Search Results (21)

A series of new isatin hydrazones bearing phosphorus-containing moiety was synthesized through a simple, high-yield and easy work-up reaction of phosphine oxide (Phosenazide) or phosphinate (2-chloroethyl (4-(dimethylamino)phenyl)(2-hydrazinyl-2-oxoethyl)phosphinate, CAPAH) hydrazides with aryl-substituted isatins. The ³¹P NMR technique showed that, in most cases, out of 12 examples in solution, the ratio of the two spatial isomers varied from 1:1 to 1:3. Quantum chemical calculations confirmed the predominance of Z,syn form both in the gas phase and in solution. According to X-ray analysis data in crystals, they exist only in Z,syn form too. Most of the phosphine oxide derivatives and 5-methoxy- and 5-bromoaryl phosphinate analogs exhibit anti-aggregant activity at the level of acetylsalicylic acid but inhibit platelet activation processes more effectively. The 5-chloro type phosphinate derivative exhibits anti-aggregant properties more effectively than acetylsalicylic acid under the conditions of the tissue factor (TF)-activated thromboelastography (TEG) model, the ex vivo thrombosis model. Thus, all the obtained results can become the basis for future pharmaceutical developments to create effective anti-aggregation drugs with broad antithrombotic potential. Full article

In response to the escalating crisis of antimicrobial resistance (AMR), there is an urgent need to research and develop novel antibiotics. This study presents the synthesis and assessment of innovative 4-aminoquinoline-benzohydrazide-based molecular hybrids bearing aryl aldehydes (HD1-23) and substituted isatin warheads (HS1-12), characterized using multispectroscopic techniques with high purity confirmed by HRMS. The compounds were evaluated against a panel of clinically relevant antibacterial strains including the Gram-positive Enterococcus faecium, Bacillus subtilis, and Staphylococcus aureus and a Gram-negative Pseudomonas aeruginosa bacterial strain. Preliminary screenings revealed that several test compounds had significant antimicrobial effects, with HD6 standing out as a promising compound. Additionally, HD6 demonstrated impressively low minimum inhibitory concentrations (MICs) in the range of (8–128 μg/mL) against the strains B. subtilis, S. aureus and P. aeruginosa. Upon further confirmation, HD6 not only showed bactericidal properties with low minimum bactericidal concentrations (MBCs) such as (8 μg/mL against B. subtilis) but also displayed a synergistic effect when combined with the standard drug ciprofloxacin (CIP), highlighted by its FICI value of (0.375) against P. aeruginosa, while posing low toxicity risk. Remarkably, HD6 also inhibited a multidrug-resistant (MDR) bacterial strain, marking it as a critical addition to our antimicrobial arsenal. Computation studies were performed to investigate the possible mechanism of action of the most potent hybrid HD6 on biofilm-causing protein (PDB ID: 7C7U). The findings suggested that HD6 exhibits favorable binding free energy, which is supported by the MD simulation studies, presumably responsible for the bacterial growth inhibition. Overall, this study provides a suitable core for further synthetic alterations for their optimization as an antibacterial agent. Full article

A series of new isatin-3-hydrazones bearing different ammonium fragments was synthesized by a simple and easy work-up reaction of Girard’s reagents analogs with 1-(3,5-di-tert-butyl-4-hydroxybenzyl)isatin. All derivatives have been shown to have antioxidant properties. In terms of bactericidal activity against gram-positive bacteria, including methicillin-resistant strains of Staphylococcus aureus, the best compounds are 3a, 3e, and 3m, bearing octyl, acetal, and brucine ammonium centers, respectively. In addition, brucine and quinine derivatives 3l, and 3j exhibit platelet antiaggregation activity at the level of acetylsalicylic acid, and this series of isatin derivatives does not adversely affect the hemostasis system as a whole. Thus, all the obtained results can lay the groundwork for future pharmaceutical developments for the creation of effective antibacterial drugs with reduced systemic toxicity due to the presence of antioxidant properties. Full article

