Pyridine coupled pyrazole analogues as lethal weapon against MRSA: An in-vitro and in-silico approach.

The treatment of Methicillin-resistant staphylococcus aureus (MRSA) infections has become challenging due to the growth of multidrug resistance in the bacteria. Here we report the synthesis of pyridine-coupled pyrazoles as an antimicrobial agent against MRSA. A series of pyridine coupled pyrazoles were synthesized and synthesized compounds were characterized using FT-IR, 1H NMR, and Mass spectroscopy. The ADMET results of all the 14 active compounds are interpreted. To identify the potent compound the synthesized compounds screened for minimum inhibitory concentrations against MRSA and compared with standard drug vancomycin. Among the synthesized compounds 6d exhibited good antibacterial activity with MIC value 21 µg/mL, bacterial cell membrane damage study was studied potassium efflux, and cellular content leakage assay. Anticoagulant study for the potent compound also studied and validated by molecular docking and molecular dynamics simulation studies. The docking study of the synthesized compound was carried out and the study depicted that the pyridine ring of all the analogues binds with the various amino acids in the binding pocket of the active site of the Staphylocoagulase and PBP2a protein of MRSA.

4-acetamido-3-nitrobenzoic acid - structural, quantum chemical studies, ADMET and molecular docking studies of SARS-CoV2.

In December 2019, a new type of SARS corona virus emerged from China and caused a globally pandemic corona virus disease (COVID-19). This highly infectious virus has been named as SARS-CoV-2 by the International Committee of the Taxonomy of Viruses. It has severely affected a large population and economy worldwide. Globally various scientific communities have been involved in studying this newly emerged virus and is lifecycle. Multiple diverse studies are in progress to design novel therapeutic agents, in which understanding of interactions between the target and drug ligand is a significant key for this challenge. Structures of proteins involved in the life cycle of the virus have been revealed in RCSB PDB by researchers. In this study, we employed molecular docking study of 4-Acetamido-3-nitrobenzoic acid (ANBA) with corona virus proteins (spike protein, spike binding domain with ACE2 receptor and Main protease, RNA-dependent RNA polymerase). Single crystal X-ray analysis and density functional theory calculations were carried out for ANBA to explore the structural and chemical-reactive parameters. Intermolecular interactions which are involved in the ligand-protein binding process are validated by Hirshfeld surface analysis. To study the behaviour of ANBA in a living organism and to calculate the physicochemical parameters, ADMET analysis was done using SwissADME and Osiris data warrior tools. Further, Toxicity of ANBA was predicted using pkCSM online software. Based on the molecular docking analysis, we introduce here a potent drug molecule that binds to the COVID-19 proteins.Communicated by Ramaswamy H. Sarma.

Design, synthesis of pyridine coupled pyrimidinone/pyrimidinthione as anti-MRSA agent: Validation by molecular docking and dynamics simulation.

Methicillin Resistant Staphylococcus aureus (MRSA) is a major cause of severe hospital and infections acquired by the population and related morbidity and mortality. In this unique situation, there is a need of dynamic strong drug candidates to control MRSA diseases. Thus, the present work focuses on the synthesis and characterization of pyrimidinones and pyrimidinthiones coupled pyridine derivatives as anti-MRSA agent. The synthesized compounds were characterized by different spectroscopic techniques and evaluated against MRSA strain. Among them, 4e and 4 g possessed better antibacterial activity with MIC values of 10 µg and 8 µg respectively. The key determinant of the wide range beta-lactam resistance in MRSA strains is the Penicillin-Binding Protein 2a (PBP2a) but the gene encodes PBP2a which has a low affinity towards ß-lactam antibiotics. Because of this, the present investigation focused on the mechanism of PBP2a protein binding studies by in-silico studies. The synthesized compounds showed very good interactions with PBP2A compared with standard drug Vancomycin, among them compound 4 g showed better interaction with the binding score of -9.8 kcal/mol. Antibacterial activity was validated with molecular docking and molecular dynamic simulation. Simulation results revealed that protein-ligand interactions of 4 g compound stably sustained up to 20,000ps.Communicated by Ramaswamy H. Sarma.

