N-acyl Hydrazones Research Articles

Synthesis, C-N/N-N bond conformational analysis and evaluation of naphtho[2,3-d][1,2,3]triazole-4,9-dione tethered N-acyl hydrazones as α-amylase inhibitors: Insights from molecular modeling and ADMET analysis

In an effort to expand the repertoire of potent α-amylase inhibitors, we sought to develop novel inhibitors by combining 1,4-naphthoquinone, 1,2,3-triazole, and N-acyl hydrazone scaffolds in a single matrix. To achieve this, twelve novel naphtho[2,3-d][1,2,3]triazole-4,9‑dione tethered N-acyl hydrazones were synthesized through condensation reaction of 2-(4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-1-yl)acetohydrazide with various substituted aryl aldehydes. Structural elucidation for all the compounds was performed using 1D, 2D-NMR, FTIR, and mass spectral analyses. The synthesized molecules were evaluated for their ability to inhibit α-amylase activity using acarbose as the standard drug. All the derivatives exhibited potent inhibition of α-amylase, with IC50 values ranging between 17.26 ± 0.07 to 25.62 ± 0.03 μg/mL. Notably, compound 9c possessing –meta substituted –NO2 group displayed the highest activity (IC50 = 17.26 ± 0.07 μg/mL) among the series. Structure-activity relationship (SAR) revealed the pivotal role of aryl ring substitutions in determining inhibitory efficacy. To validate these findings and to assess the binding stability of 9c within the catalytic site α-amylase dervied for A. oryzae (PDB ID:7TAA), in silico studies were performed. The compound 9c effectively occupies the enzyme's active pocket, with minimal RMSD fluctuations observed over 100 ns simulation, indicating stable protein-ligand complex. ADMET predictions suggested favorable drug-like properties, underscoring the potential of these compounds as novel α-amylase inhibitors for managing type 2 diabetes mellitus

An Electrosynthesis of 1,3,4-Oxadiazoles from N-Acyl Hydrazones.

The 1,3,4-oxadiazole is a widely encountered motif in the areas of pharmaceuticals, materials, and agrochemicals. This work has established a mild, mediated electrochemical synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from N-acyl hydrazones. Using DABCO as the optimal redox mediator has enabled a mild oxidative cyclisation, without recourse to stoichiometric oxidants. In contrast to previous methods, this indirect electrochemical oxidation has enabled a broad range of substrates to be accessed, with yields of up to 83%, and on gram scale. The simplicity of the method has been further demonstrated by the development of a one-pot procedure, directly transforming readily available aldehydes and hydrazides into valuable heterocycles.

Synthesis of novel 1,2,3-triazole-tethered N-acyl hydrazones as a new class of carbonic anhydrase II inhibitors: In vitro and in silico potentials

Carbonic anhydrase II (CA II) is crucial for maintaining homeostasis in several processes, including respiration, lipogenesis, gluconeogenesis, calcification, bone resorption, and electrolyte balance. It is a pivotal druggable target which is implicated in glaucoma, renal, gastric, and pancreatic carcinomas, as well as in malignant brain tumours. Therefore, to identify new CA II (bovine) inhibitors, the current study was designed to synthesize a library of 20 new triazole-linked hydrazones (6a-t). All compounds were characterized by using spectroscopic techniques such as NMR and mass spectrometry. The in-vitro evaluation resulted in impressive inhibitory capability against CA II with IC50 values ranging from 9.10 ± 0.26–48.26 ± 1.30 µM. Among all derivatives, compounds 6a, 6b, 6d, 6k–6m, 6q, 6s and 6t exhibited potent inhibitory potential with 6t deemed as the most active inhibitor. Additionally, kinetic study of the hybrid 6t revealed concentration dependent type of inhibition with Ki value 7.24 ± 0.0086 µM. Furthermore, molecular docking of 6t correlates well with the kinetic analysis. The in-silico ADMET indicated that most of the synthesized compounds have properties conducive to drug development.

