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Addition–cyclization reactions of furan-2-carbonyl isothiocyanate with nitrogen nucleophiles as a synthetic route to novel azines and azoles of potential biological activity
Abstract
Heterocyclization of furan-2-carbonyl isothiocyanate 1 with a variety of aliphatic and aromatic nitrogen nucleophiles resulted in the formation of a new series of heterocycles including triazines, pyrimidines, oxadiazines, imidazolidines, thiadiazoles and their condensed candidates. The antibacterial screening for a group of the newly synthesized compounds showed that they possess moderate antibacterial activities against examples of Gram-positive and Gram-negative bacteria.
... Functional moieties such as carbonyl, thiocarbonyl, and amines are building blocks of many drugs. These groups frequently perform a structural role, linking other functionalities and aiding in the optimal orientation for interaction with the drug's target [18,19]. The chemical reactivity of carbonyl functional groups can also allow these groups to come into close contact with the target, generating hydrogen bonds and other intermolecular interactions. ...
A series of carbamothioyl-furan-2-carboxamide derivatives were synthesized using a one-pot strategy. Compounds were obtained in moderate to excellent yields (56–85%). Synthesized derivatives were evaluated for their anti-cancer (HepG2, Huh-7, and MCF-7 human cancer cell lines) and anti-microbial potential. Compound p-tolylcarbamothioyl)furan-2-carboxamide showed the highest anti-cancer activity at a concentration of 20 μg/mL against hepatocellular carcinoma, with a cell viability of 33.29%. All compounds showed significant anti-cancer activity against HepG2, Huh-7, and MCF-7, while indazole and 2,4-dinitrophenyl containing carboxamide derivatives were found to be less potent against all tested cell lines. Results were compared with the standard drug doxorubicin. Carboxamide derivatives possessing 2,4-dinitrophenyl showed significant inhibition against all bacterial and fungal strains with inhibition zones (I.Z) in the range of 9–17 and MICs were found to be 150.7–295 μg/mL. All carboxamide derivatives showed significant anti-fungal activity against all tested fungal strains. Gentamicin was used as the standard drug. The results showed that carbamothioyl-furan-2-carboxamide derivatives could be a potential source of anti-cancer and anti-microbial agents.
... New nitro-substituted acyl thioureas (4) have been synthesized and their antioxidant, cytotoxic, antibacterial, and antifungal effects have been studied [11]. The synthesis of the latter was carried out by reacting acetyl chloride (1) with potassium thiocyanate, the formed acetyl isocyanates (2) were easily attached to various nitro-substituted anilines. ...
Acyl isothiocyanates and their functional derivatives (acyl thioureas and acyl thiosemicarbazides) are an important group of organic compounds that are widely used in the synthesis of heterocycles and in chemistry as catalysts, ligands, colorimetric hemosensors, etc. In recent years, there has been an increased interest towards this class of compounds as promising biologically active compounds, especially since the latest advances in medicinal chemistry for them are not sufficiently studied.
The aim. To summarize and systematize information for the last 10 years on methods of synthesis and biological activity of substituted acyl thioureas and acyl thiosemicarbazides.
Materials and methods. Web-tools for finding scientific information (Reaxys, Scopus, Google Scholar, ScienceResearch, SciFinder, Web of Science, etc.).
Results and discussion. Literature sources related to the methods of synthesis of substituted acyl thioureas and acyl thiosemicarbazides were systematized and analyzed. The main approaches for the formation of these compounds are revealed: stepwise formation from carboxylic acids, through acyl chlorides and acyl isothiocyanates followed by nucleophilic addition of amines or hydrazides of carboxylic acids ("one-pot synthesis"), nucleophilic addition of amines or hydrazides of carboxylic acids directly to acyl isothiocyanates and parallel microwave synthesis using acyl isothiocyanates and amines as reagents. The possibility of their use as ligands for the formation of complex compounds with transition metal ions was discussed. In the review biological activity of these structures, namely antimicrobial, fungicidal, antitumor, antiviral, antifungal and other activities was detailazed.
