Hydrazonyl Halides Research Articles

Antimicrobial and Molecular Docking Studies of 1,3,4-Thiadiazole Tethered Sulfa-Azo Derivatives via Hydrazono-Methyl Bridge

A new series of 1,3,4-thiadiazole linked to sulfa-azo derivatives via hydrazono-methyl bridge were synthesized via the reaction of methyl ((E)-(sulfa-derivatives)diazenyl) benzylidene)hydrazine-1-carbodithioates 1a-e with ethyl ester and acetyl hydrazonyl halides 2a-d. The chemical structures of the newly 1,3,4-thiadiazoles 3a-t have been clarified considring their elemental and spectral analysis. Antimicrobial activity of the newly 1,3,4-thiadiazoles was determined for Staphylococcus aureus, Escherichia coli, Candida albicans, as well as Aspergillus niger using the cup agar plate diffusion method. Out of the twenty compounds, compounds 3j, 3k, 3l, and 3s with isoxazole sulfonamides were selected for MIC assay. Compound 3j was equipotent with neomycin control drug against all tested strains, while compound 3k was 4-fold higher than neomycin against S. aureus, E. coli, and C. albicans with MIC values of 9.77, 19.53, and 19.53 μg/mL, respectively. Compound 3l was equipotent with neomycin against S. aureus and C. albicans, while it was 2-fold higher than neomycin against E. coli with MIC of 39.06 μg/mL. For 3s, it was less potent than neomycin against all tested microbs with 2-fold and 4-fold less potent. Further scanning electron microscopy (SEM) investigation has been studied to reveal the disruption effect of the selected potent antimicrobial compound (3k) on the intact cells of tested microbs S. aureus, E. coli in addition to C. albicans. Results showed that 3k exhibited a noticeable effect on destroying microbial cell walls. Furthermore, molecular docking study has been done to assess the binding behavior of two most effective compounds 3k and 3l with the target crystal structure of dihydropteroate synthase (PDB: 6CLV for S. aureus) and (PDB: 5U14 for E. coli). Compound 3k was shown to be able to form stable complexes with both target enzymes of dihydropteroate synthase through hydrogen bonding and hydrophobic interactions.

Environmentally Benign and User-Friendly In Situ Generation of Nitrile Imines from Hydrazones for 1,3-Dipolar Cycloaddition.

Nitrile imines are highly reactive and versatile dipoles and conventionally generated in situ from unstable hydrazonyl halides under basic conditions. Herein, we report the first green and user-friendly protocol for in situ generation of nitrile imines from Oxone-KBr oxidation of hydrazones and base-promoted dehydrobromination. The nitrile imines were demonstrated for 1,3-dipolar cycloaddition with various dipolarophiles, including alkene and alkyne groups. With its green nature, ease of operation, and air and moisture tolerance, we expect our method will find wide applications in organic synthesis.

Synthesis, Molecular Docking Studies and In Silico ADMET Screening of New Heterocycles Linked Thiazole Conjugates as Potent Anti-Hepatic Cancer Agents.

Thiazoles are important scaffolds in organic chemistry. Biosynthesis of thiazoles is considered to be an excellent target for the design of novel classes of therapeutic agents. In this study, a new series of 2-ethylidenehydrazono-5-arylazothiazoles 5a–d and 2-ethylidenehydrazono-5-arylazo- thiazolones 8a–d were synthesized via the cyclocondensation reaction of the appropriate hydrazonyl halides 4a–d and 7a–d with ethylidene thiosemicarbazide 3, respectively. Furthermore, the thiosemicarbazide derivative 3 was reacted with different bromoacetyl compounds 10–12 to afford the respective thiazole derivatives 13–15. Chemical composition of the novel derivatives was established on bases of their spectral data (FTIR, 1H-NMR, 13C-NMR and mass spectrometry) and microanalytical data. The newly synthesized derivatives were screened for their in vitro anti-hepatic cancer potency using an MTT assay. Moreover, an in silico technique was used to assess the interaction modes of the compounds with the active site of Rho6 protein. The docking studies of the target Rho6 with the newly synthesized fourteen compounds showed good docking scores with acceptable binding interactions. The presented results revealed that the newly synthesized compounds exhibited promising inhibition activity against hepatic cancer cell lines (HepG2).