Exploring the anticancer potential of new 3-cyanopyridine derivatives bearing N-acylhydrazone motif: Synthesis, DFT calculations, cytotoxic evaluation, molecular modeling, and antioxidant properties.

3-Cyanopyridine derivatives are known for exhibiting excellent anticancer activity due to their strong capability to inhibit various biological targets, including Pim-1 kinase, survivin, and tubulin polymerization. On the other hand, N-acylhydrazones (NAH) are known to be a very versatile motif in medicinal chemistry and drug design. Based on these data, we report in this paper, the synthesis of novel 3-cyanopyridines incorporating N-acyl hydrazine scaffold, the evaluation of their cytotoxicity on the breast (MCF-7) and ovarian (A-2780) cancer cell lines and their antioxidant properties. Excluding 4a and 4d, all tested molecules exhibited high cytotoxicity against A-2780, with IC50 values ranging from 1.14 to 1.76 µM. Conversely, only four molecules 3d, 4b, 4c, and 4d demonstrated cytotoxicity against MCF-7, with IC50 values ranging from 1.14 to 3.38 µM. On the other hand, all the tested molecules exhibited a moderate antioxidant capacity in both the DPPH and metal chelation assays. Docking and molecular dynamics studies revealed that 2d, 3d, and 4d are potential inhibitors of tubulin and the œstrogen receptor, which may explain their high cytotoxicity. These results are promising to study these newly synthesized 3-cyanopyridine-N-acylhydrazones in depth for use as potential anticancer candidates.

Synthesis, characterization, and MAO inhibitory activities of three new drug-like N-acylhydrazone derivatives

In this study, three new N-acylhydrazone derivatives with the structural motif of N'-(substitutedbenzylidene)-3-(5-methyl-2-benzoxazolinon-3-yl)propanehydrazide (5a-c) are prepared and evaluated for their MAO inhibitory activities. The structures of the synthesized compounds are elucidated through spectral methods (IR, 1H-NMR, 13C-NMR), elemental analysis and single crystal X-ray crystallography. Detailed structural and Hirshfeld surface analyses of compounds (5a-c) have provided further insights into their molecular and crystal structures and also their intermolecular interactions. Complementing the spectral and structural analyses confirmed the E-configurations of the compounds in the solid state. The Hirshfeld surface analyses of the crystal structures have indicated that the most important contributions for the crystal packings are from H ... H, H … C/C … H and H … O/O … H (for 5a-c) and H … F/F … H (for 5b and c). In vitro tests are revealed their MAO inhibitory activities, surpassing reference compounds moclobemide and selegiline. Notably, synthesized N-acylhydrazone derivatives (5a-c) are exhibited superior MAO inhibitory activities, with a higher selectivity for MAOB over MAOA (SI >10). Molecular docking studies are provided insights into the binding modes of the compounds in the active site of the target enzyme. Theoretical ADME (Absorption, Distribution, Metabolism and Excretion), gastrointestinal absorption and blood-brain barrier permeation studies revealed that the compounds possess pharmacological attributes resembling those of typical drugs. This properties and MAO inhibitory activities of N-acyl hydrazone derivatives emphasize their potentials as promising candidates in the field of medicinal chemistry.

Selective inhibition of HDAC6 by N-acylhydrazone derivative reduces the proliferation and induces senescence in carcinoma hepatocellular cells

Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths globally. Systemic therapy is the only treatment option for HCC at an advanced stage, with limited therapeutic response. In this study, we evaluated the antitumor potential of four N-acylhydrazone (NAH) derivatives, namely LASSBio-1909, 1911, 1935, and 1936, on HCC cell lines. We have previously demonstrated that the aforementioned NAH derivatives selectively inhibit histone deacetylase 6 (HDAC6) in lung cancer cells, but their effects on HCC cells have not been explored. Thus, the present study aimed to evaluate the effects of NAH derivatives on the proliferative behavior of HCC cells. LASSBio-1911 was the most cytotoxic compound against HCC cells, however its effects were minimal on normal cells. Our results showed that LASSBio-1911 inhibited HDAC6 in HCC cells leading to cell cycle arrest and decreased cell proliferation. There was also an increase in the frequency of cells in mitosis onset, which was associated with disturbing mitotic spindle formation. These events were accompanied by elevated levels of CDKN1A mRNA, accumulation of CCNB1 protein, and sustained ERK1 phosphorylation. Furthermore, LASSBio-1911 induced DNA damage, resulting in senescence and/or apoptosis. Our findings indicate that selective inhibition of HDAC6 may provide an effective therapeutic strategy for the treatment of advanced HCC, including tumor subtypes with integrated viral genome. Further, in vivo studies are required to validate the antitumor effect of LASSBio-1911 on liver cancer.

Discovery of Novel N-Acylhydrazone Derivatives as Potent Inhibitors of Sirtuin-1

AbstractSIRT1 enzyme is a key family member of Silent Information Regulators (Sirtuins), which catalyze the deacetylation of proteins. Therefore, developing new SIRT1 inhibitors has potential application in treating cancer disease and age-related metabolic disorders. In this study, we synthesized a series of N-acylhydrazone (NAH) derivatives and performed high-throughput screening of their inhibitory activity against the recombinant SIRT1 protein by a luminescent assay. Using in silico screening, we identified a new NAH derivative that features both selectivity and a high binding affinity towards the active pocket of SIRT1 that are comparable to known inhibitors such as Ex527 and Sirtinol. Such high binding affinity makes the new derivatives promising alternatives to the available inhibitors and holds promise for developing better-targeted drugs against SIRT1 activity.

Synthesis and Characterization of New N-acyl Hydrazone Derivatives of Carprofen as Potential Tuberculostatic Agents.

N-acyl hydrazone (NAH) is recognized as a promising framework in drug design due to its versatility, straightforward synthesis, and attractive range of biological activities, including antimicrobial, antitumoral, analgesic, and anti-inflammatory properties. In the global context of increasing resistance of pathogenic bacteria to antibiotics, NAHs represent potential solutions for developing improved treatment alternatives. Therefore, this research introduces six novel derivatives of (EZ)-N'-benzylidene-2-(6-chloro-9H-carbazol-2-yl)propanehydrazide, synthesized using a microwave-assisted method. In more detail, we joined two pharmacophore fragments in a single molecule, represented by an NSAID-type carprofen structure and a hydrazone-type structure, obtaining a new series of NSAID-N-acyl hydrazone derivatives that were further characterized spectrally using FT-IR, NMR, and HRMS investigations. Additionally, the substances were assessed for their tuberculostatic activity by examining their impact on four strains of M. tuberculosis, including two susceptible to rifampicin (RIF) and isoniazid (INH), one susceptible to RIF and resistant to INH, and one resistant to both RIF and INH. The results of our research highlight the potential of the prepared compounds in fighting against antibiotic-resistant M. tuberculosis strains.

Synthesis of new pyrazolidines by [3+2] cycloaddition: Anticancer, antioxidant activities, and molecular docking studies

A series of novel pyrazolidine derivatives 2a-j from N-acyl hydrazones 1a-j were designed and synthesized by N-triflylphosphoramide (NTPA) catalyzed [3 + 2] cycloaddition. The structural elucidation of synthesized compounds was carried out using a variety of spectroscopic methods, including IR, 1H and 13C NMR, MS, and elemental analysis. Cytotoxic activity of the pyrazolidine derivatives 2a-j was evaluated against human lung cancer (A549), pancreatic cancer (PANC 1), prostate cancer (DU-145), breast cancer (MCF-7), and in human dermal fibroblast (HDF) by MTS assay. The compounds 2f (IC50= 12.5 μM) and 2g (IC50= 21.8 μM) showed higher antiproliferative activity than all other compounds against the A549 human lung cancer line and PANC1 pancreatic cancer line, respectively. The antioxidant potential of the new pyrazolidines 2a-j was evaluated by the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity assay. Compounds 2a, 2d, and 2j were found to exhibit significant antioxidant activity compared to standards. Through molecular docking studies, the antiproliferative properties of the novel pyrazolidine compounds 2a–j were studied, and the interactions between the ligand and the protein were determined for the most active compounds, 2f and 2g.

