Synthesis of Arylsulfonyl Hydrazone Derivatives: Antioxidant Activity, Acetylcholinesterase Inhibition Properties, and Molecular Docking Study

Today, interest in studies on the search for new drugs to be used in diseases such as cancer, cardiovascular diseases, neurodegenerative diseases and diabetes, as well as prevention of microbial inflammation is increasing day by day. Emerging biological and pharmacological effects of sulfonyl hydrazone derivative compounds reveal their importance. In the present study, heteroatom-containing sulfonyl hydrazone derivatives have been studied for their anticancer and antimicrobial properties, as well as their effects on enzymes that could play roles in Alzheimer's dissease and diabetes. High doses of the tested compounds significantly decreased the cell viabilities of breast cancer (MCF-7) and prostate cancer (PC-3) cell lines. Furthermore, all compounds possessed antimicrobial activities against very common bacteria E. coli and S. aureus. These compounds were good inhibitors of the α-glycosidase, human carbonic anhydrase I and II isoforms and acetylcholinesterase enzyme with Ki values in the range of 1.14 ± 0.14–3.63 ± 0.26 nM for α-glycosidase, 66.05 ± 9.21–125.45 ± 11.54 nM for hCA I, 89.14 ± 10.43–170.22 ± 26.05 nM for hCA II and 754.03 ± 73.22–943.92 ± 58.15 nM for AChE, respectively. Molecular docking method was used to theoretically compare biological activities of sulfonyl hydrazone derivatives against enzymes. The theoretical results were compared with the experimental results. Thus, these compounds have strong biological activities. Communicated by Ramaswamy H. Sarma

Design, synthesis and in vitro biological activities of coumarin linked 1,3,4-oxadiazole hybrids as potential multi-target directed anti-Alzheimer agents

Acetylcholinesterase (AChE) is one of the main drug targets for treating Alzheimer's disease. This current study relies on multiple molecular modeling approaches to develop new potent inhibitors of AChE. We explored a 2D QSAR study using the statistical method of multiple linear regression based on a set of substituted 5-phenyl-1,3,4-oxadiazole and N-benzylpiperidine analogs, which were recently synthesized and proved their inhibitory activities against acetylcholinesterase (AChE). The molecular descriptors, polar surface area, dipole moment, and molecular weight are the key structural properties governing AChE inhibition activity. The MLR model was selected based on its statistical parameters: R2 = 0.701, R2test = 0.76, Q2CV = 0.638, and RMSE = 0.336, demonstrating its predictive reliability. Randomization tests, VIF tests, and applicability domain tests were adopted to verify the model's robustness. As a result, 11 new molecules were designed with higher anti-Alzheimer's activities than the model molecule. We demonstrated their improved pharmacokinetic properties through an in silico ADMET study. A molecular docking study was conducted to explore their AChE inhibition mechanisms and binding affinities in the active site. The binding scores of compounds M1, M2, and M6 were (-12.6 kcal/mol), (-13 kcal/mol), and (-12.4 kcal/mol), respectively, which are higher than the standard inhibitor Donepezil with a binding score of (-10.8 kcal/mol). Molecular dynamics simulations over 100 ns were used to validate the molecular docking results, indicating that compounds M1 and M2 remain stable in the active site, confirming their potential as promising anti-AChE inhibitors.

