Substituent Orchestration in Dimethylquinoxaline Derivatives: A Tool for Fishing Out Appropriate CDK5 Inhibitors as Potential Therapeutics for Alzheimer's.

A set of new heterocyclic analogs (Compounds I-IX), comprising of 6,7 dimethyl Quinoxalines were found to be active against the receptor GSK3ß (Compounds IV-V) (Chem. Biodiversity 2021, 18, e2100364). In an effort to modulate effective CDK5 inhibitors herein our hypothesis underpinned to fish out an appropriate derivative from the same quinoxaline series, as these two targets GSK3ß and CDK5 shared structural resemblance with each other. Aligned to the goal we have synthesized Compounds I-IX, characterized them using a combination of spectroscopic techniques and evaluated their activities against CDK5. Our analysis reflected that the adjacently located alkoxy/hydroxy functionality derivatives namely Compounds III and VI, to be the most potent (micromolar) amongst others in the series, backed by Density Functional Theory (DFT) calculations and molecular modelling studies. Also, the efficacy of the Compounds I-IX, were monitored in few other members of the CMGC family namely DYRK1A, CLK1and CK1δ that have been known to be directly involved in hyperphosphorylation of Tau. But unfortunately in none of the targets, our quinoxaline series were active. In a nut shell further optimisation of these intelligent nucleus, would not only lead to the discovery of novel pharmacophores, but also marked selectivity against a pool of kinases, thereby implementing a distinct roadmap towards the design of potential therapeutics against Alzheimer's.

Green synthesis of bio-functionalized nano-particles for the application of copper removal - characterization and modeling studies.

Green technology for the synthesis of nanoparticles has gained momentum due to its cost-effectiveness and eco-friendly nature. In this research study, silver nanoparticles (AgNps) were synthesized using an eco-friendly biological method involving the use of marine algae, Halimeda gracilis. The surface properties of the synthesized silver nanoparticles were studied using UV-visible spectroscopy, Fourier transform infrared spectroscopy and scanning electron microscopy methods. During the synthesis of nano particles, the parameters namely temperature (30 °C to 90 °C), pH (6-10), silver nitrate (AgNO3) concentration (1-3 mg/ml) and quantity of algal extract (1-3 ml) were optimized to improve the production of AgNPs. The application of the synthesized silver nanoparticles for the adsorptive removal of copper from aqueous and industrial wastewater was investigated. Intra-particle diffusion mechanism was identified to be controlling step in metal removal. Regeneration of sorbent was carried out using 2.0 M HCl and the reusability was verified for 6 cycles. A removal efficiency of copper (64.8%) from electroplating wastewater demonstrated the industrial application potential of the synthesized silver nanoparticles.

Unravelling the Selectivity of 6,7-Dimethyl Quinoxaline Analogs for Kinase Inhibition: An Insight towards the Development of Alzheimer's Therapeutics.

Untangling the most selective kinase inhibitors via pharmacological intervention remains one of the challenging affairs to date. In accordance to this drift, herein we describe the design and synthesis of a set of new heterocyclic analogs consisting of 6,7-dimethyl Quinoxaline, appended to a connector, employing Schiff base strategy (Compounds I-IX). The compounds were characterized by various spectroscopic techniques and the kinase inhibition assay were performed on few prime members of the CMGC family namely the GSK3ß, DYRK1A and CLK1 receptors, respectively, that have been known to be directly involved in hyperphosphorylation of Tau. Interestingly the biological evaluation results revealed that Compounds IV and V, with bromo/chloro functionalities in the aromatic core were advantaged of being highly selective towards the target GSK3ß over others. To strengthen our analysis, we adopted molecular modelling studies, where compounds IV/V were redocked in the same grid 4AFJ, as that of the reference ligand, 5-aryl-4-carboxamide-1,3-oxazole. Surprisingly, our investigation underpinned that for both the compounds IV/V, a primary H-bonding existed between the designed molecules (IV/V) and Val 135 residue in the receptor GSK3ß, in line with the reference ligand. We attribute this interaction to instigate potency in the compounds. Indeed the other non-covalent interaction, between the derivative's aromatic nucleus and Arg 141/Thr 138 in the receptor GSK3ß, might have been responsible for enhancing the selectivity in the targets. Overall, we feel that the present work depicts a logical demonstration towards fine tuning the efficacy of the inhibitors through systematic adjustment of electron density at appropriate positions in the aromatic ring be it the main quinoxaline or the other aromatic nucleus. Thus this pathway offers a convenient strategy for the development of efficient therapeutics for diversified neurodegenerative diseases like that of Alzheimer's.

