Synthesis of new class of non-sulfonamide bis-benzimidazoles as antitumor agents by inhibiting carbonic anhydrase-IX enzyme.

In several types of cancers, the expression of carbonic anhydrase-IX (CA-IX) enzyme is elevated than its normal level which ultimately plays a key role in the tumor growth of epithelial cells in breast and lung cancer by acidifying tumor microenvironment, therefore, inhibition of this target is important in antitumor therapy. We have synthesized bis-benzimidazole derivatives (1-25) by using 3,3'-diaminobenzidine and various aromatic aldehydes and characterized by various spectroscopic methods (UV/Visible, 1HNMR, 13CNMR, and mass spectrometry). Their inhibitory potential for human CA-IX (hCA-IX) was evaluated in-vitro, where several synthesized derivatives showed potent inhibition of hCA-IX (IC50 values in range of 5.23 ± 1.05 to 40.10 ± 1.78 µM) and compounds 3-5, 7-8, 13-16, 21 and 23 showed superior activity than the standard drug "acetazolamide" (IC50 = 18.24 ± 1.43 µM). Furthermore, all these compounds showed no toxicity on human fibroblast cell lines (BJ cell lines). Moreover, molecular docking was carried out to predict their binding modes in the active site of CA-IX and revealed a significant role of imidazole ring of synthesized entities in their effective binding with the specific residues of CA-IX. The obtained results paved the way for further in vivo and other pharmacological studies for the optimization of these molecules as possible anti-cancer agents.

Bis-1,3,4-Oxadiazole Derivatives as Novel and Potential Urease Inhibitors; Synthesis, In Vitro, and In Silico Studies.

AIMS: To synthesize bis-1,3,4-oxadiazole derivatives as novel and potential urease inhibitors. BACKGROUND: Despite many important biological activities associated with oxadiazoles, they are still neglected by medicinal chemists for their possible urease inhibitory activity. Keeping in view the countless importance of urease inhibitors, we have synthesized a new library of substituted bisoxadiazole derivatives (1-21) to evaluate their urease inhibitory potential. OBJECTIVE: The aim includes the synthesis of substituted bis-oxadiazole derivatives (1-21) in order to evaluate their urease inhibitory potential. METHODS: Bis-1,3,4-oxadiazole derivatives 1-21 were synthesized through sequential reactions using starting material isophthalic acid. Esterification reaction was done by refluxing in methanol for 2 h in the presence of the catalytic amount of concentrated H2SO4 till dissolution. In the second step, dimethyl isophthalate and hydrazine hydrate in excess (1:5) were refluxed in methanol to afford isophthalic dihydrazide. Then, isophthalic dihydrazide was treated with different substituted benzaldehydes in a 1:2 ratio under acidic conditions. RESULTS: In vitro urease, the inhibitory activity of the synthesized compounds was evaluated and the results demonstrated good activities with IC50 values in the range of 13.46 ± 0.34 to 74.45 ± 3.81 µM as compared to the standard thiourea (IC50 = 21.13 ± 0.415 µM). Most of the compounds were found to be more potent than the standard. The structure-activity relationship (SAR) suggested that the variations in the inhibitory activities of the compounds were due to different substitutions. Furthermore; in silico study was also performed. CONCLUSION: Current study identified a new class of urease inhibitors. All synthetic compounds 1-21 showed potent as well as good to moderate urease inhibitory activities except 3. SAR suggested that hydroxy-bearing analogs were identified exceptionally well. Molecular docking revealed many important interactions made by compounds with the active site of the urease enzyme.

Adsorption, kinetics and thermodynamics studies of methyl orange dye sequestration through chitosan composites films.

