Exploration of newly synthesized amantadine-thiourea conjugates for their DNA binding, anti-elastase, and anti-glioma potentials.

Three newly synthesized amantadine thiourea conjugates namely MS-1 N-(((3 s,5 s,7 s)-adamantan-1-yl)carbamothioyl)benzamide, MS-2 N-(((3 s,5 s,7 s)-adamantan-1-yl)carbamothioyl)-4-methylbenzamide and MS-3 N-((3 s,5 s,7 s)-adamantan-1-ylcarbamothioyl)-4-chlorobenzamide were investigated for their structures, bindings (DNA/ elastase), and for their impact on healthy and cancerous cells. Theoretical (DFT/docking) and experimental {UV-visible (UV-), fluorescence (Flu-), and cyclic voltammetry (CV)} studies indicated binding interactions of each conjugate with DNA and elastase enzyme. Theoretically and experimentally calculated binding parameters for conjugate - DNA interaction revealed MS-3 - DNA to have most significant binding with comparatively greater values of binding parameters {(Kb/M-1: docking, 3.8 × 105; UV-, 5.95 × 103; Flu-,1.55 × 105; CV, 1.52 × 104), (∆G/ kJmol-1: docking, -32.09; UV-, -22.40; Flu-,-30.81; CV, -24.82)}. The docked structures, greater bindings site size values (n), and the trend in DNA viscosity changes in the presence of each conjugate concentration confirmed a mixed binding mode of interaction among them. Conjugate - elastase binding by docking agreed with the experimental anti-elastase findings. Cytotoxicity studies of each tested conjugate demonstrated greater cytotoxicity for cancerous (MG-U87) cells in comparison to control, while for the normal (HEK-293) cells the cytotoxicity was found comparatively low. Overall exploration suggested that MS-3 is the most effective candidate for DNA binding, anti-elastase, and for anti-glioma activities.

Repurposing of Strychnine as the Potential Inhibitors of Aldo-keto Reductase Family 1 Members B1 and B10: Computational Modeling and Pharmacokinetic Analysis.

AKR1B1 and AKR1B10 are important members of aldo-keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule's reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of - 30.84 and - 29.36 kJ/mol respectively. To validate the stability of the protein-ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings.

Synthesis, biological evaluation and in silico investigations of benzotriazole derivatives as potential inhibitors of NIMA related kinase.

In the current study, a novel compound, bis(3-(2H-benzo[d][1,2,3]triazol-2-yl)-2-(prop-2-yn-1-yloxy)-5-(2,4,4-trimethylpentan-2-yl)phenyl)methane (TAJ1), has been synthesized by the reaction of 6,6'-methylenebis(2-(2H-benzo[d][1,2,3]triazol-2-yl)-4-(2,4,4-trimethylpentan-2-yl)phenol) (1), propargyl bromide (2) and potassium carbonate. Spectroscopic (FTIR, 1H-NMR, 13C-NMR) and single-crystal assays proved the structure of the synthesized sample. XRD analysis confirmed the structure of the synthesized compound, showing that it possesses two aromatic parts linked via a -CH2 carbon with a bond angle of 108.40°. The cell line activity reported a percent growth reduction for different cell types (HeLa cells, MCF-7 cells, and Vero cells) under various treatment conditions (TAJ1, cisplatin, and doxorubicin) after 24 hours and 48 hours. The percent growth reduction represents a decrease in cell growth compared to a control condition. Furthermore, density functional theory (DFT) calculations were utilized to examine the frontier molecular orbitals (FMOs) and overall chemical reactivity descriptors of TAJ1. The molecule's chemical reactivity and stability were assessed by determining the HOMO-LUMO energy gap. TAJ1 displayed a HOMO energy level of -0.224 eV, a LUMO energy level of -0.065 eV, and a HOMO-LUMO gap of 0.159 eV. Additionally, molecular docking analysis was performed to assess the binding affinities of TAJ1 with various proteins. The compound TAJ1 showed potent interactions with NEK2, exhibiting -10.5 kcal mol-1 binding energy. Although TAJ1 has demonstrated interactions with NEK7, NEK9, TP53, NF-KAPPA-B, and caspase-3 proteins, suggesting its potential as a therapeutic agent, it is important to evaluate the conformational stability of the protein-ligand complex. Hence, molecular dynamics simulations were conducted to assess this stability. To analyze the complex, root mean square deviation (RMSD) and root mean square fluctuation analyses were performed. The results of these analyses indicate that the top hits obtained from the virtual screening possess the ability to act as effective NEK2 inhibitors. Therefore, further investigation of the inhibitory potential of these identified compounds using in vitro and in vivo approaches is recommended.