A series of new fluorinated 1-benzylisatins was synthesized in high yields via a simple one-pot procedure in order to explore the possible effect of ortho-fluoro (3a), chloro (3b), or bis-fluoro (3d) substitution on the biological activity of this pharmacophore. Furthermore, the new isatins could be converted into water-soluble isatin-3-hydrazones using their acid-catalyzed reaction with Girard’s reagent P and its dimethyl analog. The cytotoxic action of these substances is associated with the induction of apoptosis caused by mitochondrial membrane dissipation and stimulated reactive oxygen species production in tumor cells. In addition, compounds 3a and 3b exhibit platelet antiaggregation activity at the level of acetylsalicylic acid, and the whole series of fluorine-containing isatins does not adversely affect the hemostasis system as a whole. Among the new water-soluble pyridinium isatin-3-acylhydrazones, compounds 7c and 5c,e exhibit the highest antagonistic effect against phytopathogens of bacterial and fungal origin and can be considered useful leads for combating plant diseases. Full article

Unregulated core structures, “isatin acyl hydrazones” (OXIZIDs), have quietly appeared on the market since China legislated to ban seven general core scaffolds of synthetic cannabinoids (SCs). The fast evolution of SCs presents clinical and forensic toxicologists with challenges. Due to extensive metabolism, the parent compounds are barely detectable in urine. Therefore, studies on the metabolism of SCs are essential to facilitate their detection in biological matrices. The aim of the present study was to elucidate the metabolism of two cores, “indazole-3-carboxamide” (e.g., ADB-BUTINACA) and “isatin acyl hydrazone” (e.g., BZO-HEXOXIZID). The in vitro phase I and phase II metabolism of these six SCs was investigated by incubating 10 mg/mL pooled human liver microsomes with co-substrates for 3 h at 37 °C, and then analyzing the reaction mixture using ultrahigh-performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry. In total, 9 to 34 metabolites were detected for each SC, and the major biotransformations were hydroxylation, dihydrodiol formation (MDMB-4en-PINACA and BZO-4en-POXIZID), oxidative defluorination (5-fluoro BZO-POXIZID), hydrogenation, hydrolysis, dehydrogenation, oxidate transformation to ketone and carboxylate, N-dealkylation, and glucuronidation. Comparing our results with previous studies, the parent drugs and SC metabolites formed via hydrogenation, carboxylation, ketone formation, and oxidative defluorination were identified as suitable biomarkers. Full article

A novel series of isatin-s-triazine hydrazone derivatives has been synthesized and reported herein. The synthetic methodology involved the reaction of s-triazine hydrazine precursors with isatin derivatives in the presence of CH₃COOH as a catalyst and EtOH as solvent to afford the corresponding target products 6a-e in high yields and purities. The characterization data obtained from elemental analysis, FT-IR, NMR (¹H- and ¹³C-) were in full agreement with the expected structures. Furthermore, an X-ray single crystal diffraction study of one of the target s-triazine hydrazone derivatives, 6c confirmed the structure of the desired compounds. It crystallized in the triclinic crystal system and P-1 space group with a = 10.3368(6) Å, b = 11.9804(8) Å, c = 12.7250(5) Å, α = 100.904(4)°, β = 107.959(4)° and γ = 109.638(6)°. The different non-covalent interactions which contributed in the molecular packing of 6c were analyzed using Hirshfeld analysis. The molecular packing of the organic part of the crystal structure showed important O…H (7.1%), C…H (16.4%), C…C (1.6%), H…H (34.8%), N…H (8.0%) and C…N (4.0%) interactions while for the crystal solvent, the O…H (21.3%), H…H (61.2%) and N…H (8.1%) contacts are the most significant. The studied compound 6c is polar and has a net dipole moment of 5.6072 Debye based on DFT study. Full article

