Aryl Isothiocyanates Research Articles

Synthesis and Characterization of New Dihydronaphthalene Candidates as Potent Cytotoxic Agents against MCF-7 Human Cancer Cells.

In the present work, a new series of dihydronaphthalene derivatives were synthesized starting with 6-methoxy-1-tetralone 1, and the corresponding hydrazine derivative 2. Reaction of compound 2 with aryl isothiocyanates produced thiosemicarbazides 3a-d, which were reacted with ethyl chloroacetate to give thiazolidinone derivatives 4a-d. Pyrano thiazolecarbonitrile derivatives 5a-f were prepared by heating a mixture of compounds 4a or 4c, aryl aldehydes, and malononitrile utilizing distilled water in the presence of catalytic amount of potassium hydrogen phthalate. Also, treatment of 4a with DMF-DMA under solvent-free conditions gave enaminone derivative 6, which condensed with ethyl acetoacetate or acetylacetone or malononitrile or cyanothioacetamide to give compounds 7-10, respectively. Finally, reaction of the enaminone 6 with 2-aminoimidazol or 2-aminothiazol in the presence of glacial acetic acid produced derivatives 11 and 12, respectively. Cytotoxic evaluation of eleven compounds, against MCF-7 (human breast adenocarcinoma) cell lines, was estimated. Results revealed that five of the examined compounds 5a, 5d, 5e, 10, and 3d showed potent cytotoxic activities recording, IC50 values; 0.93 ± 0.02, 1.76 ± 0.04, 2.36 ± 0.06, 2.83 ± 0.07, and 3.73 ± 0.09 μM, respectively, which were more potent than the reference used (Saturosporin, IC506.08 ± 0.15 μM). The new products were also examined towards normal epithelial breast cells (MCF10A). All of them showed very good safety profile with different degrees and were safer than the reference drug used. Compound 5a was the most effective against MCF-7 cells and was less toxic than Saturosporin by about 18.45-folds towards MCF01A normal cells. All the new compounds were fully characterized by the different spectral and analytical tools. Herein, detailed syntheses, spectroscopic, and biological data are reported.

Synthesis and antiproliferative assessments of new derivatives of isothiazolo[3,4-d]pyrimidine

ABSTRACT Various derivatives of 5-aryl-4-imino-3-(phenylamino)-4,5-dihydroisothiazolo[3,4-d]pyrimidines (3a-f) were synthesized. The synthesis has been done through treatment of 3-amino-4-cyano-5-(phenylamino)isothiazole with various aryl isothiocyanates. The isothiazole skeleton was obtained by the reaction of malononitrile and phenyl isothiocyanate followed by chloramine treatment. Some of the synthesized dihydroisothiazolo[3,4-d]pyrimidines were tested against different cancer cell lines, including ACHN, HeLa, HL-60, MCF-7, and PC3. Malignant cells were cultured in RPMI medium and incubated with different concentrations of the mentioned compounds. Cell viability was assessed using the MTS assay. The cytotoxicities of the synthesized compounds are not significant and are probably safe for other biological use.

Bio-Fe3O4 Magnetic Nanoparticles Promoted Green Synthesis of thioxo- 1,3-Oxazole Derivatives: Study of Antimicrobial and Antioxidant Activity.

In this work, 1,3-oxazoles were generated using the multicomponent reaction of α-bromo ketones, alkyl (aryl) isothiocyanates, sodium hydride and Fe3O4 MNPs in the water at room temperature in good yields. The nanoparticles generated via the biosynthesis method have potential value in different purposes, such as organic synthesis. To study the antioxidant ability of some synthesized thioxo-1,3-oxazoles, diphenyl-picrylhydrazine (DPPH) radical trapping and power of ferric reduction testes are employed. Among the studied thioxo-1,3-oxazoles, compound 4b have good power for radical trapping and reduction activity than the standard antioxidants such as BHT and TBHQ. In addition, the antimicrobial activity of some thioxo-1,3-oxazoles was studied, employing the disk diffusion test on Gram-positive bacteria and Gram-negative bacteria. The results of the disk diffusion test showed that compounds 4a, 4b, 4d and 4f prevented bacterial growth. Without employing catalyst, these reactions have low yield and busy mixture. The synthesis of compound 4a as sample reaction has a similar yield in the presence of ZnO-NPs and Fe3O4 MNPs (entry 20 and entry 30), but the removal of catalyst from the mixture of reaction after the completion of the reaction is comfortable in the presence of Fe3O4 MNPs. Structures of compound 4a-4i are confirmed by IR, 1H NMR and 13C NMR mass spectra. The reaction of α-bromo ketones, isothiocyanate and sodium hydride in the presence of the catalytic amount of Fe3O4 MNPs in water generates 1,3-oxazole derivatives in good yields. Some of the advantages of performing these reactions with the present procedure are to carry out these reactions in water as a green solvent and simple removal of catalyst.

