The rapid construction and biological evaluation of densely substituted pyrrolo[1,2-a]indoles via a BF3·OEt2-assisted cascade approach.

Lewis-acid cascade reactions promoted by BF3·OEt2 are reported for the synthesis of highly substituted pyrrolo[1,2-a]indoles and congeners of benzofuro[2,3-b]indoles. These reactions are highly regio- and diastereoselective towards generating up to five contiguous stereogenic centers, including two vicinal quaternary centers. Furthermore, an established cascade approach and the mechanism proposed herein are well supported by quantum chemistry calculations. In addition, a self-dimerization intermediate was trapped and isolated to establish a strategy for potential access to both pyrrolo and benzo indole derivatives, leaving sufficient freedom for broadening. Furthermore, in-silico molecular docking and all atomistic molecular dynamic (MD) simulation analysis suggests that the synthesized pyrrolo[1,2-a]indole derivatives stably bind at the active site of the mycobacterial secreted tyrosine phosphatase B (MptpB) enzyme, an emerging anti-mycobacterial drug target. Deep learning-based affinity predictions and MMPBGBSA-based energy calculations of the docked poses are presented herein.

Effect of Mn doping on the electronic and optical properties of Dy2Ti2O7: a combined spectroscopic and theoretical study.

Electronic and optical studies on Dy2Ti2-MnxO7(x= 0.00, 0.05, 0.10, 0.15, & 0.20) have been presented through both, theoretical (density functional theory (DFT) calculations) and experimental (ultraviolet-visible absorption and photoluminescence emission spectroscopy) approaches. DFT calculations were employed considering the local density approximation (LDA) and LDA-1/2 for exchange-correlation interactions. Computed crystallographic parameters and energy band-gap using theoretical formulations are in good agreement with experimental results. The band-gap value obtained through the LDA-1/2 approach indicates insulated ground state of Dy2Ti2-xMnxO7(x= 0.00, 0.05, 0.10, 0.15, 0.20) system. Experimentally obtained band gap value reduces from 3.82 eV to 2.45 eV with increase in positive chemical pressure asxincreases from 0 to 0.20. Reduction in band gap value is attributed to the fact that there exists a lack of hybridization between the O-2p orbital and Ti-3d orbital, which is well correlated with the crystallographic data. Jahn-Teller effect is likely to be responsible for the presence of a mixed state of Mn (explained using x-ray photoelectron spectroscopy results), resulting in the intermediate Mn state between the valence band and the conduction band with immediate inclusion of Mn at Ti site in Dy2Ti2-xMnxO7system.

Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating Cancer, Neurological and Infectious Diseases.

p97/VCP, a highly conserved type II ATPase associated with diverse cellular activities (AAA+ ATPase), is an important therapeutic target in the treatment of neurodegenerative diseases and cancer. p97 performs a variety of functions in the cell and facilitates virus replication. It is a mechanochemical enzyme that generates mechanical force from ATP-binding and hydrolysis to perform several functions, including unfolding of protein substrates. Several dozens of cofactors/adaptors interact with p97 and define the multifunctionality of p97. This review presents the current understanding of the molecular mechanism of p97 during the ATPase cycle and its regulation by cofactors and small-molecule inhibitors. We compare detailed structural information obtained in different nucleotide states in the presence and absence of substrates and inhibitors. We also review how pathogenic gain-of-function mutations modify the conformational changes of p97 during the ATPase cycle. Overall, the review highlights how the mechanistic knowledge of p97 helps in designing pathway-specific modulators and inhibitors.

Effective Synthesis and Biological Evaluation of Functionalized 2,3-Dihydrofuro[3,2-c]coumarins via an Imidazole-Catalyzed Green Multicomponent Approach.

For the first time, an eco-friendly and efficient one-pot green multicomponent approach has been described to synthesize functionalized trans-2,3-dihydrofuro[3,2-c]coumarins (DHFCs). In this synthesis, imidazole and water were used as the catalyst and solvent, respectively, under mild conditions. Applications of the developed catalytic process in a water medium revealed the outstanding activity, productivity, and broad functional group tolerance, affording a series of newly designed DHFC and derivatives in excellent yields (72-98%). Moreover, the human serum albumin (HSA) binding ability of the synthesized DHFC derivatives has been uncovered through the detailed in silico and in vitro-based structure-activity analysis. The ability to bind HSA, the most abundant serum protein, in the low micromolar ranges unequivocally reflects the suitable absorption, distribution, metabolism, and elimination profile of the synthesized compounds, which may further be envisaged for their therapeutic usage endeavors.