The Influence of Chitosan Substrate and Its Nanometric Form Toward the Green Power Generation in Sediment Microbial Fuel Cell.

A simple, environmental friendly and biologically important sediment interfaced fuel cell was developed for the green energy generation. The soil sediment used for the study is enriched of rich anthropogenic free organic carbon, sufficient manganese and high level potassium contents as evidenced from the geochemical characterizations. The saccharides produced by the catalytic reaction of substrate chitosan were utilized for the growth of microorganisms and electron shuttling processes. Chitosan substrate influenced sediment microbial fuel cells exhibited the nearly two fold power increment over the substrate free fuel cells. The fuel cell efficiencies were further increased by bringing the substrate chitosan at nanometric level, which is nearly three and two fold higher than that of substrate free and chitosan influenced sediment microbial fuel cells, respectively, and the influential parameters involved in the power and longevity issues were addressed with different perspectives.

Synthesis of Iron Nanoparticles Using Azadirachta indica Extract and Its Catalytic Activity Toward Nitrophenol Reduction.

A simple, hasty and eco-friendly approach for the synthesis of iron nanoparticles has been developed using the medicinally important Azadirachta indica extract, which act as both reducing and stabilizing agent. The formation and morphological properties of iron nanoparticles as a function of metallic precursor and Azadirachta indica extract concentration have been investigated. The influence of solvent over the size and texture of iron nanoparticles has also been evaluated in detail. The thermal behavior of prepared nanoparticles was identified from thermogravimetric analysis. Furthermore, the catalytic activity of prepared iron nanoparticles toward the reduction of p-nitrophenol was analyzed and the reduction process was occurred within 30 sec. The cost and time efficient biosynthesis process and excellent catalytic activity of the prepared iron nanoparticles construct this protocol attractive.

Optimization, equilibrium, kinetic, thermodynamic and desorption studies on the sorption of Cu(II) from an aqueous solution using marine green algae: Halimeda gracilis.

The aptitude of marine green algae Helimeda gracilis for sorption of Cu(II) ions from an aqueous solution was studied in batch experiments. The effect of relevant parameters such as function of pH, sorbent dosage, agitation speed and contact time was evaluated by using Response surface methodology (RSM). A maximum percentage removal of Cu (II) by Halimeda gracilis occurs at pH-4.49, sorbent dosage-1.98g/L, agitation speed-119.43rpm and contact time-60.21min. Further, the sorbent was characterized by using Fourier Transform Infrared Spectroscopy (FTIR) and Scanning electron microscope (SEM) analysis. Experimental data were analyzed in terms of pseudo-first order, pseudo-second order, intraparticle diffusion, power function and elovich kinetic models. The results showed that the sorption process of Cu(II) ions followed well pseudo-second order kinetics. The sorption data of Cu(II) ions at 308.15K are fitted to Langmuir, Freundlich, Dubinin-Radushkevich (D-R), Temkin, Sips and Toth isotherms. Sorption of Cu(II) onto marine green algae Helimeda gracilis followed the Langmuir and Toth isotherm models (R(2)=0.998 and R(2)=0.999) with the maximum sorption capacity of 38.46 and 38.07mg/g. The calculated thermodynamic parameters such as ΔG°, ΔH° and ΔS° showed that the sorption of Cu(II) ions onto Helimeda gracilis biomass was feasible, spontaneous and endothermic. Desorption study shows that the sorbent could be regenerated using 0.2M HCl solution, with up to 89% recovery.

