Hydrazonyl Chlorides Research Articles

Design, Synthesis, Antimicrobial Activity and Molecular Docking of Novel Pyridine, Thiophene, and Thiadiazole Scaffolds Utilizing 2-Cyano-N-(4-(1-(2-(2-cyanoacetyl)hydrazineylidene)ethyl)phenyl)acetamide

An efficient protocol is reported for synthesizing arylidene adducts, pyridine derivatives, in excellent yields by treating 2-cyano-N-(4-(1-(2-(2-cyanoacetyl) hydrazineylidene) ethyl)phenyl)acetamide with quinoline-3-carbaldehydes, 2-arylidenemalononitriles, and acetylacetone in EtOH, respectively. In addition, dithiadiazole and dithiophene adducts were synthesized from one pot reaction using phenyl isothiocyanate, and either hydrazonyl chloride or 2-bromo-1-(5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-yl)ethan-1-one in DMF containing potassium hydroxide. The structure of novel products was elucidated using spectroscopic data and elemental analyses. The synthesized compounds were evaluated for their antimicrobial activities. The compounds showed antibacterial and antifungal activities against the tested G-ve and G+ve bacteria and against the tested fungi. The MIC was mostly in the range of 100-500 μg/mL. Molecular docking was used to analyse interactions between the compounds and antimicrobial target proteins. The molecular docking simulation showed lower binding energy with different types of interaction at the active site of Sterol 14-demethylase of C. albicans, Fdc1 proteins of A. niger, DNA Gyrase of E. coli, and LasR, an activator of exotoxin. An expression of P. aeruginosa indicates that these compounds could inhibit the enzyme and cause promising antimicrobial effects.

A versatile precursor for one‐pot synthesis of novel azo‐thiazole and thiazole scaffolds as prospective antimicrobial and antioxidant agents

AbstractIn this study, we present a simple method for preparing a new series of thiazoles with excellent isolated yields. To synthesize the target thiazole scaffolds, a straightforward one‐pot procedure was developed including an amine‐mediated reaction of isoxazolethiazolidin‐4‐one derivative, thiosemicarbazide, and appropriate hydrazonyl chlorides. The reaction conditions for this one‐pot protocol were optimized by experimenting with different solvents and amines. The best results were achieved by conducting the reaction in dioxane with triethylamine at 100°C for 5 h. The structures of the desired products were proved by different elemental analyses and spectral data. Additionally, the antimicrobial efficacy of all target derivatives was assessed against various types of microorganisms. The results observed indicated that the antimicrobial activity of the thiosemicarbazone derivative 2 was the strongest activity among the new series, with MIC values ranging from 0.03 ± 0.01 to 0.98 ± 0.15 μg/mL. Moreover, antioxidant evaluations were conducted on all the desired targets, using ascorbic acid as a reference drug. Significantly, derivatives 2 and 10 demonstrated the most promising antioxidant inhibitory effects. Additionally, further toxicity studies were performed on the most active novel compounds, revealing their best drug‐like properties and varying toxicity risks in humans.

Modern Approaches to the Synthesis of Pyrazoles (A Review)

The article analyzes publications that present the results of studies of modern approaches to the synthesis of new and known heterocycles with a pyrazole fragment, as well as syntheses aimed at expanding the library of compounds of this series from hydrazines, hydrazides, semi- or thiosemicarbazides, diazo compounds, hydrazonyl chlorides. Some examples are shown that use approaches to the synthesis of pyrazoles through multicomponent reactions involving amines and hydroxamic acid or an amine and enaminoketone. References are provided to publications that reflect the results of studies of the biological activity of these heterocycles, the use of certain metals as selective extractants, the possibility of obtaining metal complexes with their participation, as well as some photochemical transformations.

Stereoselective Asymmetric Syntheses of Molecules with a 4,5-Dihydro-1H-[1,2,4]-Triazoline Core Possessing an Acetylated Carbohydrate Appendage: Crystal Structure, Spectroscopy, and Pharmacology.

A new series of chiral 4,5-dihydro-1H-[1,2,4]-triazoline molecules, featuring a β-ᴅ-glucopyranoside appendage, were synthesized via a 1,3-dipolar cycloaddition reaction between various hydrazonyl chlorides and carbohydrate Schiff bases. The isolated enantiopure triazolines (8a-j) were identified through high-resolution mass spectrometry (HRMS) and vibrational spectroscopy. Subsequently, their solution structures were elucidated through NMR spectroscopic techniques. Single-crystal X-ray analysis of derivative 8b provided definitive evidence for the 3-D structure of this compound and revealed important intermolecular forces in the crystal lattice. Moreover, it confirmed the (S)-configuration at the newly generated stereo-center. Selected target compounds were investigated for anti-tumor activity in 60 cancer cell lines, with derivative 8c showing the highest potency, particularly against leukemia. Additionally, substituent-dependent anti-fungal and anti-bacterial behavior was observed.

