Amidrazone Derivatives Research Articles

Modeling of Effectiveness of N3-Substituted Amidrazone Derivatives as Potential Agents against Gram-Positive Bacteria.

Prediction of the antibacterial activity of new chemical compounds is an important task, due to the growing problem of bacterial drug resistance. Generalized linear models (GLMs) were created using 85 amidrazone derivatives based on the results of antimicrobial activity tests, determined as the minimum inhibitory concentration (MIC) against Gram-positive bacteria: Staphylococcus aureus, Enterococcus faecalis, Micrococcus luteus, Nocardia corallina, and Mycobacterium smegmatis. For the analysis of compounds characterized by experimentally measured MIC values, we included physicochemical properties (e.g., molecular weight, number of hydrogen donors and acceptors, topological polar surface area, compound percentages of carbon, nitrogen, and oxygen, melting points, and lipophilicity) as potential predictors. The presence of R1 and R2 substituents, as well as interactions between melting temperature and R1 or R2 substituents, were also considered. The set of potential predictors also included possible biological effects (e.g., antibacterial, antituberculotic) of tested compounds calculated with the PASS (Prediction of Activity Spectra for Substances) program. Using GLMs with least absolute shrinkage and selection (LASSO), least-angle regression, and stepwise selection, statistically significant models with the optimal value of the adjusted determination coefficient and of seven fit criteria were chosen, e.g., Akaike's information criterion. The most often selected variables were as follows: molecular weight, PASS_antieczematic, PASS_anti-inflam, squared melting temperature, PASS_antitumor, and experimental lipophilicity. Additionally, relevant to the bacterial strain, the interactions between melting temperature and R1 or R2 substituents were selected, indicating that the relationship between MIC and melting temperature depends on the type of R1 or R2 substituent.

Trifluoromethylated Amidrazone Derivatives as Key Compounds for the Synthesis of 4-Aryl-3,5-bis(trifluoromethyl)-4H-1,2,4-triazoles

AbstractA novel, efficient, and solvent-free approach for the synthesis of aryl-3,5-bis(trifluoromethyl)-4H-1,2,4-triazoles is disclosed via the nucleophilic intramolecular cyclization reaction of trifluoromethylated amidrazone and 2,2,2-trifluoroacetic anhydride. The trifluoromethylated amidrazone intermediates used in this project are synthesized from the reaction of N-aryl-2,2,2-trifluoroacetimidoyl chloride derivatives and hydrazine hydrate at ambient temperature in excellent yields.

A Review of the Biological Activity of Amidrazone Derivatives.

Amidrazones are widely used in chemical synthesis, industry and agriculture. We compiled some of the most important findings on the biological activities of amidrazones described in the years 2010–2022. The data were obtained using the ScienceDirect, Reaxys and Google Scholar search engines with keywords (amidrazone, carbohydrazonamide, carboximidohydrazide, aminoguanidine) and structure strategies. Compounds with significant biological activities were included in the review. The described structures derived from amidrazones include: amidrazone derivatives; aminoguanidine derivatives; complexes obtained using amidrazones as ligands; and some cyclic compounds obtained from amidrazones and/or containing an amidrazone moiety in their structures. This review includes chapters based on compound activities, including: tuberculostatic, antibacterial, antifungal, antiparasitic, antiviral, anti-inflammatory, cytoprotective, and antitumor compounds, as well as furin and acetylocholinesterase inhibitors. Detailed information on the compounds tested in vivo, along the mechanisms of action and toxicity of the selected amidrazone derivatives, are described. We describe examples of compounds that have a chance of becoming drugs due to promising preclinical or clinical research, as well as old drugs with new therapeutic targets (repositioning) which have the potential to be used in the treatment of other diseases. The described examples prove that amidrazone derivatives are a potential source of new therapeutic substances and deserve further research.

Synthesis, characterization, and anticancer evaluation of some new N1-(anthraquinon-2-yl) amidrazone derivatives

A new series of novel N1-anthraquinon-2-yl amidrazones incorporating N-piperazines and related congeners were synthesized via reaction of the hydrazonoyl chloride derived from 2-qaminoanthraquinone with the appropriate piperazine (secondary amine). Structures of the new compounds were confirmed by a panel of spectroscopic methods including IR, NMR, and MS and by elemental analysis. The antitumor activity of the newly prepared compounds was evaluated in vitro against MCF-7 breast cancer, K562 chronic myelogenous leukemia, and dermal fibroblasts cell lines by means of a cell viability assay using the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Results revealed that compounds 13a and 13d exhibit the highest inhibitory activity against K562 and MCF-7 cell lines. These two compounds could be considered as promising as potential anticancer drugs.