One-Pot Synthesis of Benzimidazo[2,1-b]thiazoline Derivatives through an Addition/Cyclization/Oxidative Coupling Reaction.

A novel and efficient approach to the synthesis of benzimidazo[2,1-b]thiazoline derivatives has been developed through an addition/cyclization/intramolecular oxidative C-H functionalization process. A variety of alkylene benzimidazo[2,1-b] thiazolines were conveniently assembled from the reaction of aryl isothiocyanate and propargylic amine in the presence of Cu(OAc)2 and PIFA at room temperature. The product could be further converted to substituted benzimidazo[2,1-b]thiazole derivatives.

An Efficient One‐Shot Metal‐Free Electrophilic Fluorination of 2‐Iminothiazolidine‐4‐one

AbstractA highly efficient one‐pot method for the synthesis of mono fluorinated thiazolidinone derivatives have been achieved through four component reaction of primary amines, aryl isothiocyanates, ethyl bromoacetate and Selectfluor as electrophilic fluorinating agent. This protocol is practically convenient and offers the advantage of conducting easily handled sequenceof reaction in single reactor with suitable solvent medium. Reaction of primary amines with aryl isothiocyanate access forthiourea formation followed by addition of ethyl bromoacetate afforded the thiazolidinone, further on addition ofSelectfluor provides desired mono fluorinated products in short time with keen reaction procedure.

One-Pot Multicomponent Synthesis and Anticancer Activity of 1,3-Cyclopentathiazine and Pyrimidothiazine Derivatives

Novel 1,3-cyclopentathiazine and pyrimidothiazine derivatives were synthesized starting from 7-benzyl-4-phenylcyclopenta[d][1,3]thiazin-2-amine (CTA) prepared by a one-pot multicomponent reaction of cyclopentanone, benzaldehyde, and thiourea. Cyclocondensation of CTA with benzylidenemalononitrile gave a pyrimidothiazine. Oxidation of cyclopentathiazine with hydrogen peroxide afforded the corresponding epoxide, while its alkylation with ethyl iodide yielded an N-ethyl derivative. Cyclopentylidenemalononitrile was reacted with formaline and carbon disulfide to obtain pyridine-4-carbonitrile and thiapyrane, respectively, and the reactions of cyclopentylidenemalononitrile with aryl isocyanate and aryl isothiocyanate gave condensed diimino-substituted cyclopentanaphthyridine-1,6-dione and dithiaacenaphthylene-3,8-diylidedibenzamide, respectively. Heating cyclopentanone with benzoyl isothiocyanate and benzoyl chloride produced a sulfide derivative and an enolic dione, respectively. The structures of the newly synthesized compounds were confirmed by spectral analysis, and some products were screened for anticancer activity.

4-Aminocoumarin based Aroylthioureas as Potential Jack Bean Urease Inhibitors; Synthesis, Enzyme Inhibitory Kinetics and Docking Studies.