Synthesis, Biological, Spectroscopic and Computational Investigations of Novel N-Acylhydrazone Derivatives of Pyrrolo[3,4-d]pyridazinone as Dual COX/LOX Inhibitors.

Secure and efficient treatment of diverse pain and inflammatory disorders is continually challenging. Although NSAIDs and other painkillers are well-known and commonly available, they are sometimes insufficient and can cause dangerous adverse effects. As yet reported, derivatives of pyrrolo[3,4-d]pyridazinone are potent COX-2 inhibitors with a COX-2/COX-1 selectivity index better than meloxicam. Considering that N-acylhydrazone (NAH) moiety is a privileged structure occurring in many promising drug candidates, we decided to introduce this pharmacophore into new series of pyrrolo[3,4-d]pyridazinone derivatives. The current paper presents the synthesis and in vitro, spectroscopic, and in silico studies evaluating the biological and physicochemical properties of NAH derivatives of pyrrolo[3,4-d]pyridazinone. Novel compounds 5a-c-7a-c were received with high purity and good yields and did not show cytotoxicity in the MTT assay. Their COX-1, COX-2, and 15-LOX inhibitory activities were estimated using enzymatic tests and molecular docking studies. The title N-acylhydrazones appeared to be promising dual COX/LOX inhibitors. Moreover, spectroscopic and computational methods revealed that new compounds form stable complexes with the most abundant plasma proteins-AAG and HSA, but do not destabilize their secondary structure. Additionally, predicted pharmacokinetic and drug-likeness properties of investigated molecules suggest their potentially good membrane permeability and satisfactory bioavailability.

Identification of N-Acyl Hydrazones as New Non-Zinc-Binding MMP-13 Inhibitors by Structure-Based Virtual Screening Studies and Chemical Optimization.

Matrix metalloproteinase 13 plays a central role in osteoarthritis (OA), as its overexpression induces an excessive breakdown of collagen that results in an imbalance between collagen synthesis and degradation in the joint, leading to progressive articular cartilage degradation. Therefore, MMP-13 has been proposed as a key therapeutic target for OA. Here we have developed a virtual screening workflow aimed at identifying selective non-zinc-binding MMP-13 inhibitors by targeting the deep S1' pocket of MMP-13. Three ligands were found to inhibit MMP-13 in the µM range, and one of these showed selectivity over other MMPs. A structure-based analysis guided the chemical optimization of the hit compound, leading to the obtaining of a new N-acyl hydrazone-based derivative with improved inhibitory activity and selectivity for the target enzyme.

Synthesis and Molecular Docking of New N-Acyl Hydrazones- Benzimidazole as hCA I and II Inhibitors.