Spectroscopic investigation and computational studies on the interaction of Acriflavine with various estrogens.

The fluorescence quenching of Acriflavine (AFN) by certain estrogens was examined in aqueous media by employing steady state and time-resolved fluorescence measurements. The absorption spectra of AFN change with significant bathochromic shift in presence of quencher molecules. The quenching behavior was examined by correlating the bimolecular quenching rate constant (kq) with the free energy change (ΔG). The decrease in quenching rate constant depends on the increase in oxidation potential of quencher molecules. The fluorescence quenching experiments were carried out in different solvents of varying polarities and reveals the possibility of charge transfer quenching mechanism. Lifetime measurements indicate static quenching. The quenching behavior is addressed from bond dissociation enthalpy (BDE) calculations. The antioxidant activity of estrogen compounds were evaluated by deoxyribose oxidation assay.

Novel Bioactive Co(II), Cu(II), Ni(II) and Zn(II) Complexes with Schiff Base Ligand Derived from Histidine and 1,3-Indandione: Synthesis, Structural Elucidation, Biological Investigation and Docking Analysis.

Novel bioactive complexes of Co(II), Cu(II), Ni(II) and Zn(II) metal ions with Schiff base ligand derived from histidine and 1,3-indandione were synthesized and thoroughly characterized by various analytical and spectral techniques. The biological investigations were carried out to examine the efficiency of the binding interaction of all the complexes with calf thymus DNA (CT-DNA). The binding properties were studied and evaluated quantitatively by Kb and Ksq values using UV-visible, fluorescence spectroscopy and voltammetric techniques. The experimental results revealed that the mode of binding of all the complexes with CT-DNA is via intercalation. It is further verified by viscosity measurements and thermal denaturation experiments. From the results of the cleavage study with pUC19 DNA it is inferred that all the complexes possess excellent cleaving ability. The present investigation proved that the binding interaction of all the complexes are significantly strong and the order of binding strength of the complexes is [Ni(L)2] (Kb = 3.11 × 106 M-1) > [Co(L)2] (Kb = 2.89 × 106 M-1) > [Cu(L)2] (Kb = 2.64 × 106 M-1) > [Zn(L)2] (Kb = 2.41 × 105 M-1). The complexes were also screened for antibacterial and anticandidal activity. The in vitro cytotoxicity of the ligand and complexes on the NIH/3 T3 mouse fibroblast cell lines were examined using CellTiter-Blue® (CTB) Cell viability assay, which unveiled that all the complexes exhibit more potent activities against NIH/3 T3 cells. Among all the complexes [Zn(L)2] complex showed the maximum efficiency.

Synthesis, characterization and binding interactions of amino acids coupled perylene diimides with colloidal doped and undoped TiO2.

Two sensitizers based on amino acids coupled with perylene moiety having absorption in the visible region have been designed and their interaction with doped and undoped TiO2 for the application of dye sensitized solar cells (DSSCs) has been studied. The synthesized compounds PDI-PA and PDI-AA were characterized using (1)H and (13)C NMR, Mass and FT-IR spectroscopic techniques. The optical properties and lifetime measurements of the sensitizers were analyzed using various solvents with different polarity. The solvatochromism effect was studied using Lippert-Mataga plot. The electrochemical studies of both dyes were investigated in DMF with various scan rate ranging from 200 to 1000 mV s(-1). Colloidal doped and undoped TiO2 was prepared and characterized by using absorption measurements. Binding ability of the sensitizers with the nanoparticles was studied through absorption, fluorescence quenching, cyclic voltammetry and FT-IR measurements. Results obtained from all the above analysis suggest the mode of quenching may be static. The binding constant values were calculated using Kamat-Fox equation indicates the binding behavior of the sensitizers with the nanoparticles. The fluorescence quenching was mainly attributed to electron transfer from the excited state of PDI's to the conduction band of colloidal semiconductors. The electron transfer mechanism was explained based on the Rehm-Weller equation as well as the energy level diagram.

