Synthesis,antibacterial, anticancer and molecular docking studies of macrocyclic metal complexes of dihydrazide and diketone

The complexes of Co(II), Ni(II), Cu(II) and Zn(II) metal ions has been synthesized through template method by the condensation of succinic acid dihydrazide with 5-chloroisatin in alcoholic medium. Complexes were characterized by C H N analysis, molar conductance, thermal analysis, magnetic susceptibility, mass spectrometry, FTIR, EPR, ¹H NMR, UV–Visible spectroscopy. These studies suggest an octahedral geometry for all the complexes. The compounds were found active against B. subtilis and S. aureus and P. aeruginosa and E. coli bacteria. The Zn(II) complex showed significant anticancer activity against Squamous Cell Carcinoma cells tested by the MTT assay method. Molecular docking studies with EGFR tyrosine kinase were also carried out. All these results show that some of the synthesized compounds have remarkable antibacterial and anticancer property.     

4-(1-Aryl-5-chloro-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides: Synthesis,antimicrobial, anticancer evaluation and QSAR studies

A series of 4-(1-aryl-5-chloro-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzenesulfonamide derivatives (1–20) was synthesized and evaluated for its in vitro antimicrobial and anticancer activities. Antimicrobial results indicated that compounds N-(4-(1-benzoyl-5-chloro-2-oxoindolin-3-ylideneamino) phenylsulfonyl)-4-isopropoxy benzamide (9) and N-(4-(5-chloro-1-(2-chlorobenzoyl)-2-oxoindolin-3-ylideneamino) phenylsulfonyl)-4-isopropoxybenzamide (19) were found to be the most effective ones. The anticancer results indicated that almost all the synthesized compounds were more active than the standard drug carboplatin but less active than the standard drug 5-fluorouracil (5-FU) against both the cell lines (HCT116 and RAW 264.7). 4-(1-Benzoyl-5-chloro-2-oxoindolin-3-ylideneamino)-N-(pyrimidin-2-yl) benzenesulfonamide (3) was found to be most potent and exhibited selectivity toward HCT 116. QSAR studies indicated that antimicrobial activity of isatin derivatives against different microbial strains was governed by lipophilic parameter, log P and topological parameters valance zero and third order molecular connectivity indices (⁰χ^v and ³χ^v).     

Synthesis,anticancer activity and molecular docking studies of novel pyrido[1,2-a]pyrimidin-4-one derivatives

A series of novel triazolothione, thiadiazole, triazole, and oxadiazole-functionalized pyrido[1,2-a]pyrimidin-4-ones 6a–6l and 7a–7f were prepared, starting from pyridine derivatives 1a and 1b. All the compounds 6a–6l and 7a–7f were screened against four human cancer cell lines (HeLa, COLO205, Hep G2, and MCF 7), among which compounds 6d, 6h, 6j, 7b, and 7e showed promising anticancer activity. Molecular docking studies showed good binding energy and exhibited interactions and better lower free energy values, indicating more thermodynamically favored interaction.     

In-silico profiling,design, molecular docking computation,and drug kinetic model evaluation of novel curcumin derivatives as potential anticancer agents

The alarming trend of leukemia cell lines that are multidrug-resistant has prompted scientists to scramble for effective new anticancer treatments. Therefore, it remains an intriguing scientific task to optimize curcumin by trying to introduce molecular alteration to its vital structure to improve the biological effect against the P388 cell line or get around resistance phenomena. Regardless of the wide range of medications that are now being studied, Prednisone remains the most important and efficient part of chemotherapy that the WHO recommends. This article discusses the QSAR-oriented model and in silico assessment of some potent curcumin derivatives' anticancer activity against the P388 cell line. The solidity and propensity for prediction of the model were ensured by using stringent validation procedures. The activity of these derivatives was shown to be unrelated to lipophilicity, while shorter N-N distances and short substituents result in quite bioactive molecules. This information was used to design potent molecules that demonstrate good quality as per the assessment based on the Lead-Like Soft rule is acceptable for drug-like molecules. Also, molecule d2 does not possess any toxic effects risk alerts, suggesting drug-adherent conduct. While Prednisone the reference drug has a toxicity risk alert in red, suggesting non-adherent conduct for Prednisone. Hence, the novel molecules are promising anticancer agents.     