Computational and theoretical chemistry of newly synthesized and characterized 2,2'-(5,5'-(1,4-phenylene)bis(1H-tetrazole-5,1-diyl))bis-N-acetamides.

Energetic heterocycles, including pyridines, triazoles, and tetrazoles, exhibit greater density, heats of formation, and oxygen balance compared to their carbocyclic counterparts, making them a promising approach for synthesizing novel bis-tetrazole acetamides. Synthesized compounds A-F, some of which feature a chlorine atom attached to the phenyl ring, serve as valuable synthons for aryl coupling reactions. Analysis via 1H-NMR and 13C-NMR spectroscopy, as well as density functional considerations through B3LYP functional correlation with 6-311 + + G(d) and 6-31G(d) basis set, revealed the observed LUMO/HOMO energies and charge transfer within the molecule. Additionally, the dipole moment, chemical hardness, softness, ionization potential, local reactivity potential via Fukui indices and thermodynamic properties (entropy, enthalpy, and Gibbs free energy) of the molecule were calculated through density functional theory studies. In addition, Molecular Docking studies were conducted to investigate the anti-cancer potential of synthesized heterocyclic compounds against caspase 3, NF-KAPPA-B and P53 protein. Molecular docking analysis demonstrated a potent interaction between 2,2'-(5,5'-(1,4-phenylene)bis(1H-tetrazole-5,1-diyl))bis-N-(2,4-dinitrophenyl) acetamides (6d) and TP53 and NF-KAPPA-B with binding energies of - 11.8 kJ/mol and - 10.9 kJ/mol for TP53 and NF-KAPPA-B, respectively. Similarly, 2,2'-(5,5'-(1,4-phenylene)bis(1H-tetrazole-5,1-diyl))bis-N-(2-chlorophenyl) acetamides (6f) exhibited a strong interaction with caspase-3 with binding energy of -10.0 kJ/mol, indicating their potential as therapeutic agents against these proteins. Furthermore, the findings of current study was further strengthen by 100 ns molecular dynamics (MD) simulations. Finally, theoretical studies of oxygen balance and nitrogen percentage suggest that these molecules can be utilized as energetic materials.

Investigation of Newly Synthesized Bis-Acyl-Thiourea Derivatives of 4-Nitrobenzene-1,2-Diamine for Their DNA Binding, Urease Inhibition, and Anti-Brain-Tumor Activities.