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane tyrosine kinase receptor that regulates key cellular processes such as proliferation, differentiation, and survival. Aberrant activation or overexpression of EGFR has been extensively associated with the onset and progression of various malignancies, including lung, breast, and colorectal cancers. Consequently, EGFR has emerged as a validated molecular target for the design of novel anticancer therapeutics. Sulfonyl hydrazone derivatives constitute a versatile class of organic compounds exhibiting a wide spectrum of biological activities, such as antimicrobial, anti-inflammatory, and anticancer effects. Their structural flexibility, presence of electron-donating and withdrawing substituents, and ability to form stable interactions with biological macromolecules make them promising scaffolds for the development of potent EGFR inhibitors with improved pharmacological profiles. To synthesize and comprehensively evaluate the structural, electronic, optical, and biological properties of a novel sulfonyl hydrazone derivative, N′-([1,1′-biphenyl]-4-ylmethylene)-4-methylbenzenesulfonohydrazide (BMBSH), as a potential EGFR inhibitor. BMBSH was synthesized via condensation of 4-methylbenzenesulfonohydrazide with [1,1′-biphenyl]-4-carbaldehyde using H₂SO₄ as a catalyst. The compound was characterized using FT-IR, ¹H NMR, and ¹ ³C NMR. Computational studies included DFT optimization, MEP and Mulliken analyses, molecular docking, 100 ns molecular dynamics (MD) simulation, and ADMET profiling. Spectroscopic data confirmed the formation of the hydrazone linkage and the imine (C N) bond. DFT results (HOMO–LUMO gap 4.215 eV) indicated strong electronic stability and close agreement with experimental data. BMBSH showed high nonlinear optical activity (β₀ = 2.939 × 10⁻³⁰ esu). Docking and MD studies demonstrated stable EGFR binding through hydrogen bonds and π–π interactions, with better stability than doxorubicin. ADMET analysis showed excellent intestinal absorption (92.86 %), blood–brain barrier penetration, and favorable bioavailability (0.55). BMBSH is a structurally stable, electronically robust, and pharmacologically promising EGFR inhibitor with strong binding affinity, superior stability, and good drug-like properties. These results highlight its potential as a lead compound for future anticancer drug design integrating synthetic and computational approaches. • Synthesis of novel hydrazone derivatives confirmed by FT-IR and NMR spectral techniques. • Investigation of electronic properties through DFT-based analysis. • Molecular docking and Dynamics simulation analysis to evaluate the inhibitory potential of the synthesized compound. • ADMET analysis was examined.

2-methylindole analogs as cholinesterases and glutathione S-transferase inhibitors: Synthesis, biological evaluation, molecular docking, and pharmacokinetic studies

Sulfonyl hydrazone derivatives containing acetonaphtone as anticholinesterase inhibitors for the treatment of Alzheimer's: X-ray single-crystal analysis, and multifaced theoretical calculations

Lophosoria quadripinnata (J.F.Gmel.) C.Chr., a fern species from the Dicksoniaceae family, is widely distributed in Central and South America. This study aimed to identify the bioactive compounds in the aqueous extract of L. quadripinnata, evaluate its antioxidant potential through in vitro analysis, and assess its neuroprotective effects via molecular docking and dynamics studies. Fourteen compounds were identified using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-ESI-QToF-MS). In vitro assays revealed high concentrations of phenolic and flavonoid compounds, alongside significant antioxidant activity. Molecular docking studies, involving acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, and the Nrf2-Keap1 protein complex, identified three compounds-5C3M (5-O-caffeoyl-3-O-malonylquinic acid), 5GDC (5-O-glucoside-6,7-dimethoxycoumarin), and irifloside-as promising inhibitors. These compounds exhibited favorable binding affinities, minimal toxicity, and strong interactions with key residues involved in the inhibition of the enzymes and protein complex. Additionally, molecular dynamics simulations revealed stable binding with AChE, BChE, and tyrosinase, with irifloside showing the highest binding affinity. The compounds also demonstrated the ability to modulate the Nrf2-Keap1 pathway, potentially enhancing the cellular antioxidant response. These findings suggest that L. quadripinnata contains bioactive compounds with significant potential for the development of neuroprotective agents, especially in oxidative stress-related diseases such as Alzheimer's and Parkinson's.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are known to be serine hydrolase enzymes responsible for the hydrolysis of acetylcholine (ACh), which is a significant neurotransmitter for regulation of cognition in animals. Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. In this study, 30 new hydrazone derivatives were synthesized. Then we evaluated their anticholinesterase activity of compounds. We also tried to get insights into binding interactions of the synthesized compounds in the active site of both enzymes by using molecular docking approach. The compounds were synthesized by the reaction of various substituted/nonsubstituted benzaldehydes with 6-(substitute/nonsubstituephenyl)-3(2H)-pyridazinone-2-yl propiyohydrazide. Anticholinesterase activity of the compounds was determined using Ellman's method. Molecular docking studies were done by using the ADT package version 1.5.6rc3 and showed by Maestro. RMSD values were obtained using Lamarckian Genetic Algorithm and scoring function of AutoDock 4.2 release 4.2.5.1 software. The activities of the compounds were compared with galantamine as cholinesterase enzyme inhibitor, where some of the compounds showed higher BChE inhibitory activity than galantamine. Compound F111 was shown to be the best BChE inhibitor effective in 50 μM dose, providing 89.43% inhibition of BChE (IC50=4.27±0.36 μM). This study supports that novel hydrazone derivates may be used for the development of new BChE inhibitory agents.