Synthesis, Characterization, and Bioactivity of Novel Bicinnolines Having 1‐Piperazinyl Moieties

A number of novel bicinnolines containing piperazine moieties, 4a–o, were synthesized via polyphosphoric acid‐catalyzed intramolecular cyclization of the respective acyl amidrazone derivatives (3a–o). On the other hand, the amidrazones (3a–o) were prepared by reaction of N′,N″‐(biphenyl‐4,4′‐diyl)bis(2‐oxopropane hydrazonoyl chloride) (2) with the appropriate cyclic sec‐amines in the presence of trimethylamine in absolute ethanol. Structures of the newly synthesized compounds were confirmed by NMR and mass spectral data. The antitumor activity of compounds 4a–o was evaluated in vitro on human breast cancer MDA‐231 by a cell viability assay. Results revealed that compounds 4k, 4n, and 4o exhibit potential cytotoxic effects (>70%) on the cancer cells. Additionally, the antimicrobial activity of compounds 4a–o was evaluated against three clinical microbial strains: Escherichia coli (Gram‐negative bacteria), Staphylococcus aureus (Gram‐positive bacteria), and Candida albicans (fungi/yeast). Results revealed that compounds 4e and 4k exhibit good activity against all three strains included in the study and that compound 4d displays excellent activity against S. aureus strain with a minimum inhibitory concentration value of 0.187 mg/mL.

Synthesis, crystal structure, 1H, 13C and 15N NMR studies, and biological evaluation of a new amidrazone-derived Au(III) complex

A new Au(III) complex was synthesized from an amidrazone derivative and HAuCl4. Cyclization of amidrazone moiety lead to the 1,2,4-triazolo[1,5a]pyridine ring system, followed by Au(III) chelation. The crystal and molecular structure of the final compound was studied by single crystal X-ray diffraction as well as by 1H13C and 1H15N HMQC- and HMBC-NMR spectroscopy, which resulted in the assignment of all detected signals. This species was tested in vitro as an antibacterial and antiproliferative agent. It exhibited good antibacterial activity against Staphylococcus aureus and was proved to be more potent than amoxicillin against Bacillus subtilis and the drug resistant strain of Klebsiella pneumoniae. In contrast, its antiproliferative properties against cancer cell lines A549, HT-29, MV-4-11 and MCF-7 were relatively low.

Synthesis and Structure-Activity Relationship; Exploration of some Potent Anti-Cancer Phenyl Amidrazone Derivatives.

Amidrazones have been reported to have significant anti-tumor properties against several cancer cell lines. The current project aims to profile the structure-anticancer activity relationship of phenyl-amidrazons. Fifteen phenyl-amidrazone-piperazine derivatives were prepared and tested against four cancer cell lines (leukemia, prostate, breast and colon cancers). Six compounds illustrated low micromolar anticancer IC50 values, while the remaining compounds were either inactive or of moderate potencies. All compounds were virtually nontoxic against normal fibroblast cells. Docking into the oncogenic kinase bcr/abl illustrated the critical importance of (i) phalogen substituent on the ligand's phenyl ring and (ii) the presence of positive ionizable moiety at the ligand's piperazine fragment for anticancer activity.

Novel amidrazone derivatives: Design, synthesis and activity evaluation

A series of new 6-styryl-naphthalene-2-amidrazone derivatives were synthesized and evaluated as potential ASIC1a inhibitors. Among them, compound 5e showed the most activity to inhibit [Ca2+]i. elevation in acid-induced articular chondrocytes. Together with the important role of ASIC1a in the pathogenesis of tissue acidification diseases including rheumatoid arthritis, these results might provide a meaningful hint or inspiration in developing drugs targeting at tissue acidification diseases.

An Approach to Polysubstituted Triazipines, Thiadiazoles and Thiazoles Based on Benzopyran Moiety Through The Utility of Versatile Hydrazonoyl Halides as In Vitro Monoamine Oxidase Inhibitors

The chromene compound 1 is used as a key intermediate for synthesis of new heterocyclic compounds, and it reacted with hydrazonoyl chlorides in presence of TEA to give the amidrazone derivatives 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, which were cyclized to the corresponding triazepines 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h on boiling with sodium ethoxide. Conversion of compound 1 to the methylthiocarbamate derivative 6 was performed through its reaction with carbon disulfide and KOH followed by treatment with methyl iodide. Compound 6 reacted with hydrazonoyl chlorides in presence of TEA to give thiadiazoles 8a, 8b, 8c, 8d, 8e, 8f, 8g. In addition, chromene 1 combined with aminodithiocarbamic acid in DMF under reflux to furnish the thiosemicarbazide derivative 9, which in turn interacted with several hydrazonoyl chlorides to give the thiazole derivatives 11a, 11b, 11c, 11d, 11e. The structures of the prepared compounds were confirmed from their spectroscopic data and elemental analysis. The synthesized compounds were tested against both monoamine oxidase (MAO)‐A and MAO‐B and corrected to analyses showed good inhibitory activities especially against MAO‐A.