Bis-acyl-thiourea derivatives, namely N,N'-(((4-nitro-1,2-phenylene)bis(azanediyl)) bis(carbonothioyl))bis(2,4-dichlorobenzamide) (UP-1), N,N'-(((4-nitro-1,2-phenylene) bis(azanediyl))bis(carbonothioyl))diheptanamide (UP-2), and N,N'-(((4-nitro-1,2-phenylene)bis(azanediyl))bis(carbonothioyl))dibutannamide (UP-3), were synthesized in two steps. The structural characterization of the derivatives was carried out by FTIR, 1H-NMR, and 13C-NMR, and then their DNA binding, anti-urease, and anticancer activities were explored. Both theoretical and experimental results, as obtained by density functional theory, molecular docking, UV-visible spectroscopy, fluorescence (Flu-)spectroscopy, cyclic voltammetry (CV), and viscometry, pointed towards compounds' interactions with DNA. However, the values of binding constant (Kb), binding site size (n), and negative Gibbs free energy change (ΔG) (as evaluated by docking, UV-vis, Flu-, and CV) indicated that all the derivatives exhibited binding interactions with the DNA in the order UP-3 > UP-2 > UP-1. The experimental findings from spectral and electrochemical analysis complemented each other and supported the theoretical analysis. The lower diffusion coefficient (Do) values, as obtained from CV responses of each compound after DNA addition at various scan rates, further confirmed the formation of a bulky compound-DNA complex that caused slow diffusion. The mixed binding mode of interaction as seen in docking was further verified by changes in DNA viscosity with varying compound concentrations. All compounds showed strong anti-urease activity, whereas UP-1 was found to have comparatively better inhibitory efficiency, with an IC50 value of 1.55 ± 0.0288 µM. The dose-dependent cytotoxicity of the synthesized derivatives against glioblastoma MG-U87 cells (a human brain cancer cell line) followed by HEK-293 cells (a normal human embryonic kidney cell line) indicated that UP-1 and UP-3 have greater cytotoxicity against both cancerous and healthy cell lines at 400 µM. However, dose-dependent responses of UP-2 showed cytotoxicity against cancerous cells, while it showed no cytotoxicity on the healthy cell line at a low concentration range of 40-120 µM.

Synthesis, kinetic studies and in-silico investigations of novel quinolinyl-iminothiazolines as alkaline phosphatase inhibitors.

Deposition of hydroxyapatite (HA) or alkaline phosphate crystals on soft tissues causes the pathological calcification diseases comprising of end-stage osteoarthritis (OA), ankylosing spondylitis (AS), medial artery calcification and tumour calcification. The pathological calcification is symbolised by increased concentration of tissue non-specific alkaline phosphatase (TNAP). An efficient therapeutic strategy to eradicate these diseases is required, and for this the alkaline phosphatase inhibitors can play a potential role. In this context a series of novel quinolinyl iminothiazolines was synthesised and evaluated for alkaline phosphatase inhibition potential. All the compounds were subjected to DFT studies where N-benzamide quinolinyl iminothiazoline (6g), N-dichlorobenzamide quinolinyl iminothiazoline (6i) and N-nitrobenzamide quinolinyl iminothiazoline (6j) were found as the most reactive compounds. Then during the in-vitro testing, the compound N-benzamide quinolinyl iminothiazoline (6g) exhibited the maximum alkaline phosphatase inhibitory effect (IC50 = 0.337 ± 0.015 µM) as compared to other analogues and standard KH2PO4 (IC50 = 5.245 ± 0.477 µM). The results were supported by the molecular docking studies, molecular dynamics simulations and kinetic analysis which also revealed the inhibitory potential of compound N-benzamide quinolinyl iminothiazoline (6g) against alkaline phosphatase. This compound can be act as lead molecule for the synthesis of more effective inhibitors and can be suggested to test at the molecular level.

Structural and functional insight into thiazolidinone derivatives as novel candidates for anticancer drug design: in vitro biological and in-silico strategies.

The compounds 2a-2h containing a thiazolidinone pharmacophore were synthesized via hetrerocylization of thiosemicarbazones with dimethyl acetylenedicarboxylate. The hybrid molecules were evaluated for anticancer activity against the human cell lines MCF-7, T47D (human breast adenocarcinoma) and HeLa (cervical cancer). Compounds 2c showed effective cytotoxicity on MCF-7 and HeLa (GI50 6.40 ± 0.10 µM/mL and GI5010.30 ± 1.09 µM/mL), and compound 2d also showed effective cytotoxicity against MCF-7 and HeLa cell lines i.e., (GI50 16.60 ± 0.21 µM/mL and GI50 15.02 ± 0.14 µM/mL). These findings were comparable to cisplatin (azane;dichloroplatinum) the standard drug (GI50 13.20 ± µM/mL and 15.10 µM/mL respectively) and consequently nominated for determination of the mode of cell death. The results revealed the cytotoxic effects of 2c and 2d by induction of apoptosis in MCF-7 and HeLa cell lines. Moreover the results were further supported by the Molecular Docking which predicts the binding interactions of the best anticancer ligands with Ribonucleotide reductase (RNR), which is essential enzyme required for de-novo synthesis of DNA precursors. Molecular dynamic simulations were also performed to determine the stability of protein-ligand complex under different simulated conditions. In addition, the computational studies including DFTs, ADMET properties suggested these compounds can act as lead molecules, for the synthesis of novel drug candidates for the treatment of specific cancer and its associated malignancies.