The carbonic anhydrases (CAs) which are found in most living organisms is a member of the zinc-containing metalloenzyme family. The abnormal levels and activities are frequently associated with various diseases therefore CAs have become an attractive target for the design of inhibitors or activators that can be used in the treatment of those diseases. Herein, we have designed and synthesized new benzimidazole-hydrazone derivatives to investigate the effects of these synthesized compounds on CA isoenzymes. Chemical structures of synthesized compounds were confirmed by 1H NMR, 13C NMR, and HRMS. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase I and II by in vitro assay. These compounds have IC50 values of 5.156-1.684 μM (hCA I) and 4.334-2.188 μM (hCA II). Inhibition types and Ki values of the compounds were determined. The Ki values of the compounds were 5.44 ± 0.14 μM-0.299 ± 0.01 μM (hCA I) and 3.699 ± 0.041 μM-1.507 ± 0.01 μM (hCA II). The synthetic compounds displayed inhibitory action comparable to that of the clinically utilized reference substance, acetazolamide. According to this, compound 3p was the most effective molecule with an IC50 value of 1.684 μM. Accordingly, the type of inhibition was noncompetitive and the Ki value was 0.299 ± 0.01 μM. According to the in vitro test results, detailed protein-ligand interactions of the compound 3p, which is more active against hCA I than standard azithromycin (AZM), were analyzed. In addition, the cytotoxic effects of the compounds on the L929 healthy cell line were evaluated.

Novel N-Acyl Hydrazone Compounds as Promising Anticancer Agents: Synthesis and Molecular Docking Studies.

In this study, a new series of N-acyl hydrazones 7a-e, 8a-e, and 9a-e, starting from methyl δ-oxo pentanoate with different substituted groups 1a-e, were synthesized as anticancer agents. The structures of obtained target molecules were identified by spectrometric analysis methods (FT-IR, 11H NMR, 13C NMR, and LC-MS). The antiproliferative activity of the novel N-acyl hydrazones was evaluated on the breast (MCF-7) and prostate (PC-3) cancer cell lines by an MTT assay. Additionally, breast epithelial cells (ME-16C) were used as reference normal cells. All newly synthesized compounds 7a-e, 8a-e, and 9a-e exhibited selective antiproliferative activity with high toxicity to both cancer cells simultaneously without any toxicity to normal cells. Among these novel N-acyl hydrazones, 7a-e showed the most potent anticancer activities with IC50 values at 7.52 ± 0.32-25.41 ± 0.82 and 10.19 ± 0.52-57.33 ± 0.92 μM against MCF-7 and PC-3 cells, respectively. Also, molecular docking studies were applied to comprehend potential molecular interactions between compounds and target proteins. It was seen that the docking calculations and the experimental data are in good agreement.

Crystallographic and Computational Analysis of the Solid-Form Landscape of Three Structurally Related Imidazolidine-2,4-dione Active Pharmaceutical Ingredients: Nitrofurantoin, Furazidin, and Dantrolene

We present a crystallographic and computational study of three hydantoin-based active pharmaceutical ingredients─nitrofurantoin, furazidin, and dantrolene─aimed at identifying factors resulting in different propensities of these compounds to form polymorphs, hydrates, solvates, and solvate-hydrates. This study is a continuation of our research toward understanding how small structural differences in closely related compounds affect their propensity to form different crystal phases, as all three compounds contain an imidazolidine-2,4-dione scaffold and a N-acyl hydrazone moiety and all form multiple crystalline phases. Crystallographic and computational analysis of the already known and newly obtained nitrofurantoin, furazidin, and dantrolene crystal structures was performed by dissecting the properties of individual molecules and searching for differences in the tendency to form hydrogen bonding patterns and characteristic packing features. The propensity to form solvates was found to correlate with the relative packing efficiency of neat polymorphs and solvates and the ability of molecules to pack efficiently in several different ways. Additionally, the differences in the propensity to form solvate-hydrates were attributed to the different stability of the hydrate phases.

Electron transfer catalysis mediated by 3d complexes of redox non-innocent ligands possessing an azo function: a perspective.