Synthesis of silver nanoparticle and its application.

In this work, silver nanoparticles have been synthesized by wet chemical technique, green synthesis and microbial methods. Silver nitrate (10(-3)M) was used with aqueous extract to produce silver nanoparticles. From the results it was observed that the yield of nanoparticles was high in green synthesis. The size of the silver nanoparticles was determined from Scanning Electron Microscope analysis (SEM). Fourier Transform Infrared spectroscopy (FTIR) was carried out to determine the presence of biomolecules in them. Its cytotoxic effect was studied in cancerous cell line and normal cell line. MTT assay was done to test its optimal concentration and efficacy which gives valuable information for the use of silver nanoparticles for future cancer therapy.

Synthesis, properties and antibacterial activity of Ca doped Zn2SnO4 nanoparticles by microwave assisted method.

A major problem in world health care is the development of antibiotic resistance in bacteria. In light of this, pure and calcium-doped zinc tin oxide (ZTO) nanoparticles, Zn2SnO4 (S1), Zn2Sn0.7Ca0.3O4 (S2), Zn2Sn0.5Ca0.5O4 (S3), and Zn2Sn0.3Ca0.7O4 (S4), were synthesized via simple and cost effective microwave assisted method. The doping effect on antibacterial activity was studied in detail. The XRD spectrum revealed that all the deposited samples exhibited a spinel cubic structure. A decrease in crystallite size, an increase in strain and dislocation density was observed with an increase in Ca concentration. FESEM images exhibited an irregular and non-homogeneous nature with crystalline morphology having a physical dimension of nm size. EDAX confirmed the purity of deposited samples. We used the agar well diffusion technique to study the antibacterial activity of Gram-positive and Gram-negative bacteria. The doping of the ZTO matrix with Ca ions increased its antibacterial performance by 99% against Klebsiella pneumoniae bacteria, and its effectiveness was enhanced with increasing Ca ion concentration inside the Zn2SnO4 nanoparticles.

Virulence traits and novel drug delivery strategies for mucormycosis post-COVID-19: a comprehensive review.

The outbreak of a fatal black fungus infection after the resurgence of the cadaverous COVID-19 has exhorted scientists worldwide to develop a nutshell by repurposing or designing new formulations to address the crisis. Patients expressing COVID-19 are more susceptible to Mucormycosis (MCR) and thus fall easy prey to decease accounting for this global threat. Their mortality rates range around 32-70% depending on the organs affected and grow even higher despite the treatment. The many contemporary recommendations strongly advise using liposomal amphotericin B and surgery as first-line therapy whenever practicable. MCR is a dangerous infection that requires an antifungal drug administration on appropriate prescription, typically one of the following: Amphotericin B, Posaconazole, or Isavuconazole since the fungi that cause MCR are resistant to other medications like fluconazole, voriconazole, and echinocandins. Amphotericin B and Posaconazole are administered through veins (intravenously), and isavuconazole by mouth (orally). From last several years so many compounds are developed against invasive fungal disease but only few of them are able to induce effective treatment against the micorals. Adjuvant medicines, more particularly, are difficult to assess without prospective randomized controlled investigations, which are challenging to conduct given the lower incidence and higher mortality from Mucormycosis. The present analysis provides insight into pathogenesis, epidemiology, clinical manifestations, underlying fungal virulence, and growth mechanisms. In addition, current therapy for MCR in Post Covid-19 individuals includes conventional and novel nano-based advanced management systems for procuring against deadly fungal infection. The study urges involving nanomedicine to prevent fungal growth at the commencement of infection, delay the progression, and mitigate fatality risk.

Synthesis, in silico metabolic and toxicity prediction of some novel imidazolinones derivatives as potent anticonvulsant agents.