Acetophenone-Based 3,4-Dihydropyrimidine-2(1H)-Thione as Potential Inhibitor of Tyrosinase and Ribonucleotide Reductase: Facile Synthesis, Crystal Structure, In-Vitro and In-Silico Investigations.

The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-methylpent-3-en-2-one (1), 4-acetyl aniline (2) and potassium thiocyanate. The spectroscopic analysis including: FTIR, 1H-NMR, and single crystal analysis proved the structure of synthesized compound (4), with the six-membered nonplanar ring in envelope conformation. In crystal structure, the intermolecular N-H ⋯ S and C-H ⋯ O hydrogen bonds link the molecule in a two-dimensional manner which is parallel to (010) the plane enclosing R22 (8) and R22 (10) ring motifs. After that, the Hirshfeld surfaces and their related two-dimensional fingerprint plots were used for thorough investigation of intermolecular interactions. According to Hirshfeld surface analysis, the most substantial contributions to the crystal packing are from H ⋯ H (59.5%), H ⋯ S/S ⋯ H (16.1%), and H ⋯ C/C ⋯ H (13.1%) interactions. The electronic properties and stability of the compound were investigated through density functional theory (DFT) studies using B3LYP functional and 6-31G* as a basis set. The compound 4 displayed the high chemical reactivity with chemical softness of 2.48. In comparison to the already reported known tyrosinase inhibitor, the newly synthesized derivatives exhibited almost seven-fold better inhibition of tyrosinase (IC50 = 1.97 µM), which was further supported by molecular docking studies. The compound 4 inside the active pocket of ribonucleotide reductase (RNR) exhibited a binding energy of -19.68 kJ/mol, and with mammalian deoxy ribonucleic acid (DNA) it acts as an effective DNA groove binder with a binding energy of -21.32 kJ/mol. The results suggested further exploration of this compound at molecular level to synthesize more potential leads for the treatment of cancer.

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer.

Carbonic anhydrases (CA), having Zn2+ metal atoms, are responsible for the catalysis of CO2 and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including brain, renal and pancreatic carcinomas. To cope with the lack of presence of a promising therapeutic agent against these cancers, searching for an efficient and suitable carbonic anhydrase inhibitor is crucial. In the current study, ten novel 3-ethylaniline hybrid imino-thiazolidinones were synthesized and characterized by FTIR, NMR (1H, 13C), and mass spectrometry. Synthesis was carried out by diethyl but-2-ynedioate cyclization and different acyl thiourea substitutions of 3-ethyl amine. The CA (II) enzyme inhibition profile for all synthesized derivatives was determined. It was observed that compound 6e demonstrated highest inhibition of CA-II with an IC50 value of 1.545 ± 0.016 µM. In order to explore the pharmacophoric properties and develop structure activity relationship, in silico screening was performed. In silico investigations included density functional theory (DFT) studies, pharmacophore-guided model development, molecular docking, molecular dynamic (MD) simulations, and prediction of drug likeness scores. DFT investigations provided insight into the electronic characteristics of compounds, while molecular docking determined the binding orientation of derivatives within the CA-II active site. Compounds 6a, 6e, and 6g had a reactive profile and generated stable protein-ligand interactions with respective docking scores of -6.12, -6.99, and -6.76 kcal/mol. MD simulations were used to evaluate the stability of the top-ranked complex. In addition, pharmacophore-guided modeling demonstrated that compound 6e produced the best pharmacophore model (HHAAARR) compared to standard brinzolamide. In vitro and in silico investigations anticipated that compound 6e would be an inhibitor of carbonic anhydrase II with high efficacy. Compound 6e may serve as a potential lead for future synthesis that can be investigated at the molecular level, and additional in vivo studies are strongly encouraged.