Synthesis of Pyridazino[4,5-b]indoles by [3+3] Annulation of 2-Alkenylindoles and Hydrazonyl Chlorides.

A novel [3+3] annulation reaction of 2-alkenylindoles with hydrazonyl chlorides in the presence of base for the formation of pyridazino[4,5-b]indoles was developed. This approach provided a convenient and efficient way to synthesize a series of functionalized pyridazino[4,5-b]indoles derivatives. The method exhibited a broad substrate scope and provided the corresponding pyridazino[4,5-b]indoles products with excellent yields.

Novel Thiazole Derivatives Containing Imidazole and Furan Scaffold: Design, Synthesis, Molecular Docking, Antibacterial, and Antioxidant Evaluation.

Carbothioamides 3a,b were generated in high yield by reacting furan imidazolyl ketone 1 with N-arylthiosemicarbazide in EtOH with a catalytic amount of conc. HCl. The reaction of carbothioamides 3a,b with hydrazonyl chlorides 4a-c in EtOH with triethylamine at reflux produced 1,3-thiazole derivatives 6a-f. In a different approach, the 1,3-thiazole derivatives 6b and 6e were produced by reacting 3a and 3b with chloroacetone to afford 8a and 8b, respectively, followed by diazotization with 4-methylbenzenediazonium chloride. The thiourea derivatives 3a and 3b then reacted with ethyl chloroacetate in ethanol with AcONa at reflux to give the thiazolidinone derivatives 10a and 10b. The produced compounds were tested for antioxidant and antibacterial properties. Using phosphomolybdate, promising thiazoles 3a and 6a showed the best antioxidant activities at 1962.48 and 2007.67 µgAAE/g dry samples, respectively. Thiazoles 3a and 8a had the highest antibacterial activity against S. aureus and E. coli with 28, 25 and 27, 28 mm, respectively. Thiazoles 3a and 6d had the best activity against C. albicans with 26 mm and 37 mm, respectively. Thiazole 6c had the highest activity against A. niger, surpassing cyclohexamide. Most compounds demonstrated lower MIC values than neomycin against E. coli, S. aureus and C. albicans. A molecular docking study examined how antimicrobial compounds interact with DNA gyrase B crystal structures. The study found that all of the compounds had good binding energy to the enzymes and reacted similarly to the native inhibitor with the target DNA gyrase B enzymes' key amino acids.

Docking, synthesis, and anticancer assessment of novel quinoline-amidrazone hybrids

A group of new amidrazone compounds that include a quinoline component was produced through the reaction of hydrazonyl chloride, derived from 6-aminoquinoline, with appropriate secondary cyclic amines. The new compounds were confirmed through 1H-NMR, 13C-NMR, FTIR, and HRMS, and further verified by single-crystal X-ray diffraction. The antitumor potential of the synthesized compounds was tested against lung cancer (A549) and breast cancer (MCF-7) cell lines. Among the compounds, the ethyl carboxylate and o-hydroxy phenyl piperazine derivatives (10d and 10g) exhibited the strongest activity against both cell lines, with IC50 values of 43.1 and 59.1 μM for the lung and breast cancer cell lines, respectively. Moreover, the most potent compounds were subsequently docked into the c-Abl kinase binding site (PDB code: 1IEP) as a possible anticancer mechanism. In-silico ADMET study shows acceptable pharmacokinetic properties, and the toxicity profile for the most potent compounds is non-carcinogenic.

Aromatic C–C Bond Cleavage in a Curved π-System of Aminocorannulene

We report a metal- and oxidant-free aromatic C-C bond cleavage in the curved corannulene skeleton. Reaction of 1-aminocorannulene with hydrazonyl chloride generates an amidrazone intermediate that undergoes facile intramolecular proton migrations and ring annulation to give a 1,2,4-triazole derivative of planar benzo[ghi]fluoranthene, in which the release of strain associated with the curved π-surface and the formation of an aromatic triazole moiety are the driving forces. This report provides new insights into the aromatic C-C bond cleavage.

Synthesis of tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives linked morpholine moiety as CDK2 inhibitors.