Quorum Quenching-Guided Inhibition of Mixed Bacterial Biofilms and Virulence Properties by Protein Derived From Leaves of Carissa carandas.

The inhibition/degradation potential of Carissa carandas proteinaceous leaf extract against mixed bacterial biofilm of Staphylococcus aureus MTCC 96, Escherichia coli MTCC 1304, Pseudomonas aeruginosa MTCC 741, and Klebsiella pneumoniae MTCC 109, responsible for nosocomial infections, was evaluated. Distinct inhibition/degradation of mixed bacterial biofilm by the proteinaceous leaf extract of C. carandas was observed under a microscope, and it was found to be 80%. For mono-species biofilm, the maximum degradation of 70% was observed against S. aureus biofilm. The efficiency of aqueous plant extracts to inhibit the mono-species biofilm was observed in terms of minimum inhibitory concentration (MIC), and the best was found against P. aeruginosa (12.5 µg/ml). The presence of flavonoids, phenols, and tannins in the phytochemical analysis of the plant extract suggests the main reason for the antibiofilm property of C. carandas. From the aqueous extract, protein fraction was precipitated using 70% ammonium sulfate and dialyzed. This fraction was purified by ion-exchange chromatography and found to be stable and active at 10°C (pH 7). The purified fraction showed less than 40% cytotoxicity, which suggests that it can be explored for therapeutic purposes after in-depth testing. In order to investigate the mechanistic action of the biofilm inhibition, the plant protein was tested against Chromobacterium violaceum CV026, and its inhibitory effect confirmed its quorum quenching nature. Based on these experimental analyses, it can be speculated that the isolated plant protein might influence the signaling molecule that leads to the inhibition effect of the mixed bacterial biofilm. Further experimental studies are warranted to validate our current findings.

Anti-SARS-CoV-2 potential of Cissampelos pareira L. identified by connectivity map-based analysis and in vitro studies.

BACKGROUND: Viral infections have a history of abrupt and severe eruptions through the years in the form of pandemics. And yet, definitive therapies or preventive measures are not present. Herbal medicines have been a source of various antiviral compounds such as Oseltamivir, extracted using shikimic acid from star anise (Illicium verum) and Acyclovir from Carissa edulis are FDA (Food and Drug Administration) approved antiviral drugs. In this study, we dissect the anti-coronavirus infection activity of Cissampelos pareira L (Cipa) extract using an integrative approach. METHODS: We analysed the signature similarities between predicted antiviral agents and Cipa using the connectivity map ( https://clue.io/ ). Next, we tested the anti-SARS-COV-2 activity of Cipa in vitro. Molecular docking analyses of constituents of with key targets of SARS-CoV2 protein viz. spike protein, RNA­dependent RNA­polymerase (RdRp) and 3C­like proteinase. was also performed. A three-way comparative analysis of Cipa transcriptome, COVID-19 BALF transcriptome and CMAP signatures of small compounds was also performed. RESULTS: Several predicted antivirals showed a high positive connectivity score with Cipa such as apcidin, emetine, homoharringtonine etc. We also observed 98% inhibition of SARS-COV-2 replication in infected Vero cell cultures with the whole extract. Some of its prominent pure constituents e.g. pareirarine, cissamine, magnoflorine exhibited 40-80% inhibition. Comparison of genes between BALF and Cipa showed an enrichment of biological processes like transcription regulation and response to lipids, to be downregulated in Cipa while being upregulated in COVID-19. CMAP also showed that Triciribine, torin-1 and VU-0365114-2 had positive connectivity with BALF 1 and 2, and negative connectivity with Cipa. Amongst all the tested compounds, Magnoflorine and Salutaridine exhibited the most potent and consistent strong in silico binding profiles with SARS-CoV2 therapeutic targets.

Effective Synthesis and Biological Evaluation of Natural and Designed Bis(indolyl)methanes via Taurine-Catalyzed Green Approach.