Synthesis, ADMET and Docking Studies of Novel Pyrazoles Incorporating Coumarin Moiety as Tyrosine Kinase (Src) Inhibitors

Novel pyrazoles incorporating coumarin moiety have been synthesized by the 1,3-dipolar cycloaddition reaction of the nitrilimines that were generated in situ from hydrazonyl halides by the action of triethylamine and the enaminone named E-3-(3-(dimethylamino)acryloyl)-8-methoxy-2H-chromen-2-one (1) in dry benzene for 6 h. These novel compounds' chemical structures were elucidated by physical and spectral techniques, including FTIR, 1H-NMR, 13C-NMR, 1H-13C HMBC NMR, and mass spectra. These molecules were predicted to show tyrosine kinase inhibition activity, which was further validated by docking studies. These molecules also showed good ADMET properties and passed Lipinski’s filters for drug-likeness. These results collectively paved the way for developing pyrazoles incorporating coumarin moiety as possible tyrosine kinase inhibitors.

Synthesis, anticancer evaluation and molecular docking studies of new heterocycles linked to sulfonamide moiety as novel human topoisomerase types I and II poisons.

A series of heterocyclic compounds with a sulfonamide moiety were synthesized from reaction of enaminone 4 with active methylene compounds, glycine derivatives, 1,4-benzoquinone, hydroxylamine hydrochloride, hydrazonyl halides and dimethylacetylenedicarboxylate. The newly synthesized sulfonamide derivatives were characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy, elemental analysis and alternative synthetic routes. The reactions products were evaluated for their antiproliferative activity against a panel of three different human cancerous cell lines, MCF-7 (breast), HepG-2 (liver) and HCT-116 (colon) and the results were deployed to derive the structure-activity relationships (SAR). Various test compounds were potent antiproliferative to cancerous cells; reaching very low micromolar levels, as in case of 21 which showed IC50 value of 6.2μM against HepG-2 cell. In addition, treatment of cancerous cells with the synthesized compounds induced cell apoptosis and G2/M phase arrest evidenced by flow cytometric analysis. Furthermore, the activity of the synthesized compounds against TOP I and II were documented by DNA relaxation assays. Data revealed that compound 24 significantly interfered with TOP I- and II-mediated DNA relaxation, nicking and decatenation, with IC50 values 27.8 and 33.6μM, respectively. Moreover, the molecular docking studies supported the results from enzymatic assays, where compound 24 was intercalated between nucleotides flanking the DNA cleavage site via pi-pi stacking and hydrophobic interactions. In conclusion, aromatic heterocycles linked to sulfonamides are excellent molecular frameworks amenable for optimization as dual TOP I and II poisons to control various human malignancies.

Design and synthesis of some new thiophene and 1,3,4-thiadiazole based heterocycles

The reaction of 3-oxopropanenitriles with phenyl isothiocyanate in DMF containing KOH afforded the corresponding potassium salts. The latter salts were converted into ketene N,S-acetals upon acidification with hydrogen chloride. The reaction of the ketene N,S-acetals with 2-bromo-1-[5-methyl-1-(p-tolyl)-1H-1,2,3-triazol-4-yl]ethan-1-one or 3-(2-bromoacetyl)-2H-chromen-2-one gave novel thiophenes in good yields. Treatment of the ketene N,S-acetals with hydrazonyl halides afforded 1,3,4-thiadiazoles in good yields. The stereochemistry of the synthesized compounds was studied.

Heterocyclisation of 2,5-diacetyl-3,4-disubstituted-thieno[2,3-b]Thiophene Bis-Thiosemicarbazones Leading to Bis-Thiazoles and Bis-1,3,4-thiadiazoles as Anti-breast Cancer Agents

In this paper, the synthesis of bis-thiazoles and bis-1,3,4-thiadiazoles linked to a thienothiophene nucleus is described. The synthesis was achieved through interaction between 2,5-diacetylthieno[2,3-b]thiophene bis-thiosemicarbazones with a variety of hydrazonyl halides in a basic medium. All the synthesised compounds were characterised by IR, 1H NMR, 13C NMR and mass spectroscopic analyses. The newly synthesised compounds represent a variety of novel polyheteroatomic moieties containing nitrogen and sulfur. Most of the synthesised compounds were evaluated for their antitumour activity against the breast cancer MCF-7 cell line. The results revealed that four compounds are equipotent to tamoxifen (IC50 = 8.04 μg mL−1) with IC50 = 8.23, 8.26, 8.68 and 9.12 μg mL−1 respectively.