A series of 1,2,4-trisubstituted 5-imidazolinone derivatives were synthesized by Erlenmeyer condensation of benzoylglycine (hippuric acid) with different aldehydes in the presence of sodium acetate and acetic anhydride. The derivatives of the compounds were prepared by condensation of some known sulpha drugs with 5-oxazolone derivatives. The anticonvulsant activity of the compounds was determined by the protection of pentylenetetrazole-induced convulsions that was ranged from 10 to 60%. The compounds with p-OCH3, p-OH and o-Cl substitutions in the phenyl ring on 4(th) position of the imidazolinone ring exhibited good anticonvulsant activity. In silico metabolic and toxicity studies showed that all the compounds in the series are not likely to exhibit toxicity except the compounds IIIa, IIIb, VIa and VIb, that is predicted to show 29% mutagenicity and 53% irritation in comparison to the other compounds. The predicted lethal effect and hERG toxicity of the compounds showed that IIa, IVa, Va and Vb might be toxic at higher concentrations. The results successfully establish the synthesized imidazolinone derivatives as novel compounds with anticonvulsant properties, low predicted cardiotoxicity and lethal effects thus can be promising leads for further development as novel anticonvulsants.

Deep Learning Based Capsule Neural Network Model for Breast Cancer Diagnosis Using Mammogram Images.

Breast cancer is a commonly occurring disease in women all over the world. Mammogram is an efficient technique used for screening and identification of abnormalities over the breast region. Earlier identification of breast cancer enhances the prognosis of patients and is mainly based on the experience of the radiologist in interpretation of mammogram with quality of image. The advent of Deep Learning (DL) and Computer Vision techniques is widely used to perform breast cancer diagnosis. This paper presents a new Optimal Multi-Level Thresholding-based Segmentation with DL enabled Capsule Network (OMLTS-DLCN) breast cancer diagnosis model utilizing digital mammograms. The OMLTS-DLCN model involves an Adaptive Fuzzy based median filtering (AFF) technique as a pre-processing step to eradicate the noise that exists in the mammogram images. Besides, Optimal Kapur's based Multilevel Thresholding with Shell Game Optimization (SGO) algorithm (OKMT-SGO) is applied for breast cancer segmentation. In addition, the proposed model involves a CapsNet based feature extractor and Back-Propagation Neural Network (BPNN) classification model is employed to detect the existence of breast cancer. The diagnostic outcomes of the presented OMLTS-DLCN technique is examined by means of benchmark Mini-MIAS dataset and DDSM dataset. The experimental values obtained highlights the superior performance of the OMLTS-DLCN model with a higher accuracy of 98.50 and 97.55% on the Mini-MIAS dataset and DDSM dataset, respectively.

Nanorod-like Structure of ZnO Nanoparticles and Zn8O8 Clusters Using 4-Dimethylamino Benzaldehyde Liquid to Study the Physicochemical and Antimicrobial Properties of Pathogenic Bacteria.

To study their physicochemical and antimicrobial properties, zinc oxide nanoparticles were synthesized using a simple chemical route and 4-dimethylaminobenzaldehyde (4DB) as an organic additive. ZnO nanoparticles were characterized with XRD analysis, which confirmed the presence of a hexagonal wurtzite structure with different crystalline sizes. The SEM morphology of the synthesized nanoparticles confirmed the presence of nanorods in both modifications of ZnO nanoparticles. EDS analysis proved the chemical composition of the synthesized samples via different chemical approaches. In addition, the optical absorption results indicated that the use of 4DB increased the band gap energy of the synthesized nanoparticles. The synthesized Zn8O8 and Zn8O8:4DB clusters were subjected to HOMO-LUMO analysis, and their ionization energy (I), electron affinity (A), global hardness (η), chemical potential (σ), global electrophilicity index (ω), dipole moment (µ), polarizability (αtot), first-order hyperpolarizability (ßtot), and other thermodynamic properties were determined. Furthermore, the antimicrobial properties of the ZnO nanoparticles were studied against G+ (S. aureus and B. subtilis) and G- (K. pneumoniae and E. coli) bacteria in a nutrient agar according to guidelines of the Clinical and Laboratory Standards Institute (CLSI).

Anaerobic mixed consortium (AMC) mediated enhanced biosynthesis of silver nano particles (AgNPs) and its application for the removal of phenol.