An ecofriendly, inexpensive, and efficient route for synthesizing 3,3'-bis(indolyl)methanes (BIMs) and their derivatives was carried out by an electrophilic substitution reaction of indole with structurally divergent aldehydes and ketones using taurine and water as a green catalyst and solvent, respectively, under sonication conditions. Using water as the only solvent, the catalytic process demonstrated outstanding activity, productivity, and broad functional group tolerance, affording the required BIM natural products and derivatives in excellent yields (59-90%). Furthermore, in silico based structure activity analysis of the synthesized BIM derivatives divulges their potential ability to bind antineoplastic drug target and spindle motor protein kinesin Eg5. The precise binding mode of BIM derivatives with the ATPase motor domain of Eg5 is structurally reminiscent with previously reported allosteric inhibitor Arry520, which is under phase III clinical trials. Nevertheless, detailed analysis of the binding poses indicates that BIM derivatives bind the allosteric pocket of the Eg5 motor domain more robustly than Arry520; moreover, unlike Arry520, BIM binding is found to be resistant to drug-resistant mutations of Eg5. Accordingly, a structure-guided mechanism of Eg5 inhibition by synthesized BIM derivatives is proposed.

Physico-chemical characterization of kajjali, black sulphide of mercury, with respect to the role of sulfur in its formation and structure.

BACKGROUND: Kajjali is used as a base for Ayurvedic herbo-mineral medicines. It is a combination of mercury with sulfur in varying proportions. The ratio of sulfur (S) added to mercury (Hg) directly relates to the therapeutic efficacy of the compound. OBJECTIVE: To analyze the physico-chemical characteristics of samaguna gandhaka kajjali (Hg: S = 1:1) and shadaguna gandhaka kajjali (Hg: S = 1:6). MATERIALS AND METHODS: X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectroscopy (XPS), Fourier transmission infrared spectroscopy, thermo-gravimetry analysis, and atomic absorption spectroscopy were applied to characterize each type of kajjali. RESULTS: It was found that the particle size of the formed kajjali compound increases with a decrease in the mercury to sulfur ratio. The presence of excess sulfur does not change the surface oxidation states as revealed by the XPS analysis. No trace of mercury has been found in both samaguna gandhaka kajjali (SGK-1) and shadguna gandhaka kajjali (SGK-6), indicating a complete Hg reaction with S. CONCLUSION: Kajjali simulates nanomaterial of the modern era and possesses therapeutic efficacy as mentioned in classical Ayurveda texts. Complete trituration of mercury and sulfur combination ends up with this kajjali formation incorporating the potency of nanotherapeutics.

Robust spin-ice freezing in magnetically frustrated Ho2Ge x Ti2- x O7 pyrochlore.

Structural analysis of spin frustrated Ho2Ge x Ti2-x O7 (x = 0, 0.1, 0.15 & 0.25) pyrochlore oxides has been performed using high resolution x-ray diffraction pattern and low temperature synchrotron x-ray diffraction pattern. The effect of positive chemical pressure on the spin dynamics of Ho2Ge x Ti2-x O7 has been analysed through the study of static (M-T and M-H; magnetisation against temperature & magnetisation against magnetic field) and dynamical (ac susceptibility) magnetic measurements. In lower temperature regime (∼2 K), such systems are predominantly governed by competing exchange (J nn) and dipolar (D nn) magnetic interactions. Magnetic measurements indicate that the application of increased chemical pressure in Ho2Ti2O7 matrix propels the system towards diminished ferromagnetic interaction. Dipolar coupling constant remains almost unchanged but Curie-Weiss temperature (θ cw) reduces to -0.04 K from 0.33 K (for an applied magnetic field; H = 100 Oe) with increasing x in Ho2Ge x Ti2-x O7. Positive chemical pressure establishes the dominance of Ho-Ho antiferromagnetic interaction J nn over dipolar interaction D nn. Spin relaxation feature corresponding to thermally activated single ion freezing (T s∼15 K) is shifted towards lower temperature. This chemical pressure-driven T s shift is ascribed to the alteration in crystal field effect, which reduces the activation energy for singe ion spin freezing. The reduction in the activation energy indicates crystal field-phonon coupling in Ho2Ge x Ti2-x O7 system. The robustness in spin ice freezing (second spin relaxation feature in ac susceptibility curve) remains unaffected with increasingly chemical pressure. This spin freezing ('2 in-2 out' spin arrangement in tetrahedra) is related to quantum tunnelling phenomenon, at T ice ∼ 2 K. It indicates that majority of spins still follows the 'ice rule' in Ho2Ge x Ti2-x O7 even after the application of chemical pressure.