Urease enzyme catalyzes the hydrolysis of urea into ammonia and CO2, excess ammonia causes global warming and crop reduction. Ureases are also responsible for certain human diseases such as stomach cancer, peptic ulceration, pyelonephritis, and kidney stones. New urease inhibitors are developed to get rid of such problems. This article describes the synthesis of a series of novel 1-aroyl-3-(2-oxo-2H-chromen-4- yl)thiourea derivatives (5a-j) as Jack bean urease inhibitors. Freshly prepared aryl isothiocyanates were reacted with 4-aminocoumarin in the same pot in an anhydrous medium of acetone. The structures of the title thioureas (5a-j) were ascertained by their spectroscopic data. The inhibitory effects against jack bean urease were determined. It was found that compounds 5i and 5j showed excellent activity with IC50 values 0.0065 and 0.0293, µM respectively. Compound 5i bearing 4-methyl substituted phenyl ring plays a vital role in enzyme inhibitory activity. The kinetic mechanism analyzed by Lineweavere-Burk plots revealed that compound 5i inhibits the enzyme non-competitively. The Michaelis-Menten constant Km and inhibition constants Ki calculated from Lineweavere-Burk plots for compound 5i are 4.155mM and 0.00032µM, respectively. The antioxidant activity results displayed that compound 5j showed excellent radical scavenging activity. The cytotoxic effects determined against brine shrimp assay showed that all of the synthesized compounds are non-toxic to shrimp larvae. Molecular docking studies were performed against target protein (PDBID 4H9M) and it was determined that most of the synthesized compounds exhibited good binding affinity with the target protein. Molecular dynamics simulation (MDS) results revealed that compound 5i forms a stable complex with target protein showing little fluctuation. Based upon our investigations, it is proposed that 5i derivative may serve as a lead structure for devising more potent urease inhibitors.

An efficient synthesis and antimicrobial activity of N-bridged triazolo[3,4-b]thiadiazine and triazolo[3,4-b]thiadiazole derivatives under microwave irradiation

Microwave synthesis for a new series of triazolo[3,4-b]thiadiazines and triazolo[3,4-b]thiadiazoles was described. Thus, intermolecular cyclization of triazole 1 with ethyl bromoacetate, chloroacetyl chloride or different α-bromoketones under both conventional and microwave conditions afforded triazolo[3,4-b]thiadiazine derivatives in a good yield. The best results (reaction time and yield) were obtained from microwave condition. However, triazolo[3,4-b]thiadiazole derivatives were obtained via cyclization of triazole 1 with aryl isothiocyanate, ethyl chloroformate or α,α-dibromodimedone without catalyst or in the presence of sodium methoxide and triethylamine, respectively. An attempt to synthesize triazolo[3,4-b]thiadiazine derivatives from reaction of compound 1 with a variety of acetamides was failed; the obtained products are S-alkylated triazoles. Triazolo[3,4-b]thiadiazine 9b and triazolo[3,4-b]thiadiazoles 3a,b, 10 and 12, and triazol-3-ylsulfanyl acetamide derivative 14a have significant results against Escherichia coli, Pseudomonas aeruginosa as gm (–ve) bacteria and Staphylococcus aureus, Bacillus subtilis as gm (+ve) bacteria) and Candida albicans and Aspergillus flavus as pathogenic fungi.

Synthesis and Antimycobacterial Activity of Some Heterocyclic Derivatives

The research was aimed to synthesize heterocyclic derivatives containing thiazole fused p-hydroxybenzohydazide for antimycobacterial activity. As, literature survey reveals various substitutions on thiazole fused p-hydroxybenzohydazide moiety show a variety of remarkable activities, the new derivatives of thiazole fused p-hydroxybenzohydazide was prepared by using various substitutions on R and R’ positions. Considering various pharmacological activities the present work is designed to club thiazole fused p-hydroxybenzohydazide moiety with different phenacyl bromide and isothiocynate moieties. Synthetic studies started with reaction of p-hydroxymethylbenzoate (1) which on amination with hydrazine hydrate leads to form common intermediate p-hydroxybenzohydrazide (2). This intermediate (2) when undergoes nucleophilic addition reaction with aryl isothiocyanates were resulted in the formation of thiosemicarbazides (III.a-III.d). The cyclization reaction (step-III) was carried out by using different phenacyl bromides, actual cyclization takes place by using sodium acetate. Step-III was resulted in the formation of final compounds (IV.a-IV.h). All synthesized compounds were further characterized by melting point. The compounds showed single spot in TLC which assured the completion of reactions and the purity of the compounds. The compounds were synthesized by appropriate synthetic route. The melting points of compounds were determined. The melting points of compounds were determined and were uncorrected. Thin layer chromatography was carried out by using suitable solvent system selected on the basis of solubility and polarity. The Rf value was determined. All the newly synthesized compounds were subjected for characterization by Rotational and Vibrational spectra (IR), Nuclear Magnetic Resonance (NMR), Mass spectroscopy (MS) and C, H, N analysis. The newly synthesized by compounds were screened for antimycobacterial activity by radiometric method.