Investigation on the inclusion and toxicity of acriflavine with cyclodextrins: a spectroscopic approach.

Acriflavine hydrochloride (AFN) is a prospective drug worn in the eradication of HIV1 infection. The toxicity and adverse side effects renders the potent drug to limits its usage. However, to overcome the dilemma we have aimed to select carriers with great complexation efficiencies in different cyclodextrins (CDs) of varying cavity size. The interaction of AFN with α, ß and γ-CDs were investigated using absorption and steady state as well as lifetime measurements. From the obtained data it was found that AFN fits in the cavity of α and ß-CDs but unable to form inclusion complex with γ-CD. The effect of quencher molecules during the inclusion phenomena of AFN with CDs was explored via steady state measurements. The nature of binding forces responsible for the inclusion of AFN with CDs was discussed by using thermodynamic parameters. Using Benesi-Hildebrand equation the stoichiometry of AFN with CDs was predominantly found to be 1:1. To get deeper in situ, the in vitro toxicity of AFN and its complexation product were probed by Artemia salina sp. The toxicity of AFN was reduced when complexed with α and ß-CDs.

Enhancement of anti arthritic effect of quercetin using thioglycolic acid-capped cadmium telluride quantum dots as nanocarrier in adjuvant induced arthritic Wistar rats.

In this present study, we investigated thio glycolic acid-capped cadmium telluride quantum dots (TGA-CdTe QDs) as nano carrier to study the antiarthritic activity of quercetin on adjuvant induced arthritic Wistar rats. The free radical scavenging activity of QDs-QE complex was evaluated by 2,2'-azinobis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide anion scavenging assays. Fifteen days after adjuvant induction, arthritic rats received QDs-QE complex orally at the dose of 0.2 and 0.4mg/kg daily for 3 weeks. Diclofenac sodium (DF) was used as a reference drug. Administration of QDs-QE complex showed a significant reduction in inflammation and improvement in cartilage regeneration. Treatment with QDs-QE complex significantly (P<0.05) reduced the expressions lipid peroxidation and showed significant (P<0.05) increase in activities of antioxidant enzymes such as superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GPx) catalase (CAT) levels in paw tissue. C-reactive protein (CRP), rheumatoid factor (RF), red blood cells (RBC) and white blood cells (WBC) count and erythrocyte sedimentation rate (ESR) of experimental animals were also estimated. Histology of hind limb tissue in experimental groups confirmed the complete cartilage regeneration in arthritis induced rats treated with QDs-QE complex. Based on our findings, we suggest that the QDs act as nano carrier for the drugs used in the treatment of various degenerative diseases.

Bioimaging, antibacterial and antifungal properties of imidazole-pyridine fluorophores: synthesis, characterization and solvatochromism.

A series of imidazole derivatives connected with pyridine moiety through phenyl groups were synthesized by using Suzuki coupling followed by multicomponent cyclization reaction. Results obtained from spectroscopic ((1)H NMR, (13)C NMR, Mass) and single crystal X-ray diffraction analysis of synthesized compound was in very good agreement with its chemical structure. UV-Vis and fluorescence studies in various solvents with different polarity demonstrated that these compounds were sensitive to the polarity of the microenvironment. In addition, multi linear regression analysis based on Kamlet-Taft and Catalán new four parameter solvent scale results in solvatochromism and was mainly influenced by solvent polarisability and dipolarity of the environment. The electrochemical stability of the compounds was also studied by cyclic voltammetry. An excellent fluorescent nature with high quantum efficiency of the compounds was successfully utilized to probe the bacteria by using fluorescence microscopy. In addition, the antibacterial and antifungal activity of these compounds were also studied in vitro by the disk diffusion assay against one Gram-positive, three Gram-negative bacteria and Candida albicans. MPBI showed relatively good inhibitory action against Gram-negative bacteria and TPBI against Gram-positive bacteria and 3PBI against C. albicans.