Conclusions. The basic approaches to the synthesis of substituted acylthuoureas and acyl thiosemicarbazides which include the application of carboxylic acids, their derivatives (acyl halides and isothiocyanates) and N-nucleophiles as initial compounds were discussed. It was shown that aforementioned class of the compounds reveals the versatile biological activity and are promising for further structural modification aimed to the search of novel drugs
... 24 Moreover, their 13 C-NMR spectra displayed the characteristic carbon atoms of benzoyl groups at 194 and 193.5 ppm, respectively. 25 On contrary to the above behavior, reaction of acrylonitrile 2 with acetoacetanilide in boiling EtOH containing a catalytic amount of piperidine afforded 3-acetyl-5-cyanomethyl-7,11-dimethoxy-2-oxo-1-phenyl-1,5-dihydro-2H-furo[3 0 ,2 0 :6,7] chromeno[4,3-b]pyridine (6) (Scheme 4). The reaction was occurred through the non-isolable intermediate F, which underwent cyclocondensation then cycloaddition of the phenolic OH group onto the olefinic bond (Scheme 4). ...
Some novel substituted benzofurans and annulated furochromenes were obtained through the treatment of the novel (2E)-3-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromen-6-yl)acrylonitrile (2 A. A. Abu-Hashem, and M. El-Shazly, “Synthesis, Reactions and Biological Activities of Furochromones,” European Journal of Medicinal Chemistry 90 (2015): 633–65.[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) by some active carbon nucleophiles such as active methylene ketones and methylene nitriles. Thus, the reaction of acrylonitrile 2 with acetylacetone, ethyl acetoacetate, diethylmalonate, and acetoacetanilide in ethanol containing piperidine produced efficiently the corresponding polyfunctionalized benzonitrile derivatives 3–5 and furochromeno-pyridine 6, respectively. Also, treatment of acrylonitrile 2 with some methylene nitriles such as malononitrile, ethyl cyanoacetate, and malononitrile dimer afforded the annulated furochromene derivatives 7–9. Furthermore, the pyrido[1,2-a] benzimidazole system 10 was furnished via reaction of acrylonitrile 2 with 2-(1 H-benzimidazol-2-yl)acetonitrile. These reactions took place through Michael addition, retro-Michael, and γ-pyrone ring opening followed by different types of recyclization. The chemical structures of the novel products were established on the basis of their spectral data and elemental analysis.
An efficient base-promoted aerobic oxidation procedure for the synthesis of fused 1,3,5-triazines from 2-aminobenzimidazoles, aromatic aldehydes, and ammonium iodide under metal-free conditions has been developed.
Benzoylthiourea derivatives containing heterocyclic moiety strongly coordinate and stabilize the organometallic fac-[Re(CO)3]⁺ core forming both monomer and multimer organorhenium(I) complexes. The reaction of isophthaloyl dichloride with potassium thiocyanate in acetone followed by addition of diphenylamine led to a novel benzoylthiourea derivative with triazinethione moiety ligand, typically 3-(4-(diphenylamino)-6-thioxo-1,6-dihydro-1,3,5-triazin-2-yl)N(diphenylcarbamothioyl)benzamide (H2L). The purity and retention time of the ligand H2L were assessed by ultraperfomance liquid chromatography (UPLC) and analyzed by ¹H NMR, ¹³C NMR, infra-red (IR) and liquid chromatography mass spectrometry (ESI-MS). The coordination mode of H2L to the organometallic fac-[Re(CO)3]⁺ core was investigated by reacting the ligand with [Re(CO)5Br] in toluene. The reaction led to a dimeric complex [(μ-H2L)2(Re(CO)3Br)2] in which the H2L coordinates to each of the fac-[Re(CO)3]⁺ units as neutral monodentate and S-donor chelate. The dimer [(μ-H2L)2(Re(CO)3Br)2] was analyzed by ¹H NMR, infra-red (IR), high resolution mass spectrometry (HR-ESI-MS) and single crystal X-Ray crystallography.
A catalyst-free one-pot synthetic methodology was developed for the preparation of 1,3,5-triazine-2,4-dithione derivatives through three-component reactions of arylaldehydes, thiourea, and orthoformates. The procedure tolerated a diverse range of arylaldehydes and orthoformates and provided a rapid entry to a variety of 4-aryl-6-(alkylthio)-3,4-dihydro-1,3,5-triazine-2(1 H )-thiones (29 examples). The synthetic strategy relies on the dual role of thiourea in the cyclization with the aldehydes and the alkylation via an intermediate imidate formation. The structures of 1,3,5-triazine-2,4-dithione derivatives were characterized by spectroscopic techniques as well as by single crystal X-ray diffraction.
Intermolecular 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.