4-Phenyl-3-[2-(phenylamino)ethyl]-1H-1,2,4-triazole-5(4H)-thione was used as a starting compound for the synthesis of the corresponding 1,2,4-triazol-3-ylthioacetohydrazide, which reacts with isatins and various aldehydes bearing aromatic and heterocyclic moieties provided target hydrazones. Their cytotoxicity was tested by the MTT assay against human melanoma IGR39, human triple-negative breast cancer (MDA-MB-231), and pancreatic carcinoma (Panc-1) cell lines. The selectivity of compounds towards cancer cells was also studied. In general, the synthesized compounds were more cytotoxic against the melanoma cell line. N′-(2-oxoindolin-3-ylidene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide, N′-((1H-pyrrol-2-yl)methylene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide and N′-(2-hydroxy-5-nitrobenzylidene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide were identified as the most active among all synthesized compounds in 3D cell cultures. N′-(4-(dimethylamino)benzylidene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide inhibited all cancer cell migration, was characterized as relatively more selective towards cancer cells, and could be further tested as an antimetastatic candidate. Full article

Methionine aminopeptidases (MetAPs) are attractive drug targets due to their essential role in eukaryotes as well as prokaryotic cells. In this study, biochemical assays were performed on newly synthesized Isatin-pyrazole hydrazones (PS1–14) to identify potent and selective bacterial MetAPs inhibitors. Compound PS9 inhibited prokaryotic MetAPs, i.e., MtMetAP1c, EfMetAP1a and SpMetAP1a with K_i values of 0.31, 6.93 and 0.37 µM, respectively. Interestingly, PS9 inhibited the human analogue HsMetAP1b with Ki (631.7 µM) about ten thousand-fold higher than the bacterial MetAPs. The in vitro screening against Gram-positive (Enterococcus faecalis, Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, Klebsiella pneumonia and Escherichia coli) bacterial strains also exhibited their antibacterial potential supported by minimum bactericidal concentration (MBC), disk diffusion assay, growth curve and time-kill curve experiments. Additionally, PS6 and PS9 had synergistic effects when combined with ampicillin (AMP) and ciprofloxacin (CIP) against selective bacterial strains. PS9 showed no significant cytotoxic effect on human RBCs, HEK293 cells and Galleria mellonella larvae in vivo. PS9 inhibited the growth of multidrug-resistant environmental isolates as it showed the MIC lower than the standard drugs used against selective bacterial strains. Overall, the study suggested PS9 could be a useful candidate for the development of antibacterial alternatives. Full article

A series of thirty-one hydrazones of aminoguanidine, nitroaminoguanidine, 1,3-diaminoguanidine, and (thio)semicarbazide were prepared from various aldehydes, mainly chlorobenzaldehydes, halogenated salicylaldehydes, 5-nitrofurfural, and isatin (yields of 50–99%). They were characterized by spectral methods. Primarily, they were designed and evaluated as potential broad-spectrum antimicrobial agents. The compounds were effective against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus with minimum inhibitory concentrations (MIC) from 7.8 µM, as well as Gram-negative strains with higher MIC. Antifungal evaluation against yeasts and Trichophyton mentagrophytes found MIC from 62.5 µM. We also evaluated inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The compounds inhibited both enzymes with IC₅₀ values of 17.95–54.93 µM for AChE and ≥1.69 µM for BuChE. Based on the substitution, it is possible to modify selectivity for a particular cholinesterase as we obtained selective inhibitors of either AChE or BuChE, as well as balanced inhibitors. The compounds act via mixed-type inhibition. Their interactions with enzymes were studied by molecular docking. Cytotoxicity was assessed in HepG2 cells. The hydrazones differ in their toxicity (IC₅₀ from 5.27 to >500 µM). Some of the derivatives represent promising hits for further development. Based on the substitution pattern, it is possible to modulate bioactivity to the desired one. Full article