CdTe quantum dot as a fluorescence probe for vitamin B(12) in dosage form.

We here report the CdTe quantum dot (CdTe QDs)-based sensor for probing vitamin B12 derivatives in aqueous solution. In this paper, simple and sensitive fluorescence quenching measurements has been employed. The Stern-Volmer constant (KSV), quenching rate constant (kq) and binding constant (K) were rationalized from fluorescence quenching measurement. Furthermore, the fluorescence resonance energy transfer (FRET) mechanism was discussed. This method was applicable over the concentration ranging from 1 to 14µg/mL (VB12) with correlation coefficient of 0.993. The limit of detection (LOD) of VB12 was found to be 0.15µg/mL. Moreover, the present approach opens a simple pathway for developing cost-effective, sensitive and selective QD-based fluorescence sensors/probes for biologically significant VB12 in pharmaceutical sample with mean recoveries in the range of 100-102.1%.

Interaction of acriflavine with pyrimidines: a spectroscopic approach.

The interaction of acriflavine with uracils was investigated by using spectroscopic tools viz., UV-Vis absorption, steady state and time resolved fluorescence measurements. The spectroscopic data were analyzed using Stern-Volmer equation to determine the quenching process. The bimolecular quenching rate constant (k(q)), binding constant (K) and number of binding sites (n) were calculated at different temperature from the relevant fluorescence data. The experimental results obtained from life-time measurement indicate that the quenching mechanism was static via the formation of ground state complex. The free energy change (ΔGet) for electron transfer process was calculated by Rehm-Weller equation. The existence of binding forces and the interactions of acriflavine with uracils were examined.

In vitro antioxidant and antimicrobial activities of Merremia emarginata using thio glycolic acid-capped cadmium telluride quantum dots.

This study was undertaken to evaluate the antioxidant potential of an aqueous extract from Merremia emarginata leaves because this plant has a very high flavonoid and phenol content. The in vitro antioxidant activity was measured by diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid (ABTS), superoxide anion scavenging assay and lipid peroxidation activity; the total reducing capability of the plant extract indicates that this plant is a source for natural antioxidants. Furthermore, we investigated thio glycolic acid-capped cadmium telluride quantum dots (TGA-CdTe QDs) as fluorescent probes to study the antioxidant activity of the M. emarginata extract through fluorescence quenching. The antimicrobial activity was also investigated using a disc diffusion method and fluorescence microscopy. The TGA-CdTe QDs and M. emarginata complex could provide antimicrobial activity through a reactive oxygen species pathway and/or microbial endocytosis through an electrostatic attraction. Based on our findings, we suggest that the QDs act as potential probes for the in vitro antioxidant and antimicrobial activities. In addition, their cooperative effect with the plant extract indicates that QDs could be used as nanocarriers to enhance the antimicrobial capability. Further in vivo studies on the photolabelling of antioxidants with QDs will provide insights into the mechanistic pathways of secondary metabolites against various degenerative diseases.

Studies on the inclusion behavior of 9-Aminoacridine into cyclodextrins: spectroscopic and theoretical evidences.

9-Aminoacridine (9-AA) is an important attractive pharmaceutical drug employed as chemotheraptic agent for wound dressings. However, 9-AA possesses limited solubility and rapid metabolic decomposition renders this potential drug to limit its applications. Here we propose cyclodextrins (CDs) as a drug carrier to improve the bioavailability, solubility of 9-AA. The interaction between 9-AA and CDs (α-CD and ß-CD) has been studied using UV-Vis absorption, steady state time resolved fluorescence, (1)H NMR and FT-IR spectroscopy techniques. The spectroscopic measurements show that 9-AA does not form stable complex with α-CD and also confirmed by DFT calculations. On the other hand, 9-AA forms inclusion complex with ß-CD in a 1:1 stoichiometry ratio. Our DFT results suggest that 9-AA stabilizes inside the CD environment through hydrogen bonding that has unambiguously confirmed by AIM analysis. Thus our studies provide a useful insights in the development of Aminoacridine based drugs & its delivery through a suitable carrier like CDs.