Synthesis and Bioassay of Novel Substituted Pyrano[2,3‐f]cinnoline‐2‐ones

A new series of 9‐substituted‐4,10‐dimethylpyrano[2,3‐f]cinnolin‐2‐ones (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m) were synthesized via intramolecular cyclization of the respective acyl amidrazone derivatives (4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m), catalyzed by polyphosphoric acid. Compounds (4a, 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m) were synthesized through direct interaction of coumarin‐7‐yl hydrazonoyl chloride (3) with the corresponding cyclic sec‐amines in the presence of triethylamine. The structures of the new compounds were confirmed by elemental analyses, NMR, and MS spectral data. The antitumor activity of compounds 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k, 5l, 5m was evaluated in vitro on breast cancer cell line (MCF‐7) by a cell viability assay utilizing the tetrazolium dye 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide. Among the compounds tested, compounds 5d, 5f, 5k, and 5h showed potential anti‐MCF‐7 activity and were able to reduce the viability after 72 h to less than 50%.

ChemInform Abstract: Reactions of 3‐Phenyl‐1,2,4‐triazine with Some C‐Nucleophiles.

AbstractThe reaction of triazine (I) with C‐nucleophiles (II) and (IV) is reported.

Synthesis and Antitumor Activities of Some New N1‐(Flavon‐6‐yl)amidrazone Derivatives

A new series of N1-(flavon-6-yl)amidrazones were synthesized by reacting the hydrazonoyl chloride derived from 6-aminoflavone with the appropriate sec-cyclic amines. The antitumor activities of these compounds were evaluated on breast cancer (MCF-7) and leukemic (K562) cell lines. Among the compounds tested, the N-morpholine derivative was the most active against the MCF-7 and K562 cell lines, with IC50 values of 5.18 and 2.89 μM, respectively. Our docking studies showed that the N-morpholino derivative fits and blocks the oncogenic tyrosine kinases bcr/abl and epidermal growth factor receptor (EGFR) in a similar fashion to that of the potent anticancer agent imatinib.

Synthesis and Biological Evaluation of Novel3, 5-Disubstituted 4h-1, 2, 4-Triazoles

A general method was developed for the synthesis of novel unsymmetrical 3, 5-disubstituted 4H-1, 2, 4-triazoles with benzyl group in the 4-ring position (5a-j). A series of novel N-acyl amidrazone derivatives (4a-j) have been synthesized. The chemical structures of newly synthesis zed compounds were characterized by IR, H 1 NMR,C 13 NMR and mass. The newly synthesized compounds were screened for antimicrobial activity.

Reactions of 3-phenyl-1,2,4-triazine with some C-nucleophiles

Dimedone is added at C(5) of 3-phenyl-1,2,4-triazine to give stable dihydro derivative. Its reaction with 1-aryl-3-methylpyrazol-5- ones proceeds with fragmentation affording 1,1,2,2-tetrakispyrazolylethane and amidrazone derivatives.

Activation of Isocyanates and Carbon Dioxide by a Monomeric Aluminium Hydrazide as an Active Lewis Pair

The monomeric aluminium hydrazide H10 C5 NN(AltBu2 )Ad (4; Ad=adamantyl, NC5 H10 =piperidinyl) was obtained in high yield by hydroalumination of the corresponding hydrazone derivative 1. Compound 4 has a strained AlN2 heterocycle formed by a donor-acceptor bond between the β-nitrogen atom of the hydrazide group and the aluminium atom. Opening of this bond resulted in the formation of an active Lewis pair that was able to cooperatively activate carbon dioxide or isocyanates. Insertion of the heterocumulenes into the AlN bond selectively afforded a carbamate and two urea derivatives in high yield. In the first step, phenyl isocyanate gave the adduct 6, which has the oxygen atom coordinated to the aluminium atom and its central carbon atom bound to the nitrogen atom of the piperidine moiety. Adduct 6 represents a reasonable intermediate state for these activation processes. The applicability of hydroaluminated compounds, such as 4, in organic synthesis was demonstrated by the reaction with an imidoyl chloride, which gave the corresponding amidrazone derivative 9.