Appraisal of novel azomethine-thioxoimidazolidinone conjugates as ecto-5'-nucleotidase inhibitors: synthesis and molecular docking studies.

Purinergic signaling is regulated by a group of extracellular enzymes called ectonucleotidases. One of its members i.e., ecto-5'-nucleotidase (h-e5'NT) is involved in the final step of the enzymatic hydrolysis cascade that is the conversion of adenosine monophosphate (AMP) to adenosine and therefore, involves the regulation of adenosine level in extracellular space. The overexpression of h-e5'NT has been observed in various pathological conditions such as hypoxia, inflammation and cancers, and led to various complications. Hence, the identification of a potent as well as selective inhibitor of h-e5'NT is of greater importance in therapeutic treatment of various diseases. Azomethine-thioxoimidazolidinone derivatives were studied for their inhibition potential against e5'NT enzyme along with cytotoxic potential against cancer cell lines possessing overexpression of e5'NT enzyme. The derivative (E)-3-((4-((3-methoxybenzyl)oxy)benzylidene)amino)-2-thioxoimidazolidin-4-one (4g) displayed selective and significant inhibition towards h-e5'NT with an IC50 value of 0.23 ± 0.08 µM. While two other derivatives i.e., (E)-3-(((5-bromothiophen-2-yl)methylene)amino)-2-thioxoimidazolidin-4-one (4b) and 2-thioxo-3-((3,4,5-trimethoxybenzylidene)amino)imidazolidin-4-one (4e), exhibited non-selective potent inhibitory behavior against both human and rat enzymes. Moreover, these derivatives (4b, 4e and 4g) were further investigated for their effect on the expression of h-e5'NT using quantitative real time polymerase chain reaction. Additionally, molecular docking and DFT studies were also performed to determine the putative binding mode of potent inhibitors within the enzyme active site. HOMO, LUMO, ΔE, and molecular electrostatic potential maps were computed by DFT and the charge transfer regions within the molecules were identified to find out the regions for electrophilic and nucleophilic attack.

Novel adamantyl clubbed iminothiazolidinones as promising elastase inhibitors: design, synthesis, molecular docking, ADMET and DFT studies.

Porcine Pancreatic Elastase (PPE) is a serine protease that is homologous to trypsin and chymotrypsin that are involved in various pathologies like inflammatory disease, Chronic Obstructive Pulmonary Disease (COPD), acute respiratory distress syndrome, cystic fibrosis, and atherosclerosis. PPE if remained uninhibited would lead to digestion of important connective tissue. We developed new structurally diverse series of adamantyl-iminothiazolidinone hybrids to divulge elastase inhibition assay. To identify potent derivatives, in silico screening was conducted and in vitro studies disclosed that the compounds 5a, 5f, 5g, and 5h showed excellent binding energies and low IC50 values. In silico studies including molecular docking, DFT studies (using the B3LYP/SVP basis set in the gas phase) drug likeness scores and molecular dynamic simulation studies were conducted to evaluate protein-ligand interactions and to determine the stability of top ranked conformation. In silico studies further supported the results of in vitro experiments and suggest these derivatives as novel inhibitors of elastase enzyme.

Investigations on Anticancer Potentials by DNA Binding and Cytotoxicity Studies for Newly Synthesized and Characterized Imidazolidine and Thiazolidine-Based Isatin Derivatives.