Syntheses of Novel Tetrasubstituted Thiophenes from Benzene-1,2-Diamines, Ethyl Bromopyruvate, Malononitrile, and Aryl Isothiocyanates

Synthesis of highly functionalized tetrasubstituted thiophenes has been reported involving 3-(bromomethyl)quinoxalin-2(1H)-ones as activated halomethylene compounds precursors. Thus sequential base mediated condensation of readily available malononitrile with aryl isothiocyanates followed by S–alkylation of the resulting enethiolate salts with 3-(bromomethyl)quinoxalin-2(1H)-one compounds and concurrent intramolecular enamine type condensation of S–alkylated compounds affords substituted thiophenes in excellent yields.

Development of a Telescoped Flow Process for the Safe and Effective Generation of Propargylic Amines.

Propargylic amines are important multifunctional building blocks that are frequently exploited in the synthesis of privileged heterocyclic entities. Herein we report on a novel flow process that achieves the safe and effective on-demand synthesis of propargylic amines in a telescoped manner. This process minimizes exposure to hazardous azide intermediates and renders a streamlined route into these building blocks. The value of this approach is demonstrated by the rapid generation of a small selection of drug-like thiazolines that result from a high-yielding reaction cascade between propargylic amines with different aryl isothiocyanates.

Microwave Assisted Synthesis and Antimicrobial Activity of Novel 1,3,4-Thiadiazoles and 1,2,4-Triazoles Derived from 2-(3-Fluorophenyl)-4-methylthiazole-5-carbohydrazide

The precursors 2-{[2-(3-fluorophenyl)-4-methyl-1,3-thiazol-5-yl]carbonyl}-N-phenylhydrazinecarbothioamides are synthesized from 2-(3-fluorophenyl)-4-methylthiazole-5-carbohydrazide and aryl isothiocyanates. MW irradiation of the precursors under alkali or acidic conditions led to the products of cyclization 5-[2-(3-fluorophenyl)-4-methylthiazol-5-yl]-N-phenyl-1,3,4-thiadiazol-2-amine or 5-[2-(3-fluorophenyl)-4-methylthiazol-5-yl]-4-phenyl-4H-1,2,4-triazole-3-triiol, accordingly. Structures of the synthesized compounds are confirmed by IR, 1H, and 13C NMR, and mass spectra. All products are tested in vitro for their antibacterial and antifungal activity.

Choline Chloride Based Deep Eutectic Solvents as a Tuneable Medium for Synthesis of Coumarinyl 1,2,4‐Triazoles: Effect of Solvent Type and Temperature

A study of 1,2,4‐triazole synthesis from 2‐((4‐methyl‐2‐oxo‐2H‐chromen‐7‐yl)oxy)acetohydrazide (1) or 2‐(7‐hydroxy‐2‐oxo‐2H‐chromen‐4‐yl)acetohydrazide (2) and various isothiocyanates, in deep eutectic solvents, was performed. In order to find the best conditions for 1,2,4‐triazole formation, a model reaction on 1 and phenylisothiocyanate was performed in 14 different choline chloride based deep eutectic solvents, at two different temperatures (40 °C and 80 °C). Pure 1,2,4‐triazoles were obtained in choline chloride/urea (1:2) and choline chloride/N‐methyl urea (1:3) deep eutectic solvents at 80 °C. Pure thiosemicarbazides were obtained in choline chloride/ethane‐1,2‐diol (1:2), choline chloride/malic acid (1:1), choline chloride/malonic acid (1:1), choline chloride/butane‐1,4‐diol (1:3) and choline chloride/glycerole (1:2) at 40 °C. The ratio of 1,2,4‐triazoles and thiosemicarbazides in reaction mixtures was determined by HPLC and 1H NMR. After the best conditions for 1,2,4‐triazole synthesis were found, some coumarinyl 1,2,4‐triazoles were synthesized from two different coumarinyl hydrazides (1 and 2) and various alkyl and aryl isothiocyanates in one step reaction.