With the aim of developing cyclin-dependent kinase 2 (CDK2) inhibitors with strong antibreast cancer efficacy, new tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives were synthesized. The newly synthesized tri- and tetracyclic derivatives were achieved from the reaction of 4-(4-morpholin-4-yl-phenyl)-1,3,4,5,6,7-hexahydro-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-thione (5) with α-haloketone derivatives as hydrazonyl chlorides, phenacyl bromide derivatives, chloroacetone, and ethyl substituted acetate derivatives. The MCF-7 and MDA-MB-231 breast cancer cell lines were utilized to examine the anticancer properties. Compounds 5 and 8 were shown to be the most effective, with half-maximal inhibitory concentration (IC50 ) values between 5.73 and 9.11 µM, which are on the level with doxorubicin. Mechanistic studies showed that 5 and 8 caused tumor cell death by inducing apoptosis and they also produced cancer arrest in the S phase of the cell cycle. In addition, compounds 5 and 8 showed strong anti-CDK2 action (IC50 = 0.112 and 0.18 µM, respectively) comparable to roscovitine (IC50 = 0.127 µM). Moreover, the docking result demonstrated that derivatives 5 and 8 fit into the CDK2 active site in the proper orientation.

Synthesis of 4-Aryl-1,3,4-benzotriazepinones from Isatoic Anhydrides and Hydrazonyl Chlorides

An efficient synthesis of 4-aryl-1,3,4-benzotriazepinones from readily available isatoic anhydrides and hydrazonyl chlorides was developed. In this facile protocol, a series of functionalized 1,3,4-benzotriazepinones were conveniently obtained with broad substrate scope and excellent functional group tolerance.

New Arylazo-Based (Chromene-Thiazole) Hybrids as Potential MRSA Inhibitors.

A three-component protocol was established to efficiently synthesize (chromene-thiazole) and related arylazo analogs in good to excellent yields. The desired products were prepared by reacting the appropriate salicylaldehydes, 2-cyanothioacetamide, and chloroacetone or hydrazonyl chlorides. Using piperidine as a mediator in ethanol at 80 °C for 4-6 h, the three-component protocol produce the target hybrids in 87-96 % yields. The newly synthesized products showed a broad range of antibacterial activity. The addition of an arylazo unit at the chromene-C6 position significantly improved the antibacterial activity, while the impact of adding an arylazo group at the thiazole-C5 position varied based on the electronic characteristics of the para-substituted arene unit. Generally, series that is linked to two arylazo units, one at chromene-C6 and the other at thiazole-C5, showed the best activity. Some new hybrids showed effective antibacterial activity than ciprofloxacin with MIC/MBC values up to 1.9/3.9 μM against S. aureus and E. coli. Additionally, they demonstrated better effectiveness against MRSA ATCC:33591 and ATCC:43300 compared to linezolid, with MIC/MBC values up to 4.0/16.1 and 3.9/15.6 μM, respectively. The data predicted for the physicochemical properties, lipophilicity, pharmacokinetics, and drug-likeness of new arylazo-based chromene-thiazole hybrids evaluated by SwissADME. As a result of the above, products that are linked to two arylazo units can be considered drug-like scaffolds.

Structural assessment of novel spiro-naphthalene-1.2'- [1,3,4]oxadiazol-4-ones prepared under batch and flow chemistry with a concise antifungal and anti(myco)bacterial activity

The reaction of hydrazonyl chlorides with 2,3-dichloro-1,4-naphthoquinone yielded pharmaceutically important spiro-naphthalene-1,2'- [1,3,4]oxadiazol-4-ones under batch and flow synthesis methods. The regioselective cycloaddition protocol operates under mild conditions, tolerates a wide range of structural moieties and delivers versatile spiro-oxadiazole motif with high efficiency. The obtained products were elucidated by IR, 1H NMR, 13C NMR, HRMS and compound 6h was characterized by single crystal X-ray diffraction technique. The synthesized molecules have been subjected to theoretical analysis by quantum chemical calculations at DFT/B3LYP/def2-TVZP level, which provided supporting data for the experimental findings. In addition, a concise biological evaluation of some selected novel spirocyclic molecules is reported.

Regioselective Synthesis of 5-Trifluoromethyl 1,2,4-Triazoles via [3 + 2]-Cycloaddition of Nitrile Imines with CF3CN.

We herein describe a general approach to 5-trifluoromethyl 1,2,4-triazoles via the [3 + 2]-cycloaddition of nitrile imines generated in situ from hydrazonyl chloride with CF3CN, utilizing 2,2,2-trifluoroacetaldehyde O-(aryl)oxime as the precursor of trifluoroacetonitrile. Various functional groups, including alkyl-substituted hydrazonyl chloride, were tolerated during cycloaddition. Furthermore, the gram-scale synthesis and common downstream transformations proved the potential synthetic relevance of this developed methodology.