Different films comprising pure chitosan (CS) and chitosan coated sodium zeolites composites films designated as CSZ1, CSZ2, CSZ3 and CSZ4 respectively are presented here for the sequestration of MO dye. The as-synthesized films were characterized by using FSESM, XPS XRD, and TGA analysis. The sequestration of methyl orange dye (MO) was studied under various adsorption parameters i.e. pH effect, reaction temperature, catalytic dosage, interaction period, and original dye concentration in batch experiments. The adsorption power of MO dye sequestration in the presence of CSZ3 was 287 mg g-1 higher than the fine CS (201 mg g-1), and lowest for CSZ4 (173 mg g-1). The experimental data is fitted in the pseudo-second order of chemical kinetics. The Freundlich and Langmuir adsorption models were used on behalf of the analysis of experimental data that revealed multilayered adsorption of MO dye. Kinetics, equilibrium and thermodynamic process were discussed in detailed, suggesting the endothermic and spontaneous process of the adsorption of MO dye on the exterior of films. The present work is general for the MO adsorption, however, it can be applied on large scale applications and can be easily adjustable in the water purification assemblies.

Synthesis, Characterization, and Multifunctional Applications of Cu-Fe and Ni-Fe Nanomaterials.

Cu-Fe and Ni-Fe nanomaterials (NMs) were successfully obtained via a coprecipitation route. Phase analysis and the micro- and physiochemical structure studies for the as-synthesized NMs were carried out with advanced techniques such as TEM, SEM, XRD, XPS, BET, DRS, TGA, and FTIR. Particles with size ranging from 25 to 70 nm were displayed by all the characterization techniques. A surface area of ∼4.48 and 36.52m2/g and band gap energies of ∼1.79 and 1.48 eV were calculated for Cu-Fe and Ni-Fe NMs, respectively. Saturation magnetization (Ms) ∼77.95 emu/g (for Cu-Fe) and 27.70 emu/g (for Ni-Fe) revealed superparamagnetism for both the NMs. The presence of ethanol and methanol as sacrificial agents contributed effectively toward electrocatalytic H-evolution as compared to pure NMs. Furthermore, under solar light irradiations, Cu-Fe and Ni-Fe NMs displayed 85 and 91% degradation during a time interval of 50 and 110 min, respectively, for toxic industrial methylene blue (MB) dye. Different operational variables such as the catalyst amount, pH values, various scavengers, reusability, and stability were thoroughly investigated. Moreover, in situ analysis was carried out in order to determine the mechanism for degradation reactions. A detailed study about various applications categorized the synthesized NMs as efficient candidates for toxic industrial waste cleanup and energy production at an industrial level.

Complexes of N- and O-Donor Ligands as Potential Urease Inhibitors.

We report five new transition-metal complexes that inhibit the urease enzyme. Barbituric acid (BTA), thiobarbituric acid (TBA), isoniazid (INZ), and nicotinamide (NCA) ligands were employed in complexation reactions. The resulting complexes were characterized using a variety of analytical techniques including infra-red and UV-vis spectroscopy, 1H NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction analysis. We describe two mononuclear complexes with a general formula {[M(NCA)2(H2O)4](BTA)2(H2O)}, where M = Co (1) and Zn (2), a mononuclear complex {[Ni(NCA)2(H2O)4](TBA)2(H2O)} (3), and two polymeric chains of a general formula {[M(INZ) (H2O)3](BTA)2(H2O)3}, where M = Co (4) and Zn (5). These complexes displayed significant urease enzyme inhibition with IC50 values in the range of 3.9-19.9 µM.

Synthesis of AgNPs coated with secondary metabolites of Acacia nilotica: An efficient antimicrobial and detoxification agent for environmental toxic organic pollutants.