New aroyl thioureas; N-nicotinoyl-N'-(4-nitrophenyl) thiourea (3a) and N-nicotinoyl-N'-(2-nitrophenyl) thiourea (3b) were synthesized and studied as anion-binding receptors. Upon adding tetrabutyl ammonium halides (fluoride, chloride bromide and iodide), cyanide and hydroxide ions to their solutions in DMSO respectively, the colour of the solutions has shown striking changes from pale yellow to brillant yellow or red. The binding effects of the anions were investigated by UV-VIS spectroscopic method and 1H NMR titrations.
Various fused pyrimidine such as furo[2,3-d]pyrimidine,
triazolo[1,5-a]pyrimidine, tetrazolo[1,5-a]pyrimidine were synthesized from
the reactions of thioxopyrimidine-6(1H)-ones with ethyl chloroacetate (under
different reaction conditions), thiourea, and sodium nitrite. Pyrimidine
thiones reacted with POCl3/PCl5 to give the chloro derivatives which reacted
with sodium azide, and thiourea to give the tetrazolo[1,5-c]pyrimidine,
pyrimido pyrimidine. Thioxopyrimidine-6(1H)-ones reacted with benzyl amine to
give pyrrolo[2,3-d]pyrimidinethione. Theoretical calculation using MIDO/3,
Fukui indices and the heat of formation of some compounds were carried out.
The pharmacological and antimicrobial activities of some of the synthesized
products were also evaluated.
The reaction of 4-(4-chlorophenyl)-2-mercapto-6-oxo-1,6-dihydropyrimidine-5-carbonitrile 1 with benzylidenemalononitrile and/or methyl iodide has yielded dihydropyrimido[1,2-a]pyrimidine derivative 5 and methylthio derivative 6 respectively. Thiated product 7 was cyclized with chloroacetonitrile to give thienopyrimidine derivative 9. Compound 6 was reacted with hydrazine hydrate to give diaminopyrimidine derivative 10. Reaction of 10 with different reagents afforded tetrazolopyrimidine, triazolopyrimidine and pyrimidotriazepine derivatives 11-22. The antimicrobial activity was studied against examples of Gram-positive and Gram-negative bacteria using Tetracycline (Antibacterial agent) and Amphotericn B (Antifungal agent) as standard.
5-Diazoimidazoles and 5-diazopyrazoles have been shown to react with acyl isothiocyanates yielding the imidazo- and pyrazolo[5,1-d][1,2,3,5]thiatriazines stabilized by a nonbonded S center dot center dot center dot O interaction. In contrast to acyl isothiocyanates, alkyl-, aryl-, and arylsulfonyl isothiocyanates do not react with 5-diazoazoles. The nature and the strength of stabilizing intramolecular interaction between non-bonded S and O atoms have been studied by X-ray analysis for mono crystals and DFT calculations for selected azolo[5,1-d] [1,2,3,5]thiatriazines. The interaction was described in terms of Weinhold covalence ratio factors, NBO, and AIM schemes. The reaction discovered was used to develop an efficient approach toward the new 8-substituted 4-ethoxycarbonylimino-4-benzoyl- and 4-(3,4,5,6-tetrafluorobenzoy)iminoimidazo(pyrazolo)[5,1-d][1,2,3,5]thiatriazines.
6-[(4-Methoxy/4,9-dimethoxy)-7-methylfurochromen-5-ylideneamino]-2-thioxo-2,3-dihydropyrimidin-4-ones 1a,b were prepared by reaction of 6-amino-2-thiouracil with visnagen or khellin, respectively. Reaction of 1a,b with methyl iodide afforded furochromenylideneaminomethylsulfanylpyrimidin-4-ones 2a,b. Compounds 2a,b were reacted with secondary aliphatic amines to give the corresponding furochromen-ylideneamino-2-substituted pyrimidin-4-ones 3a-d. Reaction of 3a-d with phosphorus oxychloride yielded 6-chlorofurochromenylidenepyrimidinamines 4a-d, which were reacted with secondary amines to afford furochromenylideneamino-2,6-disubstituted pyrimidin-4-ones 5a-d. In addition, reaction of 5a-d with 3-chloropentane-2,4-dione gave 3-chloro-furochromenylpyrimidopyrimidines 6a-d. The latter were reacted with piperazine and morpholine to give 1-(furochromenyl)-pyrimidopyrimidine-3,6,8-triylpiperazines or -3,6,8-triylmorpholines 7a-d. The chemical structures of the newly synthesized compound ware characterized by IR, ¹H-NMR, ¹³C-NMR and mass spectral analysis. These compounds were also screened for their analgesic and anti-inflammatory activities. Some of them, particularly 3-7, exhibited promising activities.