Synthesis and greener pastures biological study of bis-thiadiazoles as potential Covid-19 drug candidates.

A novel series of bis- (Abdelhamid et al., 2017, Banerjee et al., 2018, Bharanidharan et al., 2022)thiadiazoles was synthesized from the reaction of precursor dimethyl 2,2′-(1,2-diphenylethane-1,2-diylidene)-bis(hydrazine-1-carbodithioate) and hydrazonyl chlorides in ethanol under ultrasonic irradiation. Spectral tools (IR. NMR, MS, elemental analyses, molecular dynamic simulation, DFT and LUMO and HOMO) were used to elucidate the structure of the isolated products. Molecular docking for the precursor, 3 and ligands 6a-i to two COVID-19 important proteins Mpro and RdRp was compared with two approved drugs, Remdesivir and Ivermectin. The binding affinity varied between the ligands and the drugs. The highest recorded binding affinity of 6c with Mpro was (−9.2 kcal/mol), followed by 6b and 6a, (−8.9 and −8.5 kcal/mol), respectively. The lowest recorded binding affinity was (−7.0 kcal/mol) for 6 g. In comparison, the approved drugs showed binding affinity (−7.4 and −7.7 kcal/mol), for Remdesivir and Ivermectin, respectively, which are within the range of the binding affinity of our ligands. The binding affinity of the approved drug Ivermectin against RdRp recoded the highest (−8.6 kcal/mol), followed by 6a, 6 h, and 6i are the same have (−8.2 kcal/mol). The lowest reading was found for compound 3 ligand (−6.3 kcal/mol). On the other side, the amino acids also differed between the compounds studied in this project for both the viral proteins. The ligand 6a forms three H-bonds with Thr 319(A), Sr 255(A) and Arg 457(A), whereas Ivermectin forms three H-bonds with His 41(A), Gly143(A) and Gln 18(A) for viral Mpro. The RdRp amino acids residues could be divided into four groups based on the amino acids that interact with hydrogen or hydrophobic interactions. The first group contained 6d, 6b, 6 g, and Remdesivir with 1–4 hydrogen bonds and hydrophobic interactions 1 to 10. Group 2 is 6a and 6f exhibited 1 and 3 hydrogen bonds and 15 and 14 hydrophobic interactions. Group 3 has 6e and Ivermectin shows 4 and 3 hydrogen bonds, respectively and 11 hydrophobic interactions for both compounds. The last group contains ligands 3, 6c, 6 h, and 6i gave 1–3 hydrogen bonds and 6c and 3 recorded the highest number of hydrophobic interactions, 14 for both 6c and 6 h. Pro Tox-II estimated compounds’ activities as Hepatoxic, Carcinogenic and Mutagenic, revealing that 6f-h were inactive in all five similar to that found with Remdesivir and Ivermectin. The drug-likeness prediction was carried out by studying physicochemical properties, lipophilicity, size, polarity, insolubility, unsaturation, and flexibility. Generally, some properties of the ligands were comparable to that of the standards used in this study, Remdesivir and Ivermectin.

Regioselective [3 + 2] cycloaddition synthesis and theoretical calculations of new chromene-pyrazole hybrids: A DFT-based Parr Function, Fukui Function, local reactivity indexes, and MEP analysis

The [3 + 2] cycloaddition synthesis of new series of chromene-pyrazole hybrids was the focus of this research. New chromene-based enaminones were synthesized and used as reactive ethylene derivatives in this study. The respective nitrilimines, or three-atom-components (TACs), were prepared in situ by the action of triethylamine on the appropriate hydrazonyl chlorides. The desired reaction was carried out in benzene for 3 h, yielding the target hybrids in 81–93% yields. The structure of the regioisomeric products was confirmed as 4-aroylpyrazoles rather than 5-aroyl analogues using both 1D and 2D NMR techniques. To better understand the regioselectivity observed in this [3 + 2] cycloaddition reaction, DFT calculations were performed at the B3LYP/6–31+G(d,p) computational level. The increased stability of 4-aroylpyrazoles and the possibility that they are the regioisomeric products are supported by the above calculations. Local reactivity indexes, NBO, and MEP mapping were used at the same calculation level to shed more light on the regioselectivity in the desired reaction by pinpointing the preferred regions for electrophilic and nucleophilic attack. We looked at two possible interactions between TACs and ethylene derivatives. All of the results suggest that the interaction that results in the formation of the regioisomeric 4-aroyl product is superior to the other.