A series of bis(4-amino-5-cyano-pyrimidines) was synthesized and evaluated as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To further explore the multifunctional properties of the new derivatives, their antioxidant and antibacterial activities were also tested. The results showed that most of these compounds could effectively inhibit AChE and BChE. Particularly, compound 7c exhibited the best AChE inhibitory activity (IC50 = 5.72 ± 1.53 μM), whereas compound 7h was identified as the most potent BChE inhibitor (IC50 = 12.19 ± 0.57 μM). Molecular modeling study revealed that compounds 7c, 7f, and 7b showed a higher inhibitory activity than that of galantamine against both AChE and BChE. Anticholinesterase activity of compounds 7h, 7b, and 7c was significant in vitro and in silico for both enzymes, since these compounds have hydrophobic rings (Br-phenyl, dimethyl, and methoxyphenyl), which bind very well in both sites. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activities. Indeed, in the superoxide-dimethyl sulfoxide alkaline assay, compound 7j showed very high inhibition (IC50 = 0.37 ± 0.28 μM). Also, compound 7l exhibited strong and good antibacterial activity against Staphylococcus epidermidis and Staphylococcus aureus, respectively. Taking into account the results of biological evaluation, further modifications will be designed to increase potency on different targets. In this study, the obtained results can be a new starting point for further development of multifunctional agents for the treatment of Alzheimer's disease.

A new series of chiral hydrazide-hydrazone derivatives were synthesized and evaluated their acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase and urease inhibition and antioxidant activities. The chemical structures of newly synthesized chiral aryl hydrazide-hydrazone derivatives were clarified using UV-Vis, IR, 1H and 13C NMR, and mass spectroscopies. According to NMR data, due to the partial double bond character of the amide C-N bond, two conformational isomers (E and Z) exist in solution. Based on this information, the conformational properties of the synthesized compounds were investigated using temperature-dependent NMR spectroscopy and DFT. The results of DFT studies revealed that E(C=N)-E(C(O)-N) conformer is the most stable structure for the synthesized hydrazones. In addition, the enzyme inhibition potentials of the synthesized compounds were evaluated. Among all chiral hydrazide-hydrazones, compound 3b (containing nitro group in the hydrazone part) had the best inhibition profile against AChE, whereas compound 3d was found to be the most active compound against BChE. In addition, compound 3d, which carries a methoxy group in both the benzamide and the hydrazone moiety, attracted attention due to its good activity against all examined enzymes. Furthermore, molecular docking calculations were performed to get insights into the interaction patterns between the synthesized compounds and the selected target protein.

In an effort to develop new and effective therapeutic agents for Alzheimer's disease, a series of hydrazone derivatives bearing piperidine rings have been designed and synthesized. The chemical structures of the compounds were characterized by various spectroscopic techniques. In vitro antioxidant and cholinesterase activities of the compounds were evaluated. Among the compounds, N12 exhibited the most antioxidant activity in all methods (CUPRAC, FRAP, DPPH, ABTS). In vitro acetylcholinesterase (AChE) activity results of the compounds showed good IC50 values between 14.124 ± 0.084 and 49.680 ± 0.110 µM were obtained (IC50 = 38.842 ± 0.053 µM for Donepezil). Among the compounds, N7 and N6 are much more effective derivatives than the standard compound donepezil with IC50 values of 14.124 ± 0.084 and 17.968 ± 0.072 µM, respectively. In vitro, butyrylcholinesterase (BChE) inhibition values of the compounds were between 13.505 ± 0.025 and 52.230 ± 0.027 μm. Among the compounds, N6 has the highest BChE inhibition with an IC50 value of 13.505 μm in the series. The cytotoxicity and AChE inhibitory activity of the compounds on SH-SY5Y cell lines were also evaluated. Kinetic studies were also performed to determine the behavior of the compounds as competitive or noncompetitive inhibitors. The binding modes of N6, which was determined to be highly effective according to in vitro analyses, with AChE and BChE were investigated using molecular docking studies, and the stability of the complexes was determined by molecular dynamics simulations. These findings indicated that AChE and BChE enzymes maintained their overall structural stability and compactness during interactions with compound N6.