A series of novel mono and bishydrazones each bearing a 2-oxindole moiety along with substituted phenylaminopropanamide, pyrrolidin-2-one, benzimidazole, diphenylmethane, or diphenylamine fragments were synthesized, and their anticancer activities were tested by MTT assay against human melanoma A375 and colon adenocarcinoma HT-29 cell lines. In general, the synthesized compounds were more cytotoxic against HT-29 than A375. 3-((4-Methoxyphenyl)(3-oxo-3-(2-(2-oxoindolin-3-ylidene)hydrazinyl)propyl)amino)-N′-(2-oxoindolin-3-ylidene)propanehydrazide and (N′,N‴)-1,1′-(methylenebis(4,1-phenylene))bis(5-oxo-N′-(2-oxoindolin-3-ylidene)pyrrolidine-3-carbohydrazide) were identified as the most active compounds against HT-29 in 2D and 3D cell cultures. The same compounds showed the highest antioxidant activity among the synthesized compounds screened by ferric reducing antioxidant power assay (FRAP). Their antioxidant activity is on par with that of a well-known antioxidant ascorbic acid. Full article

Recently, we have reported a series of isatin hydrazone, two of them, namely, 3-((2,6-dichlorobenzylidene)hydrazono)indolin-2-one (1) and 3-((2-chloro-6-fluorobenzylidene)hydrazono)indolin-2-one (2) having potent cytotoxicity, showing cyclin-dependent kinases (CDK2) inhibitory activity and bearing recommended drug likeness properties. Since both compounds (1 and 2) showed inhibitory activity against CDK2, we assumed it would also have multiple receptor tyrosine kinases (RTKs) inhibitory activity. Considering those points, here, above-mentioned two isatin hydrazone 1 and 2 were synthesized using previously reported method for further investigation of their potency on RTKs (EGFR, VEGFR-2 and FLT-3) inhibitory activity. As expected, Compound 1 exhibited excellent inhibitory activity against epidermal growth factor receptor (EGFR, IC₅₀ = 0.269 µM), vascular epidermal growth factor receptor 2 (VEGFR-2, IC₅₀ = 0.232 µM) and FMS-like tyrosine kinase-3 (FLT-3, IC₅₀ = 1.535 µM) tyrosine kinases. On the other hand, Compound 2 also exhibited excellent inhibitory activity against EGFR (IC₅₀ = 0.369 µM), VEGFR-2 (IC₅₀ = 0.266 µM) and FLT-3 (IC₅₀ = 0.546 µM) tyrosine kinases. A molecular docking study with EGFR, VEGFR-2 and FLT-3 kinase suggested that both compounds act as type I ATP competitive inhibitors against EGFR and VEGFR-2, and type II ATP non-competitive inhibitors against FLT-3. Full article

Thirty-six novel indole-containing compounds, mainly 3-(2-phenylhydrazono) isatins and structurally related 1H-indole-3-carbaldehyde derivatives, were synthesized and assayed as inhibitors of beta amyloid (Aβ) aggregation, a hallmark of pathophysiology of Alzheimer’s disease. The newly synthesized molecules spanned their IC₅₀ values from sub- to two-digit micromolar range, bearing further information into structure-activity relationships. Some of the new compounds showed interesting multitarget activity, by inhibiting monoamine oxidases A and B. A cell-based assay in tau overexpressing bacterial cells disclosed a promising additional activity of some derivatives against tau aggregation. The accumulated data of either about ninety published and thirty-six newly synthesized molecules were used to generate a pharmacophore hypothesis of antiamyloidogenic activity exerted in a wide range of potencies, satisfactorily discriminating the ‘active’ compounds from the ‘inactive’ (poorly active) ones. An atom-based 3D-QSAR model was also derived for about 80% of ‘active’ compounds, i.e., those achieving finite IC₅₀ values lower than 100 μM. The 3D-QSAR model (encompassing 4 PLS factors), featuring acceptable predictive statistics either in the training set (n = 45, q² = 0.596) and in the external test set (n = 14, r²_ext = 0.695), usefully complemented the pharmacophore model by identifying the physicochemical features mainly correlated with the Aβ anti-aggregating potency of the indole and isatin derivatives studied herein. Full article

