno[2,3-c]isoquinolines and Related Heterocycles.

A novel series of 1-amino-2-substituted-5-piperidinyl-6,7,8,9-tertahydrothieno[2,3-c]isoquinolines (4a–e) was synthesized upon treatment of 4-cyano-1-piperidinyl-5,6,7,8-tetrahydroisoquinline-3(2H)-thione (2) with α-halo carbonyl compounds such as chloroacetone, ethyl chloroacetate, 2-bromoacetophenone, chloroacetamide, and chloroacetanilide. Construction the pyrrolyl ring associated with the thienotetrahydroisoquinoline moiety was achieved by treatment of compounds 4a, b with 2,5-dimethoxytertahydrofuran in acetic acid. 1-Pyrrolyl-2-substituted-thieno[2,3-c]isoquinolines 5a and 5b which in turn were used as multipurpose precursors for synthesis of other new heterocycles. Assignments of the chemical structures of the respectively synthesized thienotetrahydroisoquinolines and their derivatives were established on the bases of elemental and spectral techniques (Fourier transform infrared, 1H NMR, 13C NMR, and mass spectroscopy). Furthermore, certain compounds were screened for their antimicrobial activity which revealed promising activities against various pathogenic strains of bacteria and fungi.

Synthesis of Potentially Biologically Active Fused Polyheterocycles Containing a Pyrimidine Unit

A number of new fused polyheterocyclic compounds were synthesized on the basis of 2-amino-6-sulfanylpyrirnidin-4(3H)-one. In particular, reactions of 2-amino-6-suffanylpyrirnidin-4(3H)-one with cinnamic acids, aroyl isothiocyanate, and acetic anhydride afforded imidazo[1,2-a]thieno[2,3-d]pyrimidine, [1,3]thiazino[6′,5′: 4,5]pyrimido[1,2-a][1,3,5]triazine, and imidazo[1,2-a]tWeno[2,3-d]pyrimidine derivatives, respectively. The alkylation of 2-amino-6-smfanylpyrirnidin-4(3H)-one with benzyl chloride gave 3-benzyl-6-(benzylsulfanyl)-2-imino-2,5-dihydropyrimidin-4(3H)-one which was converted to [1,3]thiazolo[5,4-d][1,2,4]triazolo-[4,3-a]pyrimidine, imidazo[1,2-a]pyrimidine, dihydropyrimido[4,5-b]quinoline, imidazo[1,2-a]pyrrolo[2,3-d]-pyrimidine, and benzo[g]imidazo[2,1-b]pteridine derivatives via reactions with nitrous acid, ethyl chloroacetate, and aniline (followed by treatment with carbon disulfide, cinnamic acid, or sodium nitrite in acetic acid). 2-Amino-3,4-dihydropyrimidin-6-sulfonic acid was obtained by oxidation of the same substrate with hydrogen peroxide in alkaline medium. Some of the synthesized compounds showed antimicrobial activity.

Synthesis and Antimicrobial Screening of Novel Azetidin-2-ones Derived from Pyromellitic Diimide via [2+2]-Cycloaddition Reaction

A series of novel 2-azetidinone derivatives have been obtained starting from pyromellitic dianhydride. Pyromellitic dianhydride was converted to pyromellitic diimide using sodium cyanate, and the diimide was alkylated with ethyl chloroacetate. The resulting diester was treated with hydrazine hydrate to obtain dihydrazide which reacted with substituted pyridine-2-carbaldehydes to give the corresponding Schiff bases, and [2+2]-cycloaddition of the latter with chloroacetyl chloride in the presence of triethylamine afforded the target azetidin-2-one derivatives. The newly synthesized compounds showed high antimicrobial activities against some bacterial and fungal strains.

Synthesis of Novel 2-(N-Substituted)imino-2,5-dihydrofuran-3-carboxamides Containing a Thiourea Residue and an Oxothiazolidinylidene Ring

Novel derivatives of 2-imino-2,5-dihydrofuran-3-carboxamides containing a thiourea residue have been synthesized by the reaction of 2-imino-2,5-dihydrofuran-3-carboxamides with thiosemicarbazide in glacial acetic acid. The synthesized N-substituted iminodihydrofurans have been condensed with ethyl chloroacetate to obtain novel derivatives of iminodihydrofurans containing an oxothiazolidinylidene ring. These methods open up new synthetic approaches to previously unknown systems containing iminodihydrofuran, thiourea and oxothiazolidinylidene fragments.