The ongoing quest for multifunctional organic molecules that exhibit both pharmaceutical and optoelectronic potential has intensified interest in heterocyclic compounds. Among them, hydrazone derivatives stand out for their diverse biological activities, including antimicrobial, antiviral, and anticancer properties, as well as their tunable electronic and optical properties. The presence of the –C N–NH– linkage enables effective conjugation and charge transfer, enhancing their chemical reactivity, stability, and nonlinear optical (NLO) behaviour. Owing to these versatile features, the design and synthesis of novel hydrazone-based heterocycles have gained prominence for potential applications in drug development and advanced material science. This study focuses on the design, synthesis, and characterization of a novel hydrazone derivative, N′-((2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)methylene)furan-2-carbohydrazide (DDMF). The compound combines furan and benzo dioxane moieties to enhance conjugation and biological activity. Its structural, electronic, and reactive properties were examined using FT-IR, ¹H NMR, ¹ ³C NMR, and DFT-based quantum chemical analyses. In addition, molecular docking and ADMET studies were performed to evaluate its binding affinity, drug-likeness, and pharmacokinetic behaviour, providing insight into its potential pharmaceutical and optoelectronic applications. The DDMF compound was synthesized and structurally confirmed using FT-IR, ¹H NMR, and ¹ ³C NMR spectroscopy. Theoretical investigations were carried out using Density Functional Theory (DFT) to study molecular geometry, electronic structure, and reactivity descriptors. Frontier Molecular Orbital (FMO), Natural Bond Orbital (NBO), and Molecular Electrostatic Potential (MEP) analyses were performed to assess charge distribution and reactive sites. In addition, UV-Vis, NLO, and molecular docking studies were conducted alongside ADMET and drug-likeness evaluations. The optimized geometry showed excellent correlation with experimental data, exhibiting minimal RMSD in bond lengths (0.020 Å) and bond angles (5.20°). FMO analysis revealed moderate reactivity and effective charge transfer, while NBO and MEP confirmed significant electron delocalization. The compound exhibited strong NLO activity and consistent NMR spectral agreement (¹H RMSD = 0.437 ppm; ¹³C RMSD = 1.24 ppm). UV-Vis spectra indicated distinct π→π* transitions at 275 and 350 nm. Docking studies showed stable interactions of DDMF with SARS-CoV-2 targets, supported by stable RMSD (∼1–2.5 Å) and low RMSF values. The compound demonstrated excellent intestinal absorption (94.63 %), favorable ADMET profiles, and high drug-likeness (MW 272.26 g/mol, LogP 1.84, TPSA 73.06 Ų). The combined experimental and theoretical investigations unequivocally confirm the successful synthesis, structural integrity, and stability of the DDMF molecule. The compound exhibits favorable electronic configuration, optical responsiveness, and pharmacological potential, as evidenced by its consistent spectroscopic characteristics, strong charge-transfer behaviour, and stable molecular interactions with biological targets. The integration of computational and spectroscopic analyses establishes DDMF as a structurally robust and functionally versatile molecule, making it a promising candidate for future advancements in both optoelectronic device fabrication and therapeutic drug development. • Synthesis of novel hydrazone derivative. • Investigation of electronic properties through DFT-based analysis. • Molecular docking analysis to evaluate the inhibitory potential of the synthesized compound. • Molecular dynamics simulation conducted over a 100 ns period to examine the dynamic interactions between the protein and ligand.