Imidazolidine and thiazolidine-based isatin derivatives (IST-01-04) were synthesized, characterized, and tested for their interactions with ds-DNA. Theoretical and experimental findings showed good compatibility and indicated compound-DNA binding by mixed mode of interactions. The evaluated binding parameters, i.e., binding constant (Kb), free energy change (ΔG), and binding site sizes (n), inferred comparatively greater and more spontaneous binding interactions of IST-02 and then IST-04 with the DNA, among all compounds tested under physiological pH and temperature (7.4, 37 °C). The cytotoxic activity of all compounds was assessed against HeLa (cervical carcinoma), MCF-7 (breast carcinoma), and HuH-7 (liver carcinoma), as well as normal HEK-293 (human embryonic kidney) cell lines. Among all compounds, IST-02 and 04 were found to be cytotoxic against HuH-7 cell lines with percentage cell toxicity of 75% and 66%, respectively, at 500 ng/µL dosage. Moreover, HEK-293 cells exhibit tolerance to the increasing drug concentration, suggesting these two compounds are less cytotoxic against normal cell lines compared to cancer cell lines. Hence, both DNA binding and cytotoxicity studies proved imidazolidine (IST-02) and thiazolidine (IST-04)-based isatin derivatives as potent anticancer drug candidates among which imidazolidine (IST-02) is comparatively the more promising.

New aryl Schiff bases of thiadiazole derivative of ibuprofen as DNA binders and potential anticancer drug candidates.

The work presented in this paper describes the synthesis of two new aryl Schiff bases [(E)-N-(4-(benzyloxy)-3-methoxybenzylidene)-5-(1-(4-isobutylphenyl)ethyl)-1,3,4-thiadiazol-2-amine] (ASB-1) and [(E)-N-(4-(benzyloxy)benzylidene)-5-(1-(4-isobutylphenyl)ethyl)-1,3,4-thiadiazol-2-amine] (ASB-2). These compounds were characterized by different analytical techniques and then studied for DNA binding. Binding studies were carried out at neutral pH (7.0) and at 37 °C by theoretical and experimental methods including DFT, molecular docking, spectroscopy (UV-visible, fluorescence), cyclic voltammetry (CV) and viscometry. Further investigations of these compounds were done on hepatocellular carcinoma; Huh-7 cancer cell line. Binding constant, free energy change and binding site size, i.e. Kb, ΔG and n were evaluated which indicated that both ASB-1 and ASB-2 bind significantly and spontaneously with the DNA. However, data revealed relatively greater binding of ASB-1 with DNA. Spectral and voltammetric results were found supportive of each other. Binding site sizes and viscosity measurements verified the mixed binding mode of interactions as observed in molecular docking analysis, i.e. intercalation with groove binding. DNA binding studies were very well correlated with the in-vitro studies performed on Huh-7 cell line as well as normal HEK-293 cell lines. The compound ASB-1 not only showed greater binding affinity toward DNA but also showed greater anticancer potency with least IC50 value as compared to ASB-2.

Bis-Schiff bases of 2,2'-dibromobenzidine as efficient corrosion inhibitors for mild steel in acidic medium.

In this work, three new bis-Schiff bases, namely 1,1'-(2,2'-dibromo-[1,1'-biphenyl]-4,4'-diyl)bis(N-phenylmethanimine) (BNSB01), 1,1'-(2,2'-dibromo-[1,1'-biphenyl]-4,4'-diyl)bis(N-(4-bromophenyl)methanimine) (BNSB02) and 4,4'-(((2,2'-dibromo-[1,1'-biphenyl]-4,4'-diyl)bis(methanylylidene))bis(azanylylidene))diphenol (BNSB03), were synthesized. These Schiff bases were evaluated for their corrosion inhibition ability on mild steel specimens in 0.5 M HCl by using electrochemical and weight loss techniques. The inhibition performance was found to increase with an increase in the inhibitor concentration and decrease with an increase in temperature. The results revealed that the synthesized compounds followed the Langmuir isotherm model and were efficient mixed-type inhibitors. The electrochemical impedance studies also indicated that with a rise in the concentration of inhibitors, the charge transfer resistance increased. The surface morphology of the inhibited and uninhibited specimens was examined using scanning electron microscopy (SEM). The efficiency of the compounds was in the order BNSB02 > BNSB03 > BNSB01. All the results obtained were in good correlation with each other.