Synthesis and Reactivity of Enaminones: A Facile Synthesis of Thiophene and 1,3,4‐Thiadiazole Derivatives Incorporating a Thiazole Moiety

Several new heterocyclic compounds such as thiophene derivatives have been synthesized by the reactions of the versatile unreported 3‐mercapto‐2‐(4‐methyl‐2‐(tosylamino)thiazole‐5‐carbonyl)‐3‐phenylaminopropenal (7) with chloroacetonitrile, ethyl 2‐bromoacetate, and 1‐aryl‐2‐bromoethanone derivatives. Reaction of potassium salt intermediate 6 with hydrazonyl halides (14a, 14b, 14c) to afford 1,3,4‐thiadiazole derivatives incorporating a thiazole moiety has been described. All newly synthesized compounds were elucidated by considering the data of both elemental and spectral analysis.

Microwave-assisted synthesis of novel pyrazole and pyrazolo[3,4-d]pyridazine derivatives incorporating diaryl sulfone moiety as potential antimicrobial agents

We present a novel, facile and efficient methodology for the synthesis of pyrazoles and pyrazolo[3,4-d]pyridazines linked to diaryl sulfone moiety using synthetic talc as a solid base catalyst under microwave irradiation, via 1,3-dipolar cycloaddition reaction of the E-3-(dimethylamino)-1-(4-(phenylsulfonyl)phenyl)prop-2-en-1-one with different hydrazonyl halides. All synthesized compounds were evaluated for antibacterial and antifungal activities. The results showed that most of the synthesized compounds exhibited promising antimicrobial activities.

Isoxazolopyrimidinethione and Isoxazolopyridopyrimidinethione Derivatives: Key Intermediates for Synthesis of Novel Fused Triazoles as Potent 5α‐Reductase Inhibitors and Anti‐Prostate Cancer

The arylideneisoxazolone derivative 1 is used for preparation of two different pyrimidinethiones 3 and 5 through interaction with thiourea and thiouracil, respectively. Compounds 3 and 5 were subjected to reaction with different hydrazonyl halides in basic medium to afford different triazolopyrimidines 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h and 13a, 13b, 13c, 13d, 13e, 13f, the structures were confirmed by their spectral and elemental analysis. All the newly synthesized products were screened against 5α‐reductase. Some of the newly synthesized compounds showed potent 5α‐reductase inhibition activities with good ED50.

3-Amino-8-hydroxy-4-imino-6-methyl-5-phenyl-4,5-dihydro-3H-chromeno [2,3-d ]pyrimidine: An Effecient Key Precursor for Novel Synthesis of Some Interesting Triazines and Triazepines as Potential Anti-Tumor Agents

A number of interesting heterocycles were prepared through interaction of the intermediate 3-amino-8-hydroxy-4-imino-6-methyl-5-phenyl-4,5-dihydro-3H-chromeno-[2,3-d]pyrimidine (1) and reagents such as hydrazonyl halides 2 to furnish triazine derivatives 4a–l. Reaction of 1 with phenacyl bromide afforded compound 5. Moreover, the title compound 1 was subjected to condensation with active methylene compounds (ethyl acetoacetate and ethyl benzoylacetate) to give triazipinones 8a,b. The condensation with aromatic aldehydes afforded either the triazole derivatives 10a–d or Schiff base 11. In addition, the behaviour of compound 1 towards activated unsaturated compounds namely dimethyl acetylene dicarboxylate and ethoxymethylenemalonitrile was studied and it was found to furnish the triazine 13 and triazepine derivative 15, respectively. Combination of title compound 1 with chlorinated active methylene compounds delivered the triazine derivatives 18a–c. Reaction of 1 with chloroacetonitrile furnished compound 20. The structures of the products were elucidated based on their microanalyses and spectroscopic data. Finally, the antitumor activity of the new compounds 4a and 8a against human breast cell MCF-7 line and liver carcinoma cell line HepG2 were recorded.

A Convenient Route to 1,3,4-Thiadiazoles, Thiazolidinone, Thiazoles, Pyridones, Coumarins, Triazolo[5,1-c]triazines, and Pyrazolo[5,1-c]triazines Incorporating Pyrazolone Moiety and Their Use as Antimicrobial Agents

Condensation of 4-acetyl-5-methyl-2-phenyl-2,4-dihydropyrazol-3-one (1) with hydrazine derivatives (2a–d) afforded hydrazone derivatives (3a–d), which reacted with alkyl halides 4a–c to give bis(alkylthio)methylene derivatives (5a–e). Also, 3a,b reacted with hydrazonyl halides 6a–d to give 1,3,4-thiadiazole (7a–d). Cyclization of 3c with ethyl bromoacetate and haloketones gave thiazolidinone and thiazole derivatives (8, 10a,b) respectively. Treatment of hydrazone (3d) with benzylidine malononitrile 13a,b gave pyridine (14a,b). In addition, cyclocondensation of 3d with phenolic aldehydes furnished coumarin derivatives (16a–c). Coupling of 3d with heterocyclic diazonium salts gave triazol[5,1-c]triazine (20) and pyrazolo[5,1-c]triazine (22). Some of the prepared products showed potent antimicrobial activity.