Remarkable stereoselectivity switch in synthesis of carbonyl substituted N2-arylamidrazones with low lipophilicity

Reaction of carbonyl substituted hydrazonoyl chlorides with amines usually leads to Z-configured amidrazone derivatives via nucleophilic substitution of the chlorine atom. Surprisingly, N,N-dimethylcarboxamide substituted hydrazonoyl chlorides yielded E-amidrazones when dialkylamines were used as nucleophilic reagent. The lipophilicities of the obtained amidrazones were found to be drastically reduced compared to their corresponding carboxanilides.

Synthesis and biological activity assays of some new N1-(flavon-7-yl)amidrazone derivatives and related congeners

A series of new N1-(flavon-7-yl)amidrazones incorporating N-piperazines and related congeners were synthesized by reacting the hydrazonoyl chloride derived from 7-aminoflavone and 7-amino-2-methylchromen-4-one with the appropriate piperazine. The chemical structures of the newly prepared compounds were confirmed by elemental analyses, 1H NMR, 13C NMR, and ESI-HRMS spectral data. The antitumor activity of these compounds was evaluated on breast cancer (MCF-7 and T47D) and Leukemic (K562) cell lines by a cell viability assay utilizing the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Although with varying degrees, a significant growth inhibitory and cytotoxic effect was observed on all three cancer cell lines. Among the compounds tested compounds, 5a, 15a, and 18b, were the most active against T47D cell line with IC50 values of 1.42, 1.92, and 2.92 μM, respectively. By using other cancer cell lines and with further characterization of their biological mechanism of action, these compounds could prove to be useful candidates as anticancer drugs.

Synthesis, crystal structure and biological activities of a novel amidrazone derivative and its copper(II) complex — A potential antitumor drug

A new linear amidrazone derivative, 6-acetyl-cyclohex-3-enecarboxylic acid [1-pyridin-2-yl-1-(pyridyn-2-yloamin)meth-(Z)-ylidene] hydrazide, H2L (2) and its Cu(II) complex, [Cu2L2]·4H2O (3) were synthesized and characterized by elemental analysis, IR and 1H NMR spectroscopy and cyclic voltammetry. Compound 2 was synthesized in the equimolar reaction of N3-substituted amidrazone with cis-1,2,3,6-tetrahydrophthalic anhydride. The Cu complex of 2 was obtained in the reaction with copper(II) acetate. The molecular structures of 2 and 3 were determined by X-ray crystallography. The parent ligand exists in its amide-hydrazone form in the solid state. The central amidrazone moiety has a Z configuration with respect to the double CN bond. Coordination to the metal center promotes Z/E isomerization of the hydrazone group of the ligand. Compound 3 is a dinuclear four-coordinated Cu(II) complex with the amidrazone ligand behaving as a tetradentate double deprotonated chelating one. Several biological activities of 2 and 3 were examined in vitro; they were: antimicrobial properties against selected bacterial and fungal strains, suppression of phytohemagglutinin A (PHA)-induced proliferation of human peripheral blood mononuclear cells (PBMC) and their effects on tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) production. The cytotoxic activity of Cu(II) complex was determined with respect to the four carcinoma cell lines (SW 984, CX-1, L-1210, A-431). The studied complex exhibited significant cytotoxic effects (particularly against CX-1 colon carcinoma), comparable to those reported for cisplatin. Both compounds have shown a relatively low antibacterial activity and were devoid of antifungal properties.

Synthesis and Tautomeric Structure of Novel 3-Arylazo-Imidazo[1,2-b]Pyrazolo[4,3-d]Pyridazines

Treatment of 3-acetyl-5-amino-4-cyano-1-phenylpyrazole with hydrazine hydrate afforded the hydrazone derivative. Reaction of the latter hydrazone with hydrazonoyl chlorides was found to be site selective as it afforded the corresponding formazan and not the amidrazone derivatives. The 1H NMR spectra of the formazan derivatives indicated that they exist as the bis-hydrazone tautomers. Acid-catalysed cyclisation of these dihydroformazans afforded the respective 9-amino-3-arylazo-6-methyl-8-phenyl-2-substituted-8 H-imidazo[1,2- b]pyrazolo[4,3- d]pyridazines whose electronic absorption spectra revealed that they exist predominantly in the arylazo tautomeric form. The structures of all compounds prepared were confirmed by spectral and elemental analyses. Also the mechanism of the reactions studied are discussed.

Novel amidrazone derivative and its Cu(II) complex: crystal structure and antitumor activity

Novel amidrazone derivative and its Cu(II) complex: crystal structure and antitumor activity