The agar diffusion assay is one method for quantifying the ability of antibiotics to inhibit bacterial growth. Interpretation of results from this assay relies on model-dependent analysis, which is based on the assumption that antibiotics diffuse freely in the solid nutrient medium. In many cases, this assumption may be incorrect, which leads to significant deviations of the predicted behaviour from the experiment and to inaccurate assessment of bacterial susceptibility to antibiotics. We sought a theoretical description of the agar diffusion assay that takes into consideration loss of antibiotic during diffusion and provides higher accuracy of the MIC determined from the assay.
We propose a new theoretical framework for analysis of agar diffusion assays. MIC was determined by this technique for a number of antibiotics and analysis was carried out using both the existing free diffusion and the new dissipative diffusion models.
A theory for analysis of antibiotic diffusion in solid media is described, in which we consider possible interactions of the test antibiotic with the solid medium or partial antibiotic inactivation during diffusion. This is particularly relevant to the analysis of diffusion of hydrophobic or amphipathic compounds. The model is based on a generalized diffusion equation, which includes the existing theory as a special case and contains an additional, dissipative term.
Analysis of agar diffusion experiments using the new model allows significantly more accurate interpretation of experimental results and determination of MICs. The model has more general validity and is applicable to analysis of other dissipative processes, for example to antigen diffusion and to calculations of substrate load in affinity purification.
Herein, we report Fe3O4@O2PO2(CH2)2NH3⁺CF3CO2⁻ as a novel and reusable ionically tagged nanomagnetic catalyst. It was characterized by several techniques including Fourier transform infrared (FT-IR) spectroscopy, thermo gravimetric analysis/differential thermal analysis (TGA/DTA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), vibrating sample magnetometer (VSM) and energy dispersive X-ray (EDX) analysis. The catalytic behaviour of the Fe3O4@O2PO2(CH2)2NH3⁺CF3CO2⁻ was examined at the synthesis 2-amino-6-(2-oxo-2H-chromen-3-yl)-4-arylnicotinonitrile derivatives. Experimental data has approved that the final step of the plausible mechanism proceeded via a vinylogous anomeric based oxidation mechanism. Described catalys shows excellent potential of recycling and reusing at the described multicomponent reaction.
An efficient, one-pot, and convenient approach for the reaction of the same precursors, trialkyl(aryl) phosphines, acetylene diesters, and benzhydroxamic acids has been developed to produce two important classes of heterocyclic compounds: N-benzoylaziridines and 1,4,2-dioxazoles. The strategy utilizes the intermediate solvation as a key step in product selectivity. The usefulness of the developed approach has been confirmed in the unprecedented highly cis-selective formation of the N-benzoylaziridines. In addition, the procedure provides a green alternative method for the synthesis of 1,4,2-dioxazoles employing a β-cyclodextrin nanoreactor in aqueous media.
Two series of biological based (nano) gelatoric ionic liquids (NGILs) were synthesized in high yield (96–98%). All the new NGILs were characterized by ¹H NMR, ¹³C NMR, FT-IR, XRD, SEM, and TGA/DTA. Their ability to act as catalysts in the synthesis of 5‑amino‑3‑(3‑nitrophenyl)‑1‑phenyl‑1H‑pyrazole‑4‑carbonitrile via vinylogous anomeric based oxidation was examined. They were reused at least two times with a marginal decreasing their activity.
The starting material 2-furan-2-yl-4-mercapto-6-methylpyrimidine-5-carbonitrile 3 was reacted with various reagents resulting in the formation of a group of new pyrimidines and condensed pyrimidines including quinazoline 6 tetrazolopyrimidine 12, pyrazolopyrimidines 14, 18, and 19, triazolopyrimidine 16, and pyrimidopyridazine 20. The antibacterial activity was evaluated for a group of the synthesized compounds against examples of Gram-positive and Gram-negative bacteria.