One pot synthesis of structurally different mono and dimeric Ni(II) thiosemicarbazone complexes and N-arylation on a coordinated ligand: a comparative biological study.

One pot synthesis of three structurally different Ni(II) thiosemicarbazone complexes 1, 2 and 3 were obtained from the reaction between [NiCl(2)(PPh(3))(2)], 1,2-bis(diphenylphosphino)ethane, and [H(2)-(Sal-tsc)]. The obtained products were characterized by various spectral and analytical techniques. From the X-ray crystallographic analysis, an unexpected N-arylation on the coordinated salicylaldehydethiosemicarbazone was found in complex 2. The comparative biological evolutions such as DNA/protein binding, antioxidant, cytotoxicity (MTT, LDH, and NO) and cellular uptake studies have been examined for [Ni(Sal-tsc)(PPh(3))] (1) and [(Ni(Sal-tsc))(2)(µ-dppe)] (3). When comparing the cytotoxicity of the complexes, 1 exhibited higher activity than 2 and 3 and by comparing with standard cis-platin, both of them were found to exhibit better activity under identical conditions.

Spectroscopic investigation on the interaction of 9-aminoacridine with certain dyes.

The fluorescence quenching of 9-Aminoacridine (9-AA) by various dyes were probed in aqueous medium using steady state and time resolved fluorescence spectroscopic techniques. From these techniques, we had rationalized the interaction of 9-AA with various dyes via ground state complex formation. The binding constant (K) and number of binding sites (n) were calculated from the relevant fluorescence quenching data. The fluorescence emission of 9-Aminoacridine was quenched by the dyes through static quenching followed by the mechanism of energy transfer. The static quenching mechanism was confirmed by lifetime measurements. The thermodynamic parameters such as free energy change (ΔG), enthalpy change (ΔH) and entropy change (ΔS), were calculated by thermodynamic equations. The results showed that Van der Waals interaction or hydrogen bond formation played a major role in the binding of 9-AA with these dyes.

Investigations on photoinduced interaction of 9-aminoacridine with certain catechols and rutin.

The fluorescence quenching of 9-aminoacridine by certain biologically important catechols and rutin was investigated using absorption, steady state and time resolved fluorescence measurements. The in vitro-antioxidant activities of the above compounds were studied using deoxyribose degradation assay and nitric oxide scavenging assay. The experimental results showed that the fluorescence of 9-aminoacridine was quenched by quencher molecules via forming ground state complex. The bimolecular quenching rate constant k(q), binding constant (K) and number of binding sites (n) were calculated at different temperatures from relevant fluorescence data. Static quenching mechanism was supported by lifetime measurement. The free energy change (ΔG(et)) for electron transfer process was calculated by Rehm-Weller equation. The binding distance of 4-nitrocatechol with 9-aminoacridine was obtained according to Forster's non-radiative energy transfer theory. Nature of binding forces and their interactions was probed based on thermodynamic parameters.

Influence of terminal substitution on structural, DNA, protein binding, anticancer and antibacterial activities of palladium(II) complexes containing 3-methoxy salicylaldehyde-4(N) substituted thiosemicarbazones.