Isatin derivatives potentially act on various biological targets. In this article, a series of novel isatin-hydrazones were synthesized in excellent yields. Their cytotoxicity was tested against human breast adenocarcinoma (MCF7) and human ovary adenocarcinoma (A2780) cell lines using MTT assay. Compounds 4j (IC₅₀ = 1.51 ± 0.09 µM) and 4k (IC₅₀ = 3.56 ± 0.31) showed excellent activity against MCF7, whereas compound 4e showed considerable cytotoxicity against both tested cell lines, MCF7 (IC₅₀ = 5.46 ± 0.71 µM) and A2780 (IC₅₀ = 18.96± 2.52 µM), respectively. Structure-activity relationships (SARs) revealed that, halogen substituents at 2,6-position of the C-ring of isatin-hydrazones are the most potent derivatives. In-silico absorption, distribution, metabolism and excretion (ADME) results demonstrated recommended drug likeness properties. Compounds 4j (IC₅₀ = 0.245 µM) and 4k (IC₅₀ = 0.300 µM) exhibited good inhibitory activity against the cell cycle regulator CDK2 protein kinase compared to imatinib (IC₅₀ = 0.131 µM). A molecular docking study of 4j and 4k confirmed both compounds as type II ATP competitive inhibitors that made interactions with ATP binding pocket residues, as well as lacking interactions with active state DFG motif residues. Full article

Developing anticancer therapeutics with no/few side effects is a challenge for medicinal chemists. The absence of antibacterial activity of an anticancer drug removes its detrimental effect toward intestinal flora and therefore leads to reduced side effects. Here, a series of novel N-benzylisatin-aryl-hydrazones was designed, synthesized and evaluated for their antimicrobial and antiproliferative activities with SAR and ADME studies, aiming to develop anticancer drugs with no antimicrobial, yet high antiproliferative activities. The results were then compared with the effects of first-line treatments for lung cancer drug Gefitinib. Novel N-benzylisatin-aryl-hydrazones were synthesized from isatin and benzyl bromide in three steps with good to moderate yields. Antimicrobial activity was tested with six Gram-positive/negative bacterial strains, antifungal activity with a fungal strain and antiproliferative activity against ‘A549’ and ‘HeLa cell lines’, respectively. As expected, synthesized hydrazones reveled no effects on any of the strains of bacteria and fungi up to 100-µg/disc concentration. However, four compounds showed two-to-four fold antiproliferative activity over Gefitinib. For instance, IC₅₀ of a compound (6c) shows concentration of 4.35 µM, whereas gefitinib shows 15.23 µM against ‘A549.’ ADME predicted studies reveled that our synthesized hydrazones exhibited higher ADME values than the Gefitinib. Therefore, our synthesized hydrazones can be an excellent scaffold for the development of anticancer therapeutics after considering further investigations. Full article

Four novel isatin hydrazones containing bipyridyl fragments were synthesized as potential ON/OFF switches. Hydrazone Z-isomers exhibit high thermal stability. The characteristic photochemical reaction for all studied hydrazones is the Z–E isomerization in CHCl₃. After irradiation of hydrazones 1 and 2 in dimethylformamide (DMF), the photoreaction products are tautomers. When using light with the appropriate wavelength, the photo-tautomerization reaction is reversible. In these conditions, studied hydrazones have ON/OFF switch properties. In the case of hydrazones 1 and 2, by alternating heat and light stimulation it is possible to control the isomerization process reversibly. In the presence of fluoride ions, NH hydrogen from the studied hydrazones is cleaved, and the corresponding anions are formed. The resulting anions of Z-isomers are changed to the corresponding E-isomer at room temperature. Full article