Synthesis,biological evaluation and molecular docking study of pyrimidine based thiazolidinone derivatives as potential anti-urease and anti-cancer agents

Hybrid analogs containing molecules are always the choice of different synthetic researcher due to their diverse biological applications and significantly more efficient. Heterocyclic being a good inhibitors against varied disease are most commonly used in drug designing and development. The current study also addressed the synthesis of pyrimidine-based thiazolidinone derivatives (1–13) using stepwise processes and their structure was confirmed using various characterization techniques such as ¹HNMR, ¹³CNMR, and HREI-MS. Furthermore, the biological significances of the synthesized scaffolds were also explored and proved to be as anti-urease and anti-cancer moieties. Their inhibitory potentials were determined using the minimum inhibitory concentration (MIC) in the presence of their standard drugs, Thiourea (IC₅₀ = 8.20 ± 0.20 µM) and Tetrandrineb (IC₅₀ = 12.30 ± 0.10 µM) respectively. Structure activity relationship (SAR) was established for all the synthesized scaffolds and compared their inhibitory potentials in which scaffolds 3 (IC₅₀ = 2.30 ± 0.30 and 3.20 ± 0.50 µM), 6 (IC₅₀ = 3.10 ± 0.20 and 6.20 ± 0.10 µM), 7 (IC₅₀ = 3.20 ± 0.20 and 3.80 ± 0.30 µM) and 10 (IC₅₀ = 4.20 ± 0.20 and 5.10 ± 0.30 µM) exhibited the most influential activity. These compounds were subsequently examined using molecular docking experiments, which evaluate the binding interaction of ligands with enzyme active sites.     

Synthesis,antimicrobial, anticancer,antiviral evaluation and QSAR studies of 4-(1-aryl-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzene sulfonamides

A series of 4-(1-aryl-2-oxo-1,2-dihydro-indol-3-ylideneamino)-N-substituted benzenesulfonamide derivatives (1–32) was synthesized and evaluated for its in vitro antimicrobial, antiviral and cytotoxic activities. Antimicrobial results indicated that compounds (11) and (18) were found to be the most effective ones. In general, the synthesized compounds were bacteriostatic and fungistatic in their action. The cytotoxic screening results indicated that the compounds were less active than the standard drug 5-fluorouracil (5-FU). None of the compounds inhibited viral replication at subtoxic concentrations. In general, the presence of a pyrimidine ring with electron releasing groups and an ortho- and para-substituted benzoyl moiety favored antimicrobial activities. The results of QSAR studies demonstrated the importance of topological parameters, valence zero order molecular connectivity index (⁰χ^v) and valence first order molecular connectivity index (¹χ^v) in describing the antimicrobial activity of synthesized compounds.     

Synthesis of spirooxindoles promoted by the deep eutectic solvent,ZnCl2+urea via the pseudo four-component reaction: anticancer,antioxidant, and molecular docking studies

Abstract

Various spirooxindoles (7a–c, 8a–c, 9a–c, and 10a–c) were efficiently synthesized using deep eutectic solvent ZnCl₂+urea and well characterized using IR, ¹H NMR, and ¹³C NMR spectroscopic techniques. The biological screening results showed that the compound 9a exhibited potent anticancer activity against MCF7 and HeLa cell lines with IC₅₀ values 6.47?±?0.01 and 9.14?±?0.32?µM, respectively. The compound 7c exhibited potent activity against the HeLa cell line with IC₅₀ value 6.81?±?0.01?µM. The compound 9a exhibited a potent antioxidant activity with IC₅₀ value 7.34?±?0.17?µM. The comparative molecular docking study against the cancer proteins EGFR and HER2 revealed that the EGFR was the best target protein receptor for the target compounds. Among all the compounds, the compound 9a exhibited the least binding energy ?10.72?kcal/mol against the protein EGFR (PDB ID: 4HJO).     