In this research, silver nano particle (AgNP), was synthesized through a novel anaerobic mixed consortium mediation method and applied for the removal of phenol. The best operating conditions for the fabrication of silver nanoparticles were identified through response surface methodology (RSM) and the maximum yield was found to be 2.65 g/100 ml of anaerobic mixed consortium at optimal conditions of pH-8.6, temperature-90 °C, silver nitrate concentration-3 mg/ml and inoculum volume-3 ml. The synthesized nano particle exhibited a maximum phenol removal of 87.65% was achieved at pH:5.8. The synthesized silver nanoparticles were characterized by superior surface area (19.26 m2/g) and the stability was confirmed by thermo gravimetric analysis (upto 500 °C). The surface morphology was well explained using High Resolution Transmission Emission Microscopy (HR-TEM) and Scanning Electron Microscope with EDS (SEM-EDS) techniques. X-ray Diffraction (XRD) analysis confirmed the changes in crystalline structure due to the adsorption of phenol. Kinetic experiments fitted well with the intra-particle diffusion model. The nature of adsorption of phenol was confirmed as monolayer by the goodness of fit with Langmuir isotherm (R2 > 0.9969).

A new approach for PEGylation of dendrimers.

Dendrimers have emerged as one of the most interesting themes for researchers as a result of unique functional architecture and macromolecular characteristics. The reported methods of PEGylation are very time consuming and required multisteps for synthesis. In present work we have synthesized PEGylated polyamidoamine (PAMAM) dendrimers using epichlorohydrin as a linker. The PEGylated dendrimers were evaluated for color reaction UV, IR and NMR studies and compared with standard data.

Design, synthesis, cytotoxic evaluation, and QSAR study of some 6H-indolo[2,3-b]quinoxaline derivatives.

In the pathway of anticancer drug development, we designed and synthesized some 6H-indolo[2,3-b]quinoxaline derivatives (which act as DNA intercalators) by structural modification. The structure of the 6H-indolo[2,3-b]quinoxaline derivatives was confirmed by IR, NMR, Mass and elemental analysis. The compounds (IDQ-5, IDQ-10, IDQ-11, IDQ-13, and IDQ-14) exhibited significant in vitro activity against a human leukemia (HL-60) cell line. The QSAR derived for modeling the cytotoxic activity of 6H-indolo[2,3-b]quinoxaline derivatives suggests that candidate structures for increased cytotoxic potency should incorporate cyclic substituents or substituents with primary carbon atoms.

3D Flower-Like FeWO4/CeO2 Hierarchical Architectures on rGO for Durable and High-Performance Microalgae Biophotovoltaic Fuel Cells.

A facile chemical reduction approach is adopted for the synthesis of iron tungstate (FeWO4)/ceria (CeO2)-decorated reduced graphene oxide (rGO) nanocomposite. Surface morphological studies of rGO/FeWO4/CeO2 composite reveal the formation of hierarchical FeWO4 flower-like microstructures on rGO sheets, in which the CeO2 nanoparticles are decorated over the FeWO4 microstructures. The distinct anodic peaks observed for the cyclic voltammograms of studied electrodes under light/dark regimes validate the electroactive proteins present in the microalgae. With the cumulative endeavors of three-dimensional FeWO4 microstructures, phase effect between rGO sheet and FeWO4/CeO2, highly exposed surface area, and light harvesting property of CeO2 nanoparticles, the relevant rGO/FeWO4/CeO2 nanocomposite demonstrates high power and stable biophotovoltaic energy generation compared with those of previous reports. Thus, these findings construct a distinct horizon to tailor a ternary nanocomposite with high electrochemical activity for the construction of cost-efficient and environmentally benign fuel cells.

QSAR study of substituted 2-pyridinyl guanidines as selective urokinase-type plasminogen activator (uPA) inhibitors.