This study concentrates on biosynthesis of Silver Nanoparticles (AgNPs) from stem extract of Acacia nilotica (A. nilotica). The reaction was completed at a temperature ~40-45 °C and time duration of 5 h. AgNPs were thoroughly investigated via advanced characterization techniques such as UV-Vis spectrophotometry (UV-Vis), Fourier Transform Infrared spectroscopy (FTIR), X-ray Diffractometry (XRD), Field Emission Scanning Electron Microscopy (FESEM), High Resolution Transmission Electron Microscopy (HRTEM), X-ray Photoelectron Spectroscopy (XPS), Thermo Gravimetric Analysis (TGA), Diffuse Reflectance Spectroscopy (DRS), Brunner-Emmett-Teller (BET), Dynamic Light Scattering (DLS), and Zeta potential analysis. AgNPs with average size below 50 nm were revealed by all the measuring techniques. Maximum surface area ~5.69 m2/g was reported for the as synthesized NPs with total pore volume ~0.0191 mL/g and average pore size ~1.13 nm. Physical properties such as size and shape have changed the surface plasmon resonance peak in UV-visible spectrum. Antimicrobial activity was reported due to denaturation of microbial ribosome's sulphur and phosphorus bond by silver ions against bacterium Methicillin Resistant Staphylococcus aureus (MRSA) and fungus Candida Albican (CA). Furthermore, AgNPs degraded toxic pollutants such as 4-nitrophenol (4-NP), 2-nitrophenol (2-NP) and various hazardous dyes such as Congo Red (CR), Methylene Blue (MB) and Methyl Orange (MO) up to 95%. The present work provided low cost, green and an effective way for synthesis of AgNPs which were utilized as potential antimicrobial agents as well as effective catalyst for detoxification of various pollutants and dyes.

Electrical, Photocatalytic, and Humidity Sensing Applications of Mixed Metal Oxide Nanocomposites.

Mixed metal oxide nanocomposites (NCs) comprising Cu-Sr (CS), Sr-Cd (SC), and Cd-Cu (CC) were fabricated via a sol-gel method. Structural investigations of fabricated samples were carried out via X-ray diffraction (XRD), scanning electron microscopy (SEM), diffuse reflectance spectroscopy (DRS), and X-ray photoelectron spectroscopy (XPS). The Maxwell-Wagner model, attributing to poor conducting layers around the conducting grains, was indicated to be followed by all of the NCs while investigating the dielectric properties. The Space-charge polarization and hoping mechanism contributed to low AC conductivity at lower frequencies and high AC conductivity at higher frequencies. The as-synthesized NCs effectively degraded two toxic water contaminants, such as crystal violet (CV) and Congo red (CR). Furthermore, the NCs were also evaluated for humidity sensing measurements. All of the NCs indicated efficient response/recovery time with better stability. The extensive investigation suggested the synthesized NCs, well suited for various optical and microelectronic applications.

A Validated Spectrofluorimetric Method for the Determination of Moxifloxacin in Its Pure Form, Pharmaceutical Preparations, and Biological Samples.

This research work presents a simple, sensitive, selective, economic, and widely applicable and interferences-free spectrofluorimetric method estimating moxifloxacin in the pure form, commercial formulations and biological samples. The method is based on the reaction of moxifloxacin with Ce(IV) in an acidic medium to generate fluorescent active species Ce(III). The excitation and emission of the fluorescent species are 250 and 362 nm, respectively. Different variables that might influence the oxidation of moxifloxacin, including the Ce(IV) concentration and volume, the effect of temperature and the heating time, the type of acids and its concentration were analyzed and boosted. The linearity was observed in the concentration range of 0.2 - 5.0 µg mL-1 with a correlation coefficient of 0.9991. The limit of detection and the limit of quantification were calculated and observed to be 0.016 and 0.056 µg mL-1 respectively. The effects of the common excipients and some co-administrated drugs usually used in the determination of moxifloxacin were investigated, and no interferences were noted. The planned method has been successfully practical for the analysis of moxifloxacin in its pure form, in pharmaceutical products and in biological samples. The obtained percent recoveries ranged from 95.50 to 101.37% for pharmaceutical products and from 95.15 to 103.18% for human blood plasma and urine.

Sodium, Potassium, and Lithium Complexes of Phenanthroline and Diclofenac: First Report on Anticancer Studies.