The variable chelating behavior of 3-methoxysalicylaldehyde-4(N)-substituted thiosemicarbazones was observed in equimolar reactions with [PdCl(2)(PPh(3))(2)]. The new complexes were characterized by various analytical, spectroscopic techniques (mass, (1)H-NMR, absorption, IR). All the new complexes were structurally characterized by single crystal X-ray diffraction. Crystallographic results showed that the ligands H(2)L(1) and H(2)L(4) are coordinated as binegative tridentate ONS donor ligands in the complexes 1 and 4 by forming six and five member rings. However, the ligands H(2)L(2) and H(2)L(3) bound to palladium in 2 and 3 as uninegative bidentate NS donors by forming a five member chelate ring. From this study, it was found that the substitution on terminal 4(N)-nitrogen may have an influence on the chelating ability of thiosemicarbazone. The presence of hydrogen bonding in 2 and 3 might be responsible for preventing the coordination of phenolic oxygen to the metal ion. The interaction of the complexes with calf-thymus DNA (CT-DNA) has been explored by absorption and emission titration methods. Based on the observations, an electrostatic binding mode of DNA has been proposed. The protein binding studies were monitored by quenching of tryptophan and tyrosine residues in the presence of complexes using Lysozyme as model protein. Antibacterial activity studies of the complexes have been screened against pathogenic bacteria such as Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa. MIC50 values of the complexes showed that they exhibited significant activity against the pathogens and among them, 3 exhibited higher activity. Further, anticancer activity of the complexes on the lung cancer cell line A549 has also been studied.

DNA, protein binding, cytotoxicity, cellular uptake and antibacterial activities of new palladium(II) complexes of thiosemicarbazone ligands: effects of substitution on biological activity.

The coordination propensities of 4(N,N')-diethylaminosalicylaldehyde-4(N)-substituted thiosemicarbazones (H(2)L(1-4)) were investigated by reacting with an equimolar amount of [PdCl(2)(PPh(3))(2)]. The new complexes were characterized by various spectroscopic techniques. The structure determination of the complexes [Pd(DeaSal-tsc)(PPh(3))] (1), [Pd(DeaSal-mtsc)(PPh(3))] (2) and [Pd(DeaSal-etsc)(PPh(3))] (3) by X-ray crystallography showed that ligands are coordinated in a dibasic tridentate ONS donor fashion forming stable five and six membered chelate rings. The binding ability of complexes (1-4) to calf-thymus DNA (CT DNA) has been explored by absorption and emission titration methods. Based on the observations, an electrostatic and an intercalative binding mode have been proposed. The protein binding studies have been monitored by quenching of tryptophan and tyrosine residues in the presence of complexes using lysozyme as a model protein. As determined by MTT assays, complex 3 exhibited a higher cytotoxic effect towards human lung cancer cell line (A549) and liver cancer cells (HepG2). LDH, NO assay and cellular uptake of the complexes have been studied. Further, antibacterial activity studies of the complexes have been screened against the pathogenic bacteria such as Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, MIC50 values of the complexes showed that the complexes exhibited significant activity against the pathogens and among the complexes, 3 exhibited higher activity.

An investigation on the fluorescence quenching of 9-aminoacridine by certain pyrimidines.

The fluorescence quenching of 9-aminoacridine by certain substituted uracils in water was studied using absorption, steady state and time resolved measurements. The bimolecular quenching rate constants (k(q)), binding constant K and number of binding sites (n) were calculated based on the fluorescence quenching data. The free energy change (ΔG(et)) for electron transfer process was calculated by Rehm-Weller equation. From lifetime measurement we observed that the quenching was mainly due to static mechanism involving ground state complex formation.

Electron transfer dynamics from the singlet and triplet excited states of meso-tetrakis(p-carboxyphenyl)porphyrin into colloidal TiO2 and AuTiO2 nanoparticles.

Electron transfer dynamics of meso-tetrakis(p-carboxyphenyl)porphyrin [TCPP] adsorbed on colloidal TiO(2) and AuTiO(2) nanoparticles have been investigated by time resolved absorption and fluorescence spectroscopy. Optical absorption studies reveal that the TCPP form complex with TiO(2) and AuTiO(2) nanoparticles. Excitation of TCPP adsorbed on the TiO(2) nanoparticle surface leads to electron injection on the conduction band of TiO(2). Electron injection has been confirmed by direct detection of cation radical of the adsorbed dye (TCPP*(+)). The rate constant for the electron injection process is determined from both the singlet and triplet state respectively. The rate of electron injection for TCPP-AuTiO(2) is much faster than TCPP-TiO(2). The injected electrons are quickly transferred to Au and it escorts to ignore the back electron transfer (recombination) process.