Role of chemical pressure on optical and electronic structure of Ho2Ge x Ti2-x O7.

Chemical pressure plays a crucial role in determining the electronic properties of the quantum materials. Investigation of electronic structure of Ho2Ge x Ti2-x O7 (x = 2, 1.9, 1.75, 1.5 1, 0.5, 0.25, 0.1 and 0) series has been performed. Pyrochlore and Pyrogermanate, Re2B2O7 (Re = Ho3+, B = Ti4+ and Ge4+; rare earth titanates and germanates), substituted with increasing amount of Ge4+ at the Ti4+ site and vice versa develops structural distortions. Distinct shrinkage effect has been established in the Ho2Ti2O7 matrix upon Ge+4 substitutions at B site, resulting in the modification of band gap value. Band gap of 5.24 eV drastically drops to 3.92 eV with immediate Ti4+ substitution in Ho2Ge2O7. Electronic states of Ho3+ (4f forbidden transitions) had also been identified. We observe favored sub level transition (Specific Stark component) corresponding to5F5 to 5I8 electronic transition for Ho3+ at λ exc. = 450 nm. The upper valence band consisted of O 2p state hybridized with Ho 5p and Ti and Ge 4p states and conduction band primarily formed by Ho 5d state hybridized with Ti 3d and Ge 4d states as obtained from density of states (DOS) calculations. Strong hybridization between Ho 5p1/2 and Ti 3p orbital upon Ti4+ inclusion in Ho2Ge2O7 has been observed through both theoretical studies using LDA-1/2 and UV-Vis, photoluminescence, ultraviolet photoelectron spectroscopy (UPS) and x-ray photoelectron spectroscopy. The evolution of total DOS of all studied composition shows that valence band edge is more sensitive than conduction band to composition. These results provide chemical pressure as an excellent tool to tailor the band gap and fine tune the intermediate electronic states in Ho2Ge x Ti2-x O7.

Signatures of consolidated superparamagnetic and spin-glass behavior in magnetite-silver core-shell nanoparticles.

A detailed investigation of magnetization relaxation for silver-coated magnetite nanostructures with three different types of magnetic behavior in a single particle is presented. Magnetite nanoparticles of diameter ∼6.5 nm synthesized via single-phase emulsion were further coated with a silver shell of thickness ∼2 nm. The synthesized nanoparticles are found to be efficiently photoluminescent. The coating of silver generates a magnetically disordered spin layer at the interface of the magnetic core and the non-magnetic shell. This intermediate layer plays a significant role in the dynamical magnetic response of nanoparticles under an external magnetic field. We present detailed magnetic measurements such as field- and temperature-dependent dc magnetization with zero-field-cooled and field-cooled protocols, ac susceptibility and time decay of magnetization relaxation along with their analysis using various formalisms viz. Néel-Arrhenius, Vogel-Fulcher and power law models. The relaxation analysis suggests the consolidated presence of two characteristic relaxation times corresponding to the superparamagnetic and spin-glass behavior of silver-coated magnetite nanoparticles.

Development of thermal energy storage materials for biomedical applications.

The phase change materials (PCMs) have been utilized widely for solar thermal energy storage (TES) devices. The quality of these materials to remain at a particular temperature during solid-liquid, liquid-solid phase transition can also be utilized for many biomedical applications as well and has been explored in recent past already. This study reports some novel PCMs developed by them, along with some existing PCMs, to be used for such biomedical applications. Interestingly, it was observed that the heating/cooling properties of these PCMs enhance the quality of a variety of biomedical applications with many advantages (non-electric, no risk of electric shock, easy to handle, easy to recharge thermally, long life, cheap and easily available, reusable) over existing applications. Results of the present study are quite interesting and exciting, opening a plethora of opportunities for more work on the subject, which require overlapping expertise of material scientists, biochemists and medical experts for broader social benefits.