Base-controlled annulation of tryptamine-derived isocyanides with nitrile imines for access to polycyclic spiroindoline derivatives

An annulation reaction of tryptamine-derived isocyanides with hydrazonyl chlorides in the presence of bases was developed. Controlled by different bases, [1+ ​2+3] annulation and [1+ ​2+3]/[2 ​+ ​3] annulation cascade were realized. In the latter reaction, five new chemical bonds as well as three new heterocycles were formed in one step. It showed extremely high efficiency, relatively broad substrate scope, milder reaction conditions, good tolerance of functional groups and good chemoselectivity.

Quadruple Functionalized Pyrazole Pharmacophores by One-pot Regioselective [3+2] Cycloaddition of Fluorinated Nitrile Imines and Dicyanoalkenes.

Here we present a quadruple functionalization approach for the modular construction of fully substituted N1 -aryl 3-di/trifluoro-methyl-4/5-cyanopyrazole pharmacophores from readily available hydrazonyl chlorides and dicyanoalkenes. The realization of this [3+2] cycloaddition reaction hinges upon the employment of N-aryl di/trifluoromethyl nitrile imines as the 1,3-dipoles to bypass external synthetic steps and dicyanoalkenes as the dipolarophiles to tune the regioselectivity. This one-pot strategy offers access to a divergent library of cyano analogues of prevalent 3-di/trifluoromethyl pyrazole pharmacophores, among which several compounds have shown potent inhibitory activity towards cyclooxygenase 2 (COX-2) compared with marketed drug Celecoxib.

New piperazine-based bis(thieno[2,3-b]pyridine) and bis(pyrazolo[3,4-b]pyridine) hybrids linked to benzofuran units: Synthesis and in vitro screening of potential acetylcholinesterase inhibitors

Two series of piperazine-based bis(thieno[2,3-b]pyridines) and bis(pyrazolo[3,4-b]pyridines) were prepared, in good yields, utilizing the appropriate bis(pyridinethione). The first series was obtained by reacting the previous synthon with different α-halogenated reagents, whereas the second series was produced by reacting the synthon with various hydrazonyl chlorides, and then cyclizing the resulting bis(hydrazonothioates). At 50 and 100 µM concentrations, the two series were screened as potential acetylcholinesterase inhibitors. The reference donepezil had inhibition percentages of 90.7 and 93.5 at the tested concentrations. Generally, bis(thieno[2,3-b]pyridine) series was found to be more effective than the other series of bis(pyrazolo[3,4-b]pyridine). Bis(thieno[2,3-b]pyridine-2-carbonitrile) inhibited acetylcholinesterase the best, with inhibition percentages of 55.2 and 88.4 at 50 and 100 µM concentrations, respectively. Furthermore, when tested at a concentration of 25 µg/mL, the prior hybrid demonstrated the best DPPH antioxidant activity, with an inhibition percentage of 81.5 when compared to the reference ascorbic acid (inhibition percentage of 88.7).

Highly diastereoselective cascade dearomatization of 3-(2-isocyanoethyl)indoles with nitrile imines: a facile access to unexpected polycyclic indolines

A novel cascade annulation between 2-isocyanoethylindoles and hydrazonyl chlorides has been realized to assemble a variety of unexpected polycyclic indoline derivatives with excellent diastereoselectivities under simple reaction conditions.

Pyridine‐2(1H)‐thiones: Versatile precursors for one‐pot synthesis of new nicotinonitrile‐thiazole hybrids

AbstractIn the current study, we report a facile procedure for the preparation of a new series of nicotinonitrile‐thiazoles, in excellent isolated yields. For this purpose, pyridine‐2(1H)‐thiones were investigated as key building blocks for the synthesis of new nicotinonitrile‐linked 2‐hydroxybenzaldehyde derivatives. To prepare the target thiazole hybrids, a facile one‐pot procedure was developed involving amine‐mediated reaction of the prior aldehydes, thiosemicarbazide, and the appropriate of hydrazonyl chlorides. The reaction conditions of this one‐pot protocol were optimized by repeating the reaction using different solvents and amines. The optimized conditions were conducting the reaction in dioxane containing triethylamine at 100°C for 5 h. The prior protocol gave, in each case, new series of nicotinonitrile‐linked thiazole and thiazol‐4(5H)‐one hybrids, bearing aryldiazenyl or arylhydrazineylidene units. Repeating the prior one‐pot protocol using the appropriate halogen containing reagents instead of hydrazonyl chlorides afforded the target thiazoles in excellent isolated yields. By considering their elemental analyses and spectral findings, the structures of the new hybrids were clarified.