Synthesis and characterization of some novel bis‐thiazoles

AbstractThe bis‐thiosemicarbazone derivative 3 was prepared and reacted with N‐aryl‐2‐oxopropane hydrazonoyl chloride 4a‐g and ethyl (N‐arylhydrazono)chloroacetate 7a‐e in absolute ethanol in the presence of triethylamine at reflux afforded a new series of thiazoles 6a‐g and 9a‐e, respectively. Also, thiosemicarbazone derivative 3 was reacted with N′‐phenylbenzohydrazonoyl chloride 10 to give the respective bis‐thiadiazole derivative 12. Moreover, the reaction of 3 with a number of haloketones and haloesters furnished the respective bis‐thiazole derivatives 14, 16, 18, and 20. The mechanisms that account for formation of products 6, 9, and 12 were discussed. Also, the molecular structure of the synthesized compounds was illustrated by spectroscopic and elemental analysis.

One pot synthesis of ethyl carboxylate and acetyl selenolo[2,3-b]quinoline derivatives and their tetra/pentacyclic systems

Ethylcarboxylate and acetyl selenoloquinoline derivatives were prepared in a one pot synthesis via reaction of sodium hydrogen selenide and 2-chloro-3-cyano-4-methylquinoline followed by reactions with ethyl chloroacetate and chloro acetone respectively which used as precursors to synthesize many of tetra and pentacyclic systems. A new series of pyrimido [4′,5′:4,5]selenolo[2,3-b]quinoline, thiazino[2’,3’:4,5]selenolo[2,3-b]quinoline, oxazino[2',3':4,5]selenolo[3,2-b]quinoline, pyrido[2′,3′:4,5]selenolo[2,3-b]quinoline, pyrido[2′,3′:4,5]selenolo[2,3-b]quinoline-2-substituted selenyl and selenolo[2′,3′:5,6]pyrido[2″,3″:4,5]selenolo[2,3-b]quinoline derivatives were prepared. Elemental analysis, IR, 1H NMR, 13C NMR and mass spectra confirmed the structures of the newly synthesized compounds.

The transition state conformational effect on the activation energy of ethyl acetate neutral hydrolysis

We report a first-principles study on ethyl acetate neutral hydrolysis in which we focus on the activation energy variation resulting from the conformational effect in the transition state. We use the conformers of ethyl formate, ethyl acetate, ethyl fluoroacetate, and ethyl chloroacetate as the ester models and one water molecule with a one-step reaction mechanism. We also consider the long-range interaction and the surrounding water in the form of PCM. Our results show that the various conformers yield a significant range of activation energy. Moreover, the gauche conformer has lower activation energy than the trans conformer. The activation energy in its own right is lowered by the halogen atoms. Finally, we remark that the long-range correction and PCM stabilize the transition state geometry but raise the activation energy.

Alkylation of 5,5-Substituted N-[4-Methyl-3-phenylfuran-2(5H)-ylidene]-N′-phenylthioureas

The alkylation of 5,5-disubstituted N-[4-methyl-3-phenylfuran-2(5H)-ylidene]-N′-phenylthioureas with ethyl chloroacetate in the presence of potassium carbonate at a ratio of 1:1:0.6 led to the formation of the corresponding S-(ethoxycarbonylmethyl) derivatives. The reaction with an equimolar amount of potassium carbonate involved intramolecular cyclization of the alkylation products to give spirocyclic compounds.

Synthesis and Antioxidant Activity of Some Novel Nicotinonitrile Derivatives Bearing a Furan Moiety

As a part of ongoing studies in developing new potent antioxidant agents, 2‐amino‐4‐(furan‐2‐yl)‐5,6‐dimethylnicotinonitrile 4 was utilized as a key intermediate for the synthesis of some new pyrimidines 5 and 11, form (acet)amide 6, 7, urea and thiourea 9, 10, 1,8‐naphthyridines 12, 13, and 14. Moreover, condensation of 4 with 5,5‐dimethyl‐1,3‐cyclohexanedione and cyclohexanone in ethanol furnished the pyridine derivatives 16 and 17, respectively. Furthermore, refluxing of 4 with ethylenediamine in carbon disulfide afforded the 4,5‐dihydro‐1H‐imidazol‐2‐yl pyridine derivative 19. In addition, refluxing of 4 with carbon disulfide and concentrated sulfuric acid furnished the pyridine derivatives 20 and 21, respectively. The reaction of 4 with phenacyl chloride and ethyl chloroacetate in dimethylformamide in the presence of catalytic amount of triethylamine afforded the pyridine derivatives 22 and 23, respectively. Finally, heating of 4 with 1‐phenyl‐3‐(piperidin‐1‐yl)propan‐1‐one hydrochloride in glacial acetic acid afforded phenylpropylamino pyridine derivative 24. The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, 1H‐NMR, and mass spectral data. Representative compounds of the synthesized products were evaluated as antioxidant agents. Compounds 8, 19, and 22 are promising compounds.