Diclofenac or 2-[(2',6'-dichlorophenyl)amino]phenyl}acetic acid (dcf) is a nonsteroidal anti-inflammatory drug, and 1,10-phenanthroline (phen) is a well-known enzyme inhibitor. In this study, three new alkali metal complexes (1-3) containing both phen and dcf were prepared, and their structures were characterized by a variety of analytical techniques including infrared and UV-vis spectroscopy, 1H NMR and 13C NMR elemental analysis, mass spectrometry, and single-crystal X-ray diffraction analysis. In these complexes, phen binds via a N,N'-chelate pocket, while the monoanionic dcf-ligand remains either uncoordinated (in the case of 1 and 3) or coordinated in a bidentate fashion (in the case of 2). All three complexes crystallize in the triclinic space group P-1. [Na2(phen)2 (H2O)4][dcf]2 (1) is a dinuclear sodium complex, where two crystallographically identical Na+ cations adopt a distorted five-coordinate spherical square-pyramidal geometry, with a [N2O3] donor set. [K2(phen)2(dcf)2(H2O)4] (2) is also a dinuclear complex where the crystallographically unique K+ cation adopts a distorted seven-coordinate geometry comprising a [N2O5] donor set. [Li(phen)(H2O)2][dcf] (3) is a mononuclear lithium complex where the Li+ cation adopts a four-coordinate distorted tetrahedral geometry comprising a [N2O2] donor set. The complexes were evaluated for their anticancer activity against lung and oral cancer cell lines as well as for their antibacterial potential. The prepared complexes displayed very good antibacterial and anticancer activities with an excellent bioavailability.

Crystal structure, shape analysis and bioactivity of new LiI, NaI and MgII complexes with 1,10-phenanthroline and 2-(3,4-dichlorophenyl)acetic acid.

Reactions of 1,10-phenanthroline (phen) and 2-(3,4-dichlorophenyl)acetic acid (dcaH) with Mn(CO3) (M = LiI, NaI and MgII; n = 1 and 2) in MeOH yield the mononuclear lithium complex aqua[2-(3,4-dichlorophenyl)acetato-κO](1,10-phenanthroline-κ2N,N')lithium(I), [Li(C8H5Cl2O2)(C12H8N2)(H2O)] or [Li(dca)(phen)(H2O)] (1), the dinuclear sodium complex di-µ-aqua-bis{[2-(3,4-dichlorophenyl)acetato-κO](1,10-phenanthroline-κ2N,N')sodium(I)}, [Na2(C8H5Cl2O2)2(C12H8N2)2(H2O)2] or [Na2(dca)2(phen)2(H2O)2] (2), and the one-dimensional chain magnesium complex catena-poly[[[diaqua(1,10-phenanthroline-κ2N,N')magnesium]-µ-2-(3,4-dichlorophenyl)acetato-κ2O:O'] 2-(3,4-dichlorophenyl)acetate monohydrate], {[Mg(C8H5Cl2O2)(C12H8N2)(H2O)2](C8H5Cl2O2)·H2O}n or {[Mg(dca)(phen)(H2O)2](dca)·H2O}n (3). In these complexes, phen binds via an N,N'-chelate pocket, while the deprotonated dca- ligands coordinate either in a monodentate (in 1 and 2) or bidentate (in 3) fashion. The remaining coordination sites around the metal ions are occupied by water molecules in all three complexes. Complex 1 crystallizes in the triclinic space group P-1 with one molecule in the asymmetric unit. The Li+ ion adopts a four-coordinated distorted seesaw geometry comprising an [N2O2] donor set. Complex 2 crystallizes in the triclinic space group P-1 with half a molecule in the asymmetric unit, in which the Na+ ion adopts a five-coordinated distorted spherical square-pyramidal geometry, with an [N2O3] donor set. Complex 3 crystallizes in the orthorhombic space group P212121, with one Mg2+ ion, one phen ligand, two dca- ligands and three water molecules in the asymmetric unit. Both dcaH ligands are deprotonated, however, one dca- anion is not coordinated, whereas the second dca- anion coordinates in a bidentate fashion bridging two Mg2+ ions, resulting in a one-dimensional chain structure for 3. The Mg2+ ion adopts a distorted octahedral geometry, with an [N2O4] donor set. Complexes 1-3 were evaluated against urease and α-glucosidase enzymes for their inhibition potential and were found to be inactive.