Synthesis,cytotoxicity, apoptosis and molecular docking studies of novel phenylbutyrate derivatives as potential anticancer agents

Phenylbutyrate (PB), a small aromatic fatty acid, has been known as an interesting compound with the ability of anti-proliferation and cell growth inhibition in cancer cells. In the present study, a series of PB derivatives were synthesized by Passerini multicomponent reaction and their cytotoxic activities against various human cancer cell lines including A549 (non-small cell lung cancer), MDA-MB-231 (breast cancer), and SW1116 (colon cancer) were evaluated. The results revealed that B9, displayed significantly higher in vitro cytotoxicity with IC₅₀ of 6.65, 8.44 and 24.71 μM, against A549, MDA-MB-231 and, SW1116, respectively, in comparison to PB. The effects of these compounds on the proliferation of MCF-10A as non-tumoral breast cell line, showed good selectivity of the compounds between tumorigenic and non-tumorigenic cell lines. Moreover, B9 has indicated apoptosis-inducing activities to MDA-MB-231 cancer cell line in a dose-dependent manner. The molecular docking studies of the synthesized compounds on pyruvate dehydrogenase kinase 2 (PDK2; PDB ID: 2BU8) and histone deacetylase complex (HDAC; PDB ID: 1C3R), as the main targets of PB were applied to predict the binding sites and binding orientation of the compounds to these targets.     

Synthesis,in vitro evaluation,and molecular docking studies of benzofuran based hydrazone a new inhibitors of urease

This work has described the synthesis of novel class (1–25) of benzofuran based hydrazone. The hybrid scaffolds (1–25) of benzofuran based hydrazone were evaluated in vitro, for their urease inhibition. All the newly synthesized analogues (1–25) were found to illustrate moderate to good urease inhibitory profile ranging from 0.20 ± 0.01 to 36.20 ± 0.70 µM. Among the series, compounds 22 (IC₅₀ = 0.20 ± 0.01 µM), 5 (IC₅₀ = 0.90 ± 0.01 µM), 23 (IC₅₀ = 1.10 ± 0.01 µM) and 25 (IC₅₀ = 1.60 ± 0.01 µM) were found to be the many folds more potent than thiourea as standard inhibitor (IC₅₀ = 21.86 ± 0.40 µM). The elevated inhibitory profile of these analogues might be due to presence of dihydroxy and flouro groups at different position of phenyl ring B attached to hydrazone skeleton. These dihydroxy and fluoro groups bearing compounds have shown many folds better inhibitory profile through involvement of oxygen of dihydroxy groups in hydrogen bonding with active site of enzymes. Various types of spectroscopic techniques such as ¹H-, ¹³C- NMR and HREI-MS spectroscopy were used to confirm the structure of all the newly developed compounds. To find SAR, molecular docking studies were performed to understand, the binding mode of potent inhibitors with active site of enzymes and results supported the experimental data.     

A comparative QSAR analysis and molecular docking studies of phenyl piperidine derivatives as potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors

Depression is a critical mood disorder that affects millions of patients. Available therapeutic antidepressant agents are associated with several undesirable side effects. Recently, it has been shown that Neurokinin 1 receptor (NK₁R) antagonists can potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs). In this study, a series of phenyl piperidine derivatives as potent dual NK₁R antagonists/serotonin transporter (SERT) inhibitors were applied to quantitative structure–activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis–based multiple linear regression (FA-MLR), principal component regression (PCR), and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were applied to make relations between structural characteristics and NK₁R antagonism/SERT inhibitory of these compounds. The best multiple linear regression equation was obtained from GA-PLS and MLR for NK₁R and SERT, respectively. Based on the resulted model, an in silico-screening study was also conducted and new potent lead compounds based on new structural patterns were designed for both targets. Molecular docking studies of these compounds on both targets were also conducted and encouraging results were acquired. There was a good correlation between QSAR and docking results. The results obtained from validated docking studies indicate that the important amino acids inside the active site of the cavity that are responsible for essential interactions are Glu33, Asp395 and Arg26 for SERT and Ala30, Lys7, Asp31, Phe5 and Tyr82 for NK₁R receptors.     