It was first reported almost two decades ago that ligands with azo functions are capable of accepting electron(s) upon coordination to produce azo-anion radical complexes, thereby exhibiting redox non-innocence. Over the past two decades, there have been numerous reports of such complexes along with their structures and diverse characteristics. The ability of a coordinated azo function to accept one or more electron(s), thereby acting as an electron reservoir, is currently employed to carry out electron transfer catalysis since they can undergo redox transformation at mild potentials due to the presence of energetically accessible energy levels. The cooperative involvement of redox non-innocent ligand(s) containing an azo group and the coordinated metal centre can adjust and modulate the Lewis acidity of the latter through selective ligand-centred redox events, thereby manipulating the capacity of the metal centre to bind to the substrate. We have summarized the list of first row transition metal complexes of iron, cobalt, nickel, copper and zinc with redox non-innocent ligands incorporating an azo function that have been exploited as electron transfer catalysts to effectuate sustainable synthesis of a wide variety of useful chemicals. These include ketazines, pyrimidines, benzothiazole, benzoxazoles, N-acyl hydrazones, quinazoline-4(3)H-ones, C-3 alkylated indoles, N-alkylated anilines and N-alkylated heteroamines. The reaction pathways, as demonstrated by catalytic loops, reveal that the azo function of a coordinated ligand can act as an electron sink in the initial steps to bring about alcohol oxidation and thereafter, they serve as an electron pool to produce the final products either via HAT or PCET processes.

Molecular Hybridization Strategy on the Design, Synthesis, and Structural Characterization of Ferrocene-N-acyl Hydrazones as Immunomodulatory Agents.

Immunomodulatory agents are widely used for the treatment of immune-mediated diseases, but the range of side effects of the available drugs makes necessary the search for new immunomodulatory drugs. Here, we investigated the immunomodulatory activity of new ferrocenyl-N-acyl hydrazones derivatives (SintMed(141−156). The evaluated N-acyl hydrazones did not show cytotoxicity at the tested concentrations, presenting CC50 values greater than 50 µM. In addition, all ferrocenyl-N-acyl hydrazones modulated nitrite production in immortalized macrophages, showing inhibition values between 14.4% and 74.2%. By presenting a better activity profile, the ferrocenyl-N-acyl hydrazones SintMed149 and SintMed150 also had their cytotoxicity and anti-inflammatory effect evaluated in cultures of peritoneal macrophages. The molecules were not cytotoxic at any of the concentrations tested in peritoneal macrophages and were able to significantly reduce (p < 0.05) the production of nitrite, TNF-α, and IL-1β. Interestingly, both molecules significantly reduced the production of IL-2 and IFN-γ in cultured splenocytes activated with concanavalin A. Moreover, SintMed150 did not show signs of acute toxicity in animals treated with 50 or 100 mg/kg. Finally, we observed that ferrocenyl-N-acyl hydrazone SintMed150 at 100 mg/kg reduced the migration of neutrophils (44.6%) in an acute peritonitis model and increased animal survival by 20% in an LPS-induced endotoxic shock model. These findings suggest that such compounds have therapeutic potential to be used to treat diseases of inflammatory origin.

Cytotoxic Activity and Docking Studies of 2-arenoxybenzaldehyde N-acyl Hydrazone and 1,3,4-Oxadiazole Derivatives against Various Cancer Cell Lines.

To understand whether previously synthesized novel hydrazone and oxadiazole derivatives have promising anticancer effects, docking studies and in vitro toxicity assays were performed on A-549, MDA-MB-231, and PC-3 cell lines. The antiproliferative properties of the compounds were investigated using molecular docking experiments. Each compound's best-docked poses, binding affinity, and receptor-ligand interaction were evaluated. Compounds' molecular weights, logPs, TPSAs, abilities to pass the blood-brain barrier, GI absorption qualities, and CYPP450 inhibition have been given. When the activities of these molecules were examined in vitro, for the A-549 cell line, hydrazone 1e had the minimum IC50 value of 13.39 μM. For the MDA-MB-231 cell line, oxadiazole 2l demonstrated the lowest IC50 value, with 22.73 μM. For PC-3, hydrazone 1d showed the lowest C50 value of 9.38 μM. The three most promising compounds were determined as compounds 1e, 1d, and 2a based on their minimum IC50 values, and an additional scratch assay was performed for A-549 and MDA-MB-231 cells, which have high migration capacity, for the three most potent molecules; it was determined that these molecules did not show a significant antimetastatic effect.