Derivatives of 6-Nitrobenzimidazole Inhibit Fructose-Mediated Protein Glycation and Intracellular Reactive Oxygen Species Production.

BACKGROUND: Benzimidazoles are important pharmacophores in drug discovery, and currently its derivatives such as flubendazole, omeprazole, and astemizole are used for the treatment of anthelmintic, ulcerative, and histaminic diseases, respectively. OBJECTIVES: The aim of the current study was to investigate the antiglycation activity of nitrobenzimidazole derivatives against fructose-mediated human serum albumin (HSA) glycation. The study was also aimed at investigating the effects of newly identified antiglycation inhibitors on AGEsinduced intracellular reactive oxygen species (ROS) production, and associated impaired proliferation of the hepatocytes. METHODS: The present study focuses on the antiglycation activity of 6-nitrobenzimidazole derivatives 1-13 in in-vitro human serum albumin (HSA)- fructose model. These derivatives were also identified as non-toxic against 3T3 mouse fibroblast cell-line in MTT-based assay. The effect of the most promising derivative 5, 4-(6-nitro-1H-benzimidazol-2-yl)-1,2,3-benzenetriol, was studied in a dose dependent manner, co-incubated with fructose-derived AGEs (0- 200 µg/mL) on rat hepatocytes proliferation and associated intracellular generation of ROS via MTT-based assay and DCFHDA technique, respectively. RESULTS: We found that derivative 5 ameliorates the elevated intracellular oxidative stress and associated diminished proliferation of the hepatocytes in response to AGEs. CONCLUSION: In conclusion, we identified novel 6-nitrobenzimidazole derivatives as antiglycation agents through in-vitro, and cell-based models.

Production of biologically active oxidized derivatives of finasteride through metabolism by Aspergillus niger culture.

CONTEXT: Among the 4-azasteroids, finasteride is biologically the most important compound having preventive effect against male pattern baldness (MPH) and benign prostatic hyperplasia commonly called enlargement of prostate gland. OBJECTIVE: The microbial transformation of finasteride by fungus Aspergillus niger (ATCC 10549) has been investigated to obtain biologically more potent derivatives. MATERIALS AND METHODS: Fermentation of finasteride was performed with filamentous fungus Aspergillus niger (ATCC 10549). This transformation resulted in the production of two transformed products, which were purified through column chromatography. In vitro lipoxygenase inhibitory potential was determined by incubating 20 mL of the enzyme with 10 mL of test sample (100 µM) in 0.1 mM (pH 7.0) phosphate buffer for 5 min at 258 °C followed by addition of 10 µL of substrate (linolenic acid) to reaction mixture and measuring the formation of complex spectrophotometrically. RESULTS: Structure elucidation of biotransformed metabolites was ascertained through extensive 1D and 2D spectroscopic techniques. This study established the fact that A. niger promoted stereospecific dihydroxylation at C-11 and C-15 of finasteride. The resulting biotransformed metabolites were characterized as 11α-hydroxyfinasteride and 15ß-hydroxyfinasteride, respectively. Finasteride along with transformed metabolites were analyzed for their in vitro lipoxygenase (LOX) inhibition assay. Among the tested compounds 15ß-hydroxyfinasteride showed good activity with IC50 value 112.56 ± 2.23 µM while inhibitory effect in case of 11α-hydroxyfinasteride was low with IC50 value 186.05 ± 1.34 µM. Standard compound baicalein revealed IC50 value being 22.0 ± 0.05 µM. CONCLUSION: The present investigation highlighted the fact that potentially active compound can be produced through the technology of biotransformation.

Withanolides: Biologically Active Constituents in the Treatment of Alzheimer's Disease.