A comparative study of volatiles, antioxidant activity, phytotoxic activity, as well as in silico molecular docking and ADMET study, was conducted for essential oils from three Vitex species, viz., V. agnus-castus, V. negundo, and V. trifolia. Essential oils (OEs) extracted by hydrodistillation were subjected to compositional analysis using GC-MS. A total number of 37, 45, and 43 components were identified in V. agnus-castus, V. negundo, and V. trifolia, respectively. The antioxidant activity of EOs, assessed using different radical-scavenging (DPPH, H2O2 and NO), reducing power, and metal chelating assays, were found to be significant as compared with those of the standards. The phytotoxic potential of the EOs was performed in the receptor species Raphanusraphanistrum (wild radish) and the EOs showed different levels of intensity of seed germination inhibition and root and shoot length inhibition. The molecular docking study was conducted to screen the antioxidant and phytotoxic activity of the major and potent compounds against human protein target, peroxiredoxin 5, and 4-hydroxyphenylpyruvate dioxygenase protein (HPPD). Results showed good binding affinities and attributed the strongest inhibitory activity to 13-epi-manoyl oxide for both the target proteins.

The current study was designed to investigate the antioxidant and cytotoxic activities of Thonningia sanguinea whole-plant extract. The total phenolic content was determined using Folin–Ciocalteu reagent and found to be 980.1 mg/g, calculated as gallic acid equivalents. The antioxidant capacity was estimated for the crude extract and the phenolic portion of T. sanguinea, whereupon both revealed a dose-dependent scavenging rate of DPPH• with EC50 values of 36.33 and 11.14 µg/mL, respectively. Chemical profiling of the plant extract was achieved by LC-ESI-TOF-MS/MS analysis, where 17 compounds were assigned, including ten compounds detected in the negative mode and seven detected in the positive mode. The phenolic portion exhibited promising cytotoxic activity against MCF-7 and HepG2 cells, with IC50 values of 16.67 and 13.51 μg/mL, respectively. Phenolic extract treatment caused apoptosis in MCF-7 cells, with total apoptotic cell death 18.45-fold higher compared to untreated controls, arresting the cell cycle at G2/M by increasing the G2 population by 39.7%, compared to 19.35% for the control. The apoptotic investigation was further validated by the upregulation of proapoptotic genes of P53, Bax, and caspases-3,8 9, and the downregulation of Bcl-2 as the anti-apoptotic gene. Bcl-2 inhibition was also virtualized by good binding interactions through a molecular docking study. Taken together, phenolic extract exhibited promising cytotoxic activity in MCF-7 cells through apoptosis induction and antioxidant activation, so further fractionation studies are recommended for the phenolic extract for specifying the most active compound to be developed as a novel anti-cancer agent.

COVID-19 (Coronavirus disease 2019) is a transmissible disease initiated and propagated through a new virus strain SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) since 31st December 2019 in Wuhan city of China and the infection has outspread globally influencing millions of people. Here, an attempt was made to recognize natural phytochemicals from medicinal plants, in order to reutilize them against COVID-19 by the virtue of molecular docking and molecular dynamics (MD) simulation study. Molecular docking study showed six probable inhibitors against SARS-CoV-2 Mpro (Main protease), two from Withania somnifera (Ashwagandha) (Withanoside V [10.32 kcal/mol] and Somniferine [9.62 kcal/mol]), one from Tinospora cordifolia (Giloy) (Tinocordiside [8.10 kcal/mol]) and three from Ocimum sanctum (Tulsi) (Vicenin [8.97 kcal/mol], Isorientin 4′-O-glucoside 2″-O-p-hydroxybenzoagte [8.55 kcal/mol] and Ursolic acid [8.52 kcal/mol]). ADMET profile prediction showed that the best docked phytochemicals from present work were safe and possesses drug-like properties. Further MD simulation study was performed to assess the constancy of docked complexes and found stable. Hence from present study it could be suggested that active phytochemicals from medicinal plants could potentially inhibit Mpro of SARS-CoV-2 and further equip the management strategy against COVID-19-a global contagion. Highlights Holistic approach of Ayurvedic medicinal plants to avenge against COVID-19 pandemic. Active phytoconstituents of Ayurvedic medicinal plants Withania somnifera (Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi) predicted to significantly hinder main protease (Mpro or 3Clpro) of SARS-CoV-2. Through molecular docking and molecular dynamic simulation study, Withanoside V, Somniferine, Tinocordiside, Vicenin, Ursolic acid and Isorientin 4′-O-glucoside 2″-O-p-hydroxybenzoagte were anticipated to impede the activity of SARS-CoV-2 Mpro. Drug-likeness and ADMET profile prediction of best docked compounds from present study were predicted to be safe, drug-like compounds with no toxicity. Communicated by Ramaswamy H. Sarma