Being responsible for the development of many cancer types, EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor 2) were the focus of this study where a series of novel 4-anilino-furo[2,3-d]pyrimidine derivatives was designed, synthesized and biologically evaluated. Modification of the solvent accessible 5-position side chain greatly affected the in-vitro EGFR/HER2 inhibitory activity. Three derivatives bearing 5-carboxylic acid side chain, namely the 3-chloroanilino derivative (8c), the 3-bromoaniline (8d) and the lapatinib analogue (10) demonstrated the most significant submicromolar EGFR inhibition. Surprisingly, the in-vitro assay of the ester 7h and its acid analogue 10 showed a significant variation of results between the antiproliferative activity against A549 cell line (IC50 0.5 and 21.4 μM) respectively and EGFR inhibitory activity (18% and 100%) respectively, suggesting that 7h might be a prodrug for 10. This assumption was also affirmed by the in-vivo results, where the in-vivo antitumor assessment against EAC (Ehrlich Ascites Carcinoma) solid tumor model revealed that 7h and 8d (10 mg/kg dose) exhibited antitumor activity comparable to that of gefitinib at the same dose, exhibiting TGI% of 67%, 71% and 70%, respectively. This effect could be explained, at least partly, via activation of apoptosis, where 7h and 8d caused more than 2-fold increase of caspase 3 and cytochrome c expression than the control group which is comparable to that of gefitinib-treated group. Finally, 7h was the most effective apoptotic inducer, resulting in a significant elevation in annexin V-FITC-positive apoptotic cells (both early and late apoptosis) by 25 and 79-folds, respectively, compared to control, which is higher than that of gefitinib (22 and 61-folds, respectively).
Reactions of carbonyl isothiocyanates with enamines of the type CH 3 -C(NH 2 )=CH-X (X = CN, COOC 2 H 5 , or COCH 3 ) were investigated. The formation of products of Ad N , S N , and cyclization reactions is discussed on the basis of their IR, UV and mass spectra. In one case, the thermal cyclization was followed by differential thermal analysis.
The reaction of 4-arylalkyl- and 4-arylthiosemicarbazides with aroyl isothiocyanates gave substituted 1,2-bis(thiocarbamoyl)hydrazines,
which readily cyclize to give previously unreported 4-aroyl 5-arylalkyl- and 4-aroyl-5-arylamino-2H-1,2,4-triazole-3-thiones,
respectively. A spectral study of 9-anthrylmethylthiosemicarbazides and derived dihydrotriazolethione indicated the chemosensor
activity of these compounds relative to a cation series.
The reaction of aroyl isothiocyanate with malononitrile, ethyl acetoacetate and/or cyanothioacetamide and the chemical transformation of the resultant compounds is reported.
Structural evidence for the existence of a ‘vinylogous’ anomeric effect is presented for a series of 4H-4-benzotriazolyl-2,6-diarylpyrans 1a,b and for their benzo-fused derivatives 2–5 and nitrogen analogue 6. X-Ray crystal structure analyses reveal changes in the geometry of the central ring and exocyclic C–N bond, which are discussed in terms of an interaction of the benzotriazole fragment with a heteroatom through four bonds.
A traceless solid supported protocol for the synthesis of 2-aminobenzothiazoles is described, employing resin-bound acyl-isothiocyanate and a series of anilines. Cyclization of the resulting N-acyl, N'-phenyl-thioureas generates the 2-aminobenzothiazole scaffold, which can be further elaborated prior to hydrazine-mediated cleavage of the final products from the carboxy-polystyrene resin. A small, focused library of 2-aminobenzothiazoles was prepared.
Two series of N-[5-(2-furanyl)-2-methyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl]-carboxamide (4a-m) and 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno[2,3-d]pyrimidin-4-ones (5a-m) were synthesised using appropriate synthetic route. All the test compounds 4a-m and 5a-m were assayed in vitro for antibacterial activity against two different strains of Gram-negative (Escherichia coli and S. typhi) and Gram-positive (S. aureus, B. subtilis) bacteria and the antimycobacterial activity was evaluated against M. tuberculosis and M. avium strains. The minimum inhibitory concentration (MIC) was determined for test compounds as well as for reference standards. The test compounds have shown significant antibacterial and antimycobacterial activity against all the microbial strains used, when tested in vitro. In general, along with the thienopyrimidinone ring, substituted amido or imino side chain at position 3 is essential for antimicrobial activity. Among the compounds tested, compounds 4c, 4e and 4g in N-[5-(2-furanyl)-2-methyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl]-carboxamide series and compounds 5c, 5e and 5g in 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno[2,3-d]pyrimidin-4-ones series were found to be the most potent. Further the toxicity of most potent compounds 4c, 4e and 4g and 5c, 5e and 5g were assessed using hemolytic assay and minimal hemolytic concentration (MHCs) were determined. In general, test compounds were found to be non-toxic up to a dose level of 200 micromol L(-1) (MHC).