Green synthesis of selenium based N-heterocyclic carbene compounds; structural,in-vitro anticancer and molecular docking studies

Benzimidazolium salts (3−6) were synthesized as stable N-Heterocyclic Carbene (NHC) precursors and their selenium-NHC compounds/Selenones (7−10) were prepared using water as a solvent. Characterization of each of the synthesized compounds was carried out by various analytical and spectroscopic (FT-IR, ¹H-, ¹³C NMR) methods. X-ray crystallographic analyses of single crystals obtained for salts 3 and 5 were carried out. Synthesized salts and their Se-NHCs were tested in-vitro for their anticancer potential against Cervical Cancer Cell line from Henrietta Lacks (HeLa), Breast cancer cell line (MDA-MB-231), Adenocarcinoma cell line (A549) and human normal endothelial cell line (EA.hy926). MTT assay was used for analysis and compared with standard drug 5-flourouracil. Benzimidazolium salts (3−6) and their selenium counter parts (7−10) were found potent anticancer agents. Salt 3–5 were found to be potent anticancer against HeLa with IC₅₀ values 0.072, 0.017 and 0.241 μM, respectively, which are less than standard drug (4.9 μM). The Se-NHCs (7–10) had also shown significant anticancer potential against HeLa with IC₅₀ values less than standard drug. Salts 3, 4 against EA.hy926, compounds 3,5,6, and 10 against MDA-MB-321, and compounds 4, 10 against A-549 cell line were found more potent anticancer agents with IC₅₀ values less than standard drug. Molecular docking for (7−10) showed their good anti-angiogenic potential having low binding energy and significant inhibition constant values with VEGFA (vascular endothelial growth factor), EGF (human epidermal growth factor), COX1 (cyclooxygenase-1) and HIF (hypoxia inducible factor).     

Diorganotin(IV) carboxylates of 3-methylphenyl ethanoic acid: Synthesis,crystal structure,antibacterial, anticancer and molecular docking studies

Abstract

Di-n-butyl- (1) and diethyltin(IV) (2) derivatives of 3-methylphenylethanoic acid were synthesized and characterized by elemental analysis, atomic absorption, IR, ¹H and 13C NMR spectroscopy and mass spectrometry. The spectroscopic data and single crystal X-ray diffraction studies for complex 2 have confirmed a bidentate coordination mode of the carboxylate ligand and the presence of hexacoordinated tin atoms in the complexes. The complexes were screened for their in vitro antibacterial activity against selected gram positive and gram negative bacterial strains. The anticancer potential was assessed against prostate cancer cell lines. Both complexes have shown higher activities than the ligand acid. Complex 1 with an IC₅₀ value of 4.97?±?0.27?μg/mL was found to be better anti prostate cancer agent than complex 2 (IC₅₀ = 11.26?±?2.18?μg/mL). Molecular docking study has suggested antibacterial action of the complexes in terms of their ability to develop hydrogen bonding and hydrophobic interactions with vital residues of the target proteins like tyrosyl-tRNA synthase from Staphylococcus aureus (gram-positive bacteria) and undecaprenyl diphosphate synthase from Escherichia coli (gram-negative bacteria).     

Synthesis,urease inhibitory activities,and molecular docking studies of two Cu(II) complexes

Two mononuclear copper(II) complexes, [Cu(C₄H₃N₂O₂)₂?·?4H₂O] (1) and [Cu(C₁₂H₁₁N₂O₂Cl₂)₂] (2), were synthesized and structurally characterized by single-crystal X-ray analysis. The copper(II) adopts a square-planar environment in 1, while the geometry in 2 can be described as distorted square-pyramidal. Complexes 1 and 2 were evaluated for their inhibitory activities against jack bean urease in vitro and both were found to have strong inhibitory activities comparable to that of acetohydroxamic acid. A docking simulation was performed to position 2 into the jack bean urease active site to determine the probable binding conformation.     