A quantitative structure-activity relationship analysis was conducted on two different series of pyridinylguanidines acting as inhibitors of urokinase-type plasminogen activator using QuaSAR descriptors of molecular modeling software MOE. Multiple linear regression analysis following a stepwise scheme was employed to generate QSARs that relate molecular descriptors to uPA inhibitory activity data of the title compounds. Among the several QSARs generated by MLR analysis, the best models were selected on the basis of their statistical significance and predictive potential. The interpretation of the selected QSAR models suggest that uPA inhibitory activity of compounds in series 1 is influenced by their molecular shape, molecular flexibility and halogen atoms in the molecule whereas the uPA inhibitory potency of compounds in series 2 is dependent on molecular lipophilicity, number of double bonds and spatial orientation of bulky substituents in the molecule.

Quantitative structure activity analysis of 2-alkoxydihydrocinnamates as PPARalpha/gamma dual agonist.

To optimize the physiochemical properties of 2-alkoxydihydrocinnamates as PPARalpha/gamma dual agonist, a quantitative structure activity relationship, Hansch approach was made using combination of various thermodynamic, electronic and spatial descriptors. Several regression expressions are obtained using multiple linear regression analysis. The best QSAR model is further validated by leave-one-out cross validation method. Analyses of results from the present QSAR study suggest that for favorable dual PPARalpha/gamma agonist activity electronic property of the substituents in hydrophobic tail phenyl ring plays a key role. The contribution of Hammett constant and dipole moment in the models deduced the importance of electron withdrawing substituents for dual activity. Additionally the study also indicates that bulky substituents in head acid moiety not confer selectivity towards the PPAR activity. Thus the QSAR study brings important structural insight to aid the design of dual PPARalpha/gamma receptor agonist.

Aerobic digestion of starch wastewater in a fluidized bed bioreactor with low density biomass support.

A solid-liquid-gas, multiphase, fluidized bed bioreactor with low density particles was used in this study to treat the high organic content starch industry wastewater. The characteristics of starch wastewater were studied. It shows high organic content and acidic nature. The performance of a three phase fluidized bed bioreactor with low density biomass support was studied under various average initial substrate concentrations, by varying COD values (2250, 4475, 6730 and 8910 mg/L) and for various hydraulic retention times (8, 16, 24, 32 and 40 h) based on COD removal efficiency. The optimum bed height for the maximum COD reduction was found to be 80 cm. Experiments were carried out in the bioreactor at an optimized bed height, after the formation of biofilm on the surface of low-density particles (density=870 kg/m(3)). Mixed culture obtained from the sludge, taken from starch industry effluent treatment plant, was used as the source for microorganisms. From the results it was observed that increase in initial substrate concentration leads to decrease in COD reduction and COD reduction increases with increase in hydraulic retention time. The optimum COD removal of 93.8% occurs at an initial substrate concentration of 2250 mg/L and for the hydraulic retention time of 24h.

One-pot green synthesis of reduced graphene oxide (RGO)/Fe3O4 nanocomposites and its catalytic activity toward methylene blue dye degradation.

The reduced graphene oxide (RGO)/Fe3O4 nanocomposites were synthesized through a facile one-pot green synthesis by using solanum trilobatum extract as a reducing agent. Spherical shaped Fe3O4 nanoparticles with the diameter of 18 nm were uniformly anchored over the RGO matrix and the existence of fcc structured Fe3O4 nanoparticles over the RGO matrix was ensured from X-ray diffraction patterns. The amide functional groups exist in the solanum trilobatum extract is directly responsible for the reduction of Fe(3+) ions and GO. The thermal stability of GO was increased by the removal of hydrophilic functional groups via solanum trilobatum extract and was further promoted by the ceramic Fe3O4 nanoparticles. The ID/IG ratio of RGO/Fe3O4 was increased over GO, indicating the extended number of structural defects and disorders in the RGO/Fe3O4 composite. The catalytic efficiency of prepared nanostructures toward methylene blue (MB) dye degradation mediated through the electron transfer process of BH4(-) ions was studied in detail. The π-π stacking, hydrogen bonding and electrostatic interaction exerted between the RGO/Fe3O4 composite and methylene blue, increased the adsorption efficiency of dye molecules and the large surface area and extended number of active sites completely degraded the MB dye within 12 min.