Design, synthesis and biological evaluation of trinary benzocoumarin-thiazoles-azomethines derivatives as effective and selective inhibitors of alkaline phosphatase.

Design, synthesis and characterization of new trinary Benzocoumarin-Thiazoles-Azomethine derivatives having three bioactive scaffolds in a single structural unit were carried out. The newly synthesized molecules were investigated for the inhibitory activity on human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP) isozymes. All the tested compounds exhibited the potent inhibition profile on both isozymes of alkaline phosphatase i.e., h-TNAP and h-IAP. Molecular docking studies were performed to explore the putative binding mode of interactions of selective inhibitors. Moreover, the synthesized derivatives were evaluated against cervical cancer cell line, HeLa and a few compounds exhibited significant inhibition in the range of 21.0-69.7%. The derivatives can be potential and selective alkaline phosphatase inhibitors for future studies.

Aroylthiourea derivatives of ciprofloxacin drug as DNA binder: Theoretical, spectroscopic and electrochemical studies along with cytotoxicity assessment.

Aroylthiourea derivatives of ciprofloxacin drug - [1-cyclopropyl-6-fluoro-7-(4-((4-methoxybenzoyl)carbamothioyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] ATU-1, [1-cyclopropyl-7-(4-((2,4-dibromobenzoyl)carbamothioyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] ATU-2, and [1-cyclopropyl-7-(4-((3,5-dinitrobenzoyl)carbamothioyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid] ATU-3 were synthesized, characterized and investigated for DNA binding at stomach pH (4.7) and at 37 °C. All findings by using DFT, molecular docking, spectroscopic (UV-, fluorescence; FL-), cyclic voltammetric (CV) and viscometric techniques revealed that these compounds have the potency to bind with DNA via a mixed mode of interaction. The binding affinity of ATU-1 was evaluated comparatively greater with Kb × 104/M-1 (docking; 5.55, UV-; 7.93, FL-; 5.62, CV; 6.06), ΔG/kJmol-1(docking; -27.07, UV-; -29.07, FL-; -28.18, CV; -28.38) and n (FL-; 1.20, CV; 2.72). Stern-Volmer quenching constant (Ksv) further pointed towards comparatively greater binding affinity of ATU-1 for DNA, while bimolecular quenching constant (Kq) values showed the involvement of static quenching mechanism in the compound - DNA interaction. Comparatively lesser IC50 (7.1 µM) value obtained from biological work on Huh-7 cancer cell line further confirmed the greater anticancer potential of ATU-1 than that of ATU-2&3.

Novel C-2 Symmetric Molecules as α-Glucosidase and α-Amylase Inhibitors: Design, Synthesis, Kinetic Evaluation, Molecular Docking and Pharmacokinetics.

A series of symmetrical salicylaldehyde-bishydrazine azo molecules, 5a-5h, have been synthesized, characterized by 1H-NMR and 13C-NMR, and evaluated for their in vitro α-glucosidase and α-amylase inhibitory activities. All the synthesized compounds efficiently inhibited both enzymes. Compound 5g was the most potent derivative in the series, and powerfully inhibited both α-glucosidase and α-amylase. The IC50 of 5g against α-glucosidase was 0.35917 ± 0.0189 µM (standard acarbose IC50 = 6.109 ± 0.329 µM), and the IC50 value of 5g against α-amylase was 0.4379 ± 0.0423 µM (standard acarbose IC50 = 33.178 ± 2.392 µM). The Lineweaver-Burk plot indicated that compound 5g is a competitive inhibitor of α-glucosidase. The binding interactions of the most active analogues were confirmed through molecular docking studies. Docking studies showed that 5g interacts with the residues Trp690, Asp548, Arg425, and Glu426, which form hydrogen bonds to 5g with distances of 2.05, 2.20, 2.10 and 2.18 Å, respectively. All compounds showed high mutagenic and tumorigenic behaviors, and only 5e showed irritant properties. In addition, all the derivatives showed good antioxidant activities. The pharmacokinetic evaluation also revealed promising results.