Biological Evaluation and Molecular Docking Studies of Novel 1,3,4-Oxadiazole Derivatives of 4,6-Dimethyl-2-sulfanylpyridine-3-carboxamide.

To date, chronic inflammation is involved in most main human pathologies such as cancer, and autoimmune, cardiovascular or neurodegenerative disorders. Studies suggest that different prostanoids, especially prostaglandin E2, and their own synthase (cyclooxygenase enzyme-COX) can promote tumor growth by activating signaling pathways which control cell proliferation, migration, apoptosis, and angiogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) are used, alongside corticosteroids, to treat inflammatory symptoms particularly in all chronic diseases. However, their toxicity from COX inhibition and the suppression of physiologically important prostaglandins limits their use. Therefore, in continuation of our efforts in the development of potent, safe, non-toxic chemopreventive compounds, we report herein the design, synthesis, biological evaluation of new series of Schiff base-type hybrid compounds containing differently substituted N-acyl hydrazone moieties, 1,3,4-oxadiazole ring, and 4,6-dimethylpyridine core. The anti-COX-1/COX-2, antioxidant and anticancer activities were studied. Schiff base 13, containing 2-bromobenzylidene residue inhibited the activity of both isoenzymes, COX-1 and COX-2 at a lower concentration than standard drugs, and its COX-2/COX-1 selectivity ratio was similar to meloxicam. Furthermore, the results of cytotoxicity assay indicated that all of the tested compounds exhibited potent anti-cancer activity against A549, MCF-7, LoVo, and LoVo/Dx cell lines, compared with piroxicam and meloxicam. Moreover, our experimental study was supported by density functional theory (DFT) and molecular docking to describe the binding mode of new structures to cyclooxygenase.

Synthesis, Molecular Docking and Biological Evaluation of Napthyl N-Acyl Hydrazone Derivatives

A series of 2-(benzamido)-N′-((naphthalen-1-yl)methylene)-3-(substituted phenyl)acrylo hydrazides (4a-m, 5a-b) were synthesized by condensation of 2-(benzamido)-3-(substituted phenyl)acrylohydrazides with 1-naphthaldehyde in presence of few drops of acetic acid in ethanol. Structural elucidation of final compounds was confirmed by spectral data. Title compounds were evaluated for antioxidant and antibacterial activities and subjected to in silico studies and molecular docking studies with cyclooxygenase-II (COX-II, PDB I’d: 3LN1) and active compounds from docking studies were selected for in vivo evaluation of their antiinflammatory activity. Among the series, compound 4i showed good antioxidant activity; 5b showed good antibacterial activity. All the six derivatives with good docking scores were selected for in vivo evaluation of their antiinflammatory activity. Among the selected active compounds from docking studies, compound 4m showed good antiinflammatory activity which is comparable with that of standard drug diclofenac. In silico studies indicated that all the compounds followed Lipinski’s rule and exhibited good oral absorption and bioavailability.

Synthesis, Bioactivity Assessment, and Molecular Docking of Non-sulfonamide Benzimidazole-Derived N-Acylhydrazone Scaffolds as Carbonic Anhydrase-II Inhibitors.

This research reports the synthesis of new benzimidazole-derived N-acylhydrazones (NAH), their characterization using various spectroscopic methods, and in vitro evaluation as potent carbonic anhydrase-II inhibitors. Among the target compounds (9–29), few showed higher inhibition than the standard acetazolamide (IC50: 18.6 ± 0.43 μM), for example, compound 9 (IC50: 13.3 ± 1.25 μM), 10 (IC50: 17.2 ± 1.24 μM), 12 (IC50: 14.6 ± 0.62 μM), and 15 (IC50: 14.5 ± 1.05 μM). Molecular docking was performed on the most active compounds, which revealed their binding interactions with the active site of the enzyme, thus supporting the experimental findings.