Synthesis and biological evaluation of SHetA2 (NSC-721689) analogs against the ovarian cancer cell line A2780

A series of Flexible Heteroarotinoid (Flex-Het) analogs was synthesized and their biological activities were evaluated against the A2780 ovarian cancer cell line. The objective of this study was to establish structure-activity relationships (SARs) for new Flex-Het derivatives, which were previously inaccessible due to the limited availability of aryl isothiocyanate precursors. The current work developed a synthesis of isothiocyanate 13 and used it to prepare 14 diverse thiourea analogs of the lead compound SHetA2 (1, NSC-721689) from a range of commercial amines. Additionally, five new ureas were prepared along with nine N-benzylthioureas, five derivatives incorporating hydrazine or hydrazide linkers and four desmethyl compounds. Potencies and efficacies were determined for each derivative. Some of the new Flex-Hets displayed high activity with IC50 values ranging from 1.86 to 4.70 μM and 85.6–95.9% efficacies, which are comparable to or better than the lead compound (IC50 3.17 μM, 84.3% efficacy). Although SHetA2 is scheduled to enter clinical trials in the near future, alternative backup drug candidates have been identified in this work. The new agents possess similar pharmacological properties and retain selective activity against A2780 ovarian cancer cells. Although a mixed SAR was obtained for these analogs, diversified, highly potent molecules were identified for further investigation. In particular, agents 2c-d and 3e-f, which incorporated CF3 and OCF3 groups in place of NO2 on the pendent aryl ring, displayed high activity and excellent differentiation between normal and cancerous cells.

Facile, capable, atom-economical one-pot multicomponent strategy for the direct regioselective synthesis of novel isoxazolo[5,4-d]pyrimidines

Facile and efficient NaOH-promoted one-pot regioselective synthesis of 5,7-dimethyl-3-(arylamino)isoxazolo[5,4-d]pyrimidine-4,6(5H,7H)-diones and 5,7-dimethyl-3-(arylamino)-6-thioxo-6,7-dihydroisoxazolo[5,4-d]pyrimidin-4(5H)-ones as pharmaceutically interesting compounds has been developed based on a three-component reaction between aryl isothiocyanates, N,N-dimethylbarbituric acid or N,N-dimethyl-2-thiobarbituric acid, and hydroxylamine hydrochloride in N,N-dimethylformamide (DMF) at room temperature. This new protocol has advantages such as simple operation, regioselectivity, metal-free operation, high atom economy, moderate to high yield, easy work-up procedure, and applicability on the gram scale.

Organotellurium Chemistry: Synthesis and Properties of 2-Acylamino- and 2-Arylamino-1,3-benzotellurazoles

Synthetic methods have been developed to prepare novel 1,3-benzotellurazoles carrying acylamino and arylamino moieties in position 2, in order to investigate their propensity to self-assemble to supramolecular structures. The targeted compounds were obtained in yields ranging from 44% to 67%, by reacting bis(2-aminophenyl) ditelluride with acyl- and aryl isothiocyanates, respectively, and subsequent reductive cyclization of the resulting thiourea derivatives. Seven novel 1,3-benzotellurazole derivatives were prepared: 2-benzoylamino-1,3-benzotellurazole, 2-(4-chlorobenzoylamino)-1,3-benzotellurazole, 2-(2-bromobenzoylamino)-1,3-benzotellurazole, 2-(4-bromobenzoylamino)-1,3-benzotellurazole, 2-(4-methoxybenzoylamino)-1,3-benzotellurazole, 2-phenylamino-1,3-benzotellurazole, and 2-(4-chlorophenylamino-1,3-benzotellurazole. A simplified protocol was employed to synthesize all acyl isothiocyanates needed for their preparation from benzoyl halide derivatives and potassium thiocyanate. The reductive cyclization of the intermediate thioureas was challenging, only the use of hydroxymethanesulfinate in the presence of elemental mercury provided synthetically useful product yields. A mechanism was proposed, consisting of the insertion of mercury into the Te-Te bond, followed by intramolecular nucleophilic attack of the thiocarbonyl moiety by the resulting insertion product. All 2-acylamino-1,3-benzotellurazoles are crystalline solids, which are stable to ambient light, air and moderate heat. A characterization of selected samples by X-ray crystallography indicated that they form dimers in solid state, resulting from hydrogen bonding between the exocyclic and endocyclic nitrogen atoms of two adjacent molecules. This sets them apart from 2-alkyl- and 2-aryl-1,3-benzotellurazoles, which are known to self-assemble into supramolecular wires.