Synthesis, theoretical, spectroscopic and electrochemical DNA binding investigations of 1, 3, 4-thiadiazole derivatives of ibuprofen and ciprofloxacin: Cancer cell line studies.

Two new 1,3,4-thiadiazole derivatives of ibuprofen and ciprofloxacin namely {(5-(1-(4-isobutylphenyl)ethyl)-1,3,4-thiadiazol-2-amine)} 1 and {(3-(5-amino-1,3,4-thiadiazol-2-yl)-1-cyclopropyl-6-fluoro-7-(piperazin-1-yl)quinolin-4(1H)-one)} 2 were synthesized and characterized by spectroscopic and elemental analysis. DFT and molecular docking were done initially for theoretical binding possibilities of the investigated compounds. In vitro DNA binding investigations were carried out with UV-visible spectroscopic, fluorescence spectroscopic, cyclic voltammetric (CV) experiments under physiological conditions of the stomach (4.7) and blood (7.4) pH and at normal body temperature (37 °C). Both theoretical and experimental results suggested spontaneous and significant intercalative binding of the compounds with DNA. Kinetic and thermodynamic parameters (Kb, ΔG) were evaluated greater for compound 2 which showed comparatively more binding and more spontaneity of 2 than 1 to bind with DNA at both pH values. Binding site sizes were found greater (n > 1) and revealed the possibility of other sites for interactions along with intercalation. Overall results for DNA binding were found more significant for 2 at Stomach (4.7) pH. Viscometric studies further verified intercalation as a prominent binding mode for both compounds. IC50 values obtained from human hepatocellular carcinoma (Huh-7) cell line studies revealed 2 as potent anticancer agent than 1 as value found 25.75 µM (lesser than 50 µM). Theoretical and experimental DNA binding studies showed good correlation with cancer cell (Huh-7) line activity of 1 and 2 and further suggested that these compounds could act as potential anti-cancer drug candidates.

Exploration of carboxy pyrazole derivatives: Synthesis, alkaline phosphatase, nucleotide pyrophosphatase/phosphodiesterase and nucleoside triphosphate diphosphohydrolase inhibition studies with potential anticancer profile.

In the present work we report the synthesis of new aryl pyrazole derivatives using 1,3-dicarbonyl motifs. The reaction was proceeded by the cyclization of pentane-2,4-dione (1a), 3-chloropentane-2,4-dione (1b) or ethyl 3-oxobutanoate (1c) with different aryl hydrazines. The products, which can be regarded as 1H-pyrazol-1-yl-one analogues (3a-f, 3g-o, 4a-c, 5a-b) and represent drug like molecules along with well-developed structure-activity relationships, were obtained in good to excellent yield. The structures of synthesized compounds were charcterized on the basis of FT-IR, 1H NMR, 13C NMR and mass spectroscopic data. Considering alkaline phosphatases (APs), nucleotide pyrophosphatases/phosphodiesterases (NPPs) and nucleoside triphosphate diphosphohydrolase as the molecular targets, the effects of these synthesized compounds were investigated on different isozymes of APs, NPPs and NTPDases. The data revealed that the synthesized compounds inhibited both enzymes but most of them inhibited tissue non-specific alkaline phosphatase (TNAP) more selectively. The antitumor activity results indicated that the synthesized derivatives have strong inhibitory effects on the growth of selected cell lines from different tissues such as breast, bone marrow and cervix (MCF-7, K-562 and Hela) but with varying intensities. Moreover the binding mode of interactions were explained on the basis of molecular docking and in-silico studies.