The use of natural products in drug discovery and development have an important history. Several therapeutic agents have been investigated during the biological screenings of natural compounds. It is well documented that plants are possibly the core of novel substances that led to the discovery of new, novel, and effective therapeutic agents. Therefore, in the last few decades, scientists were thoroughly attempting for the search of benevolent drugs to protect mankind from various diseases and discomforts. The diverse chemical structures of natural products are the key element of their success in modern drug discovery. Cholinesterase enzyme inhibitors (ChEI) are chemicals which inhibit the splitting of cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase). Acetyl cholinesterase (AChE) and butyrylcholinesterase (BChE) are two types of cholinesterase enzymes that have been identified in vertebrates that are responsible for Alzheimer's disease and related dementia. Withanolides are affective plant secondary metabolites which inhibit acetylcholinesterase and butyrylcholinesterase enzyme and thus possibly will be the future drug for Alzheimer's disease. By viewing the importance of natural products in drug discovery and development, we present here, the importance of withanolides in the treatment of Alzheimer's disease. In this article, we also describe the classification and structural characterization of withanolides. This review comprises of 114 compounds.

2,4,6-Trichlorophenylhydrazine Schiff bases as DPPH radical and super oxide anion scavengers.

Syntheses of thirty 2,4,6-trichlorophenylhydrazine Schiff bases 1-30 were carried out and evaluated for their in vitro DPPH radical and super oxide anion scavenging activities. Compounds 1-30 have shown a varying degree of DPPH radical scavenging activity and their IC50 values range between 4.05-369.30 µM. The compounds 17, 28, 18, 14, 8, 15, 12, 2, 29, and 7 exhibited IC50 values ranging between 4.05±0.06-24.42±0.86 µM which are superior to standard n-propylgallate (IC50=30.12±0.27 µM). Selected compounds have shown a varying degree of superoxide anion radical scavenger activity and their IC50 values range between 91.23-406.90 µM. The compounds 28, 8, 17, 15, and 14, showed IC50 values between 91.23±1.2-105.31±2.29 µM which are superior to standard n-propylgallate (IC50=106.34±1.6 µM).

6-Nitrobenzimidazole derivatives: potential phosphodiesterase inhibitors: synthesis and structure-activity relationship.

6-Nitrobenzimidazole derivatives (1-30) synthesized and their phosphodiesterase inhibitory activities determined. Out of thirty tested compounds, ten showed a varying degrees of phosphodiesterase inhibition with IC(50) values between 1.5±0.043 and 294.0±16.7 µM. Compounds 30 (IC(50)=1.5±0.043 µM), 1 (IC(50)=2.4±0.049 µM), 11 (IC(50)=5.7±0.113 µM), 13 (IC(50)=6.4±0.148 µM), 14 (IC(50)=10.5±0.51 µM), 9 (IC(50)=11.49±0.08 µM), 3 (IC(50)=63.1±1.48 µM), 10 (IC(50)=120.0±4.47 µM), and 6 (IC(50)=153.2±5.6 µM) showed excellent phosphodiesterase inhibitory activity, much superior to the standard EDTA (IC(50)=274±0.007 µM), and thus are potential molecules for the development of a new class of phosphodiesterase inhibitors. A structure-activity relationship is evaluated. All compounds are characterized by spectroscopic parameters.

Synthesis of 2,4,6-trichlorophenyl hydrazones and their inhibitory potential against glycation of protein.

2,4,6-Trichlorophenyl hydrazones 1-35 were synthesized and their in vitro antiglycation potential was evaluated. Compounds 14 (IC50 = 27.2 ± 0.00 µM), and 18 (IC50 = 55.7 ± 0.00 µM) showed an excellent activity against glycation of protein, better than the standard (rutin, IC50 = 70 ± 0.50 µM). This study thus identified a novel series of antiglycation agents. A structure-activity relationship has been studied, and all the compounds were characterized by spectroscopic techniques.