Synthesis,spectral analysis,antibacterial activity,quantum chemical studies and supporting molecular docking of Schiff base (E)-4-((4-bromobenzylidene) amino)benzenesulfonamide

A new Schiff base (E)-4-((4-bromobenzylidene) amino) benzenesulfonamide (M2) was synthesized by the reaction between 4-bromobenzaldehyde and sulfanilamide followed by characterization using IR, Raman, UV–Visible, ¹HNMR, and ¹³CNMR spectral techniques. This was followed by electronic structure studies using DFT and TD-DFT. We simulated the IR spectrum using B3LYP/6-31+G(d,p) level of theory, followed by a comparison with experimental spectra and detailed potential energy distribution and vibrational assignment analysis. The comparison of experimental UV and simulated UV spectrum using TD-DFT B3LYP/6-31+G(d,p) in DMSO solvent atmosphere gave good agreement. As Schiff bases are biologically active, we checked for the potential activity of the synthesized compound with the help of ADMET prediction and found it to be active. Wavefunctions related properties like ELF, LOL, and ELF are also reported. Prediction of biological activity spectrum study indicated possible antibacterial activity against bacteria, which is supported by molecular docking against Staphylococcus aureus (3U2D) protein with a docking score of ?7.1 kcal/mol. Experimental antibacterial study using the compound and standard drugs confirmed this prediction.     

Inner metal complexes of tetradentate Schiff base: Synthesis,characterization, biological activity and molecular docking studies

A novel Schiff base ligand, namely 2,2′‐((1E,1′E)‐(1,3‐phenylenebis(azanylylidene))bis(methanylylidene))diphenol (H₂L), was synthesized by condensation of m‐phenylenediamine and 2‐hydroxybenzaldehyde (in 1:2 ratio). Series of complexes were obtained from the reaction of La(III), Er(III) and Yb(III) chlorides with H₂L. The ligand and complexes were characterized using elemental analysis, infrared, ¹H NMR, UV–visible and mass spectroscopies, magnetic susceptibility and conductivity measurements and thermal analysis. Infrared and ¹H NMR spectra indicated the coordination of the azomethine nitrogens and deprotonated phenolic oxygen atoms in a tetradentate manner (ONNO). The thermal behaviour of the complexes was studied from ambient temperature to 1000°C. The complexes were found to have water molecules of hydration and coordinated water molecules. The complexes were found to possess high biological activities against various organisms compared to the free ligand (Gram‐positive bacteria Staphylococcus aureus and Bacillus subtilis, Gram‐negative bacteria Salmonella sp., Escherichia coli and Pseudomonas aeruginosa and fungi Aspergillus fumigatus and Candida albicans). The more effective and probable binding modes between H₂L with different active sites of colon cancer (PDB code: 2hq6) and lung cancer (PDB code: 1x2j) receptors were investigated using molecular docking studies.     

Synthesis,characterization, biological applications,and molecular docking studies of amino-phenol-derived mixed-ligand complexes with Fe(III), Cr(III), and La(III) ions

A new series of Fe(III), Cr(III), and La(III) mixed-ligand complexes, resulting from the interaction of 2-aminophenol with 2-hydroxy acetophenone (HL₁) as primary ligand and L- histidine (L₂) as a secondary ligand, has been investigated using various physicochemical studies such as elemental analyses, molar conductivity, magnetic moment, infrared, UV/Vis, ¹H NMR, and mass spectroscopic techniques. The microanalytical results indicate that the mixed ligand complexes were designed in a 1:1:1 M ratio. The electronic spectral data indicated that all the synthesized complexes have an octahedral structure. The disc diffusion assay was used to determine the disc inhibition zone (IZ, mm) and minimum inhibitory concentration (MIC, g/mL) of the investigated compounds against the growth of the pathogenic bacterial strains S. aureus, E. faecalis, P. aeruginosa, Klebsiella sp., and E. coli. The MTT test was used to determine the cytotoxicity of these reported compounds against the human hepatocellular liver cancer (HEPG-2) cell lines. The molecular docking study for the compounds against the EGFR tyrosine kinase receptor (PDB code: 1 M17) was conducted to examine the interactions in protein–ligand complexes. Furthermore, the biological activity of the ligand was investigated using quantitative structure–activity relationship studies (QSAR).