Cu(i) catalysed annulation of isothiocyanates/isocyanates with 2-iodo-sulfonamides: synthesis of benzodithiazines, benzothiadiazinones, benzothiazinylidene-anilines and benzothiazolylidene-anilines.

An efficient Cu(i)-catalysed cyclisation reaction of 2-iodobenzene sulfonamides with aryl-isothiocyanates and isocyanates that affords functionalised benzodithiazines and benzothiadiazinones, respectively, has been developed. Thus, in the reaction with aryl isothiocyanates (Ar-N[double bond, length as m-dash]C[double bond, length as m-dash]S), the C[double bond, length as m-dash]S moiety participates in the cyclisation leading to a dithiazine. By contrast, in the case of aryl isocyanates (Ar-N[double bond, length as m-dash]C[double bond, length as m-dash]O), the N[double bond, length as m-dash]C part is involved in the cyclisation and a thiadiazinone is obtained. Analogous reactions of isothiocyanates with N-tosyl-2-iodo-anilines and 2-iodo-benzyl sulfonamides afford (benzothiazin-2-ylidene)anilines and (benzothiazol-2-ylidene)anilines, respectively. Probable mechanistic pathways are briefly discussed.

Diaminomaleonitrile as a versatile building block for the synthesis of 4,4′-biimidazolidinylidenes and 4,4′-bithiazolidinylidenes

Abstract Ring closure reactions of diaminomaleonitrile (DAMN) with electrophilic aryl isocyanates and aryl isothiocyanates lead to the formation of the target 5,5′-diimino-1,1′-diaryl-4,4′-biimidazolidinylidene-2,2′-diones 2a,b and 2,2′-diarylimino-4,4′-bithiazolidinylidenes 4a–e, respectively. The protocol provides a new strategy for the synthesis of a wide range of alkenes with two electron-donating and two withdrawing substituents of DAMN in moderate to good yields.

Heterocyclization of Isoniazid: Synthesis and Antimicrobial Activity of Some new Pyrimidine 1, 3-Thiazole, 1, 2, 4-Thiadiazole, and 1, 2, 4-Triazole, Derivatives Derived from Isoniazid

The reaction of isonicotinic hydrazide (1) (isoniazid) with cinnamoyl isothiocyanate (2) afforded cinnamoyl thiosemicarbazide derivative 3. Treatment of 3 with lead acetate in acetic acid, sodium ethoxide, sulphuric acid, chloroacetylchloride and sodium hypochlorite and sodium hydroxide gave the corresponding dihydropyrimidine 4, triazolethiazine 5, 1,3,4-thiadiazole 6, 1,3-thiazole 7 and 1,2,4-thiadiazole 8, respectively. The reactivity of isoniazid 1 towards ammonium thiocyanate, cyclohexanone and acetophenone to give 1,2,4-triazole thione 10, hydrazones 9 and 12 was studied. Treatment of hydrazones 9 and 12 with carbon disulfide and aryl isothiocyanates gave 1,3,4-thiadiazolidine 11 and 1,2,4-triazole thione derivatives 13a, b. The antimicrobial activity of these new compounds has been evaluated against 6 microbial strains. Some of the newly synthesized compounds showed a moderate activity.

Synthesis of 3-(N-arylthiocarbamoyl)chromones from 2-hydroxyaryl amino enones and isothiocyanates

New both 2-unsubstituted and 2-substituted 3-(N-arylthiocarbamoyl)chromones were obtained by the reaction between 3-dimethylamino-1-(2-hydroxyaryl)prop-2-en-1-ones and aryl isothiocyanates.