Ultrasound promoted synthesis of substituted pyrazoles and isoxazoles containing sulphone moiety

Novel pyrazoles and isoxazoles were synthesized from the reaction of the carbanions of 1-aryl-2-(phenylsulphonyl)-ethanone with different hydrazonyl halides and 1-aryl-2-bromo-2-hydroximinoethanone in ethanol, respectively. Reactions were carried out under silent and ultrasonic conditions. In general, it was found that ultrasound irradiations enable some reactions to occur which could not be carried out under silent condition in addition to improvement in reaction times. The products were obtained in high yields and their structures were determined by elemental analyses, spectral data and X-ray diffraction.

Ultrasound assisted synthesis of some new 1,3,4-thiadiazole and bi(1,3,4-thiadiazole) derivatives incorporating pyrazolone moiety

Novel substituted 1,3,4-thiadiazole and bi(1,3,4-thiadiazole) were synthesized from reaction of 1-methyl-5-oxo-3-phenyl-2-pyrazolin-4-thiocarbox-anilide with a series of different hydrazonyl halides or N,N′-diphenyl-oxalodihydrazonoyl dichloride. The reactions were carried out under both conventional and ultrasonic irradiation conditions. In general, improvement in rates and yields were observed when reactions were carried out under sonication compared with classical condition. Structures of the products were established on analytical and spectral data.

Studies on enaminonitriles: A new synthesis of 1,3-substituted pyrazole-4-carbonitrile

3-Diethylaminoacrylonitrile (1) reacts with hydrazonyl halides (2a-d) to yield 1,3-disubstituted pyrazole-4-carbonitriles 5a-d. The acetyl 1-p-chlorophenylpyrazole-4-carbonitrile (5a) condensed with hydrazine hydrate to yield the bishydrazone 10 and with dimethylformamide dimethylacetal to yield 1-aryl-3-(3-dimethylamino)acryloyl pyrazole-4-carbonitrile (11). This enamine reacts with hydrazine hydrate to yield the pyrazolylpyrazole (12) and with naphthoquinone to yield the 3-naphthofuranoyl pyrazole 13. The pyra-zolyl pyridine derivative 14 was obtained upon treatment of 11 with acetylacetone in the presence of ammonium acetate. Compound 11 was coupled with p-chlorobenzene diazonium chloride to yield the hydrazone 16 that was coupled further with p-chlorobenzenediazonium chloride to yield the formazane 18.

ChemInform Abstract: Facile Synthesis of Hydrazonyl Halides by Reaction of Hydrazones with N‐Halosuccinimide‐Dimethyl Sulfide Complex.

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Facile synthesis of hydrazonyl halides by reaction of hydrazones with N-halosuccinimide-dimethyl sulfide complex

A new and convenient method is described for the synthesis of hydrazonyl halides. Hydrazones on treatment with N-chlorosuccinimide-dimethyl sulfide complex result in the formation of the corresponding hydrazonyl chlorides in good yields. Similarly, treatment of hydrazones with N-bromosuccinimide-dimethyl sulfide complex gives the corresponding hydrazonyl bromide under extremely mild conditions.

An efficient entry to perfluoroalkyl substituted azoles starting from β-perfluoroalkyl-β-dicarbonyl compounds

5-Perfluoroalkylpyrazoles 6, 5-perfluoroalkylisoxazoles 11, and 4-perfluoroacylisoxazoles 13 are obtained in high chemical yields and complete site and regioselectivity through the reaction of β-perfluoroalkyl-β-dicarbonyls 2 with hydrazonyl halides 1 and halooximes 8 in the presence of bases.

A one step synthesis of 1,3-disubstituted indeno[1,2-c] pyrazol-4(1H)-ones

A new synthesis of 1,3-disubstituted ideno[1,2-c]-pyrazol-4(1H)-ones has been developed using hydrazonyl halides and 1,3-indanedione.

ChemInform Abstract: Reaction of Alkinylthiophosphinous and Phosphonous Acid S‐Esters with Nitrilimines.

AbstractThe phosphinites (I) and (IV) or the phosphonites (VI) and (VIII) are coupled with nitrilimines, generated in situ from hydrazonyl halides such as (II), to give the diazaphosphorines (III), (V), (VII), and (IX) respectively.