Cp*Ir(III) complexes catalyzed solvent-free synthesis of quinolines, pyrroles and pyridines via an ADC strategy.

A trio of Ir(III) complexes that are held together by a picolinamidato moiety were created. In our earlier research, we demonstrated the catalytic activity of the complexes for producing alpha-alkylated ketones from a ketone or secondary alcohol with a primary alcohol in the presence of a catalytic amount of a Cp*Ir(III) catalyst and tBuOK in toluene at 110 °C using the hydrogen-borrowing technique. Earlier many research groups had synthesized quinoline, pyrrole, and pyridine derivatives using 2-amino alcohol and ketone or secondary alcohol derivatives as starting materials, but in all those cases the reaction conditions are not suitable in terms of green synthesis like more catalyst loading, base loading, long reaction time, and high temperature. In addition, most of the reactions contain phosphine a hazardous by-product, along with the catalyst. Keeping in mind these shortcomings, we tried to expand the use of our catalysts after achieving an excellent result in our previous work, and we were successful in producing quinoline, pyrrole, and pyridine derivatives through acceptor-less dehydrogenative coupling (ADC) procedures at 90-110 °C under neat/solvent-free conditions and achieved good to exceptional yields of those nitrogen-containing heterocycles. This methodology is attractive because it is environmentally benign and allows for the "green" synthesis of nitrogen-containing heterocycles. All that is required is a modest quantity of catalyst and base, and the by-products are merely H2O and H2.

Design, synthesis, and apoptotic antiproliferative action of new 1,2,3-triazole/1,2,4-oxadiazole hybrids as dual EGFR/VEGFR-2 inhibitors.

A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (7a-o) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a-o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI50 values ranging from 28 to 104 nM, compared to Erlotinib (GI50 = 33 nM), and compounds 7i-m were the most potent. Compounds 7h, 7i, 7j, 7k, and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j, 7k, and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j, 7k, and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j, 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.

Pharmacoinformatics-based identification of transmembrane protease serine-2 inhibitors from Morus Alba as SARS-CoV-2 cell entry inhibitors.

Transmembrane protease serine-2 (TMPRSS2) is a cell-surface protein expressed by epithelial cells of specific tissues including those in the aerodigestive tract. It helps the entry of novel coronavirus (n-CoV) or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the host cell. Successful inhibition of the TMPRSS2 can be one of the crucial strategies to stop the SARS-CoV-2 infection. In the present study, a set of bioactive molecules from Morus alba Linn. were screened against the TMPRSS2 through two widely used molecular docking engines such as Autodock vina and Glide. Molecules having a higher binding affinity toward the TMPRSS2 compared to Camostat and Ambroxol were considered for in-silico pharmacokinetic analyses. Based on acceptable pharmacokinetic parameters and drug-likeness, finally, five molecules were found to be important for the TMPRSS2 inhibition. A number of bonding interactions in terms of hydrogen bond and hydrophobic interactions were observed between the proposed molecules and ligand-interacting amino acids of the TMPRSS2. The dynamic behavior and stability of best-docked complex between TRMPRSS2 and proposed molecules were assessed through molecular dynamics (MD) simulation. Several parameters from MD simulation have suggested the stability between the protein and ligands. Binding free energy of each molecule calculated through MM-GBSA approach from the MD simulation trajectory suggested strong affection toward the TMPRSS2. Hence, proposed molecules might be crucial chemical components for the TMPRSS2 inhibition.

Pharmacoinformatics approach based identification of potential Nsp15 endoribonuclease modulators for SARS-CoV-2 inhibition.

In the current study, a structure-based virtual screening paradigm was used to screen a small molecular database against the Non-structural protein 15 (Nsp15) endoribonuclease of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 is the causative agent of the recent outbreak of coronavirus disease 2019 (COVID-19) which left the entire world locked down inside the home. A multi-step molecular docking study was performed against antiviral specific compounds (~8722) collected from the Asinex antiviral database. The less or non-interacting molecules were wiped out sequentially in the molecular docking. Further, MM-GBSA based binding free energy was estimated for 26 compounds which shows a high affinity towards the Nsp15. The drug-likeness and pharmacokinetic parameters of all 26 compounds were explored, and five molecules were found to have an acceptable pharmacokinetic profile. Overall, the Glide-XP docking score and Prime-MM-GBSA binding free energy of the selected molecules were explained strong interaction potentiality towards the Nsp15 endoribonuclease. The dynamic behavior of each molecule with Nsp15 was assessed using conventional molecular dynamics (MD) simulation. The MD simulation information was strongly favors the Nsp15 and each identified ligand stability in dynamic condition. Finally, from the MD simulation trajectories, the binding free energy was estimated using the MM-PBSA method. Hence, the proposed final five molecules might be considered as potential Nsp15 modulators for SARS-CoV-2 inhibition.

Structure-based identification of SARS-CoV-2 main protease inhibitors from anti-viral specific chemical libraries: an exhaustive computational screening approach.

Worldwide coronavirus disease 2019 (COVID-19) outbreak is still threatening global health since its outbreak first reported in the late 2019. The causative novel virus has been designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 emergent with significant mortality, there is no availability of definite treatment measures. It is now extremely desirable to identify potential chemical entities against SARS-CoV-2 for the treatment of COVID-19. In the present study, a state-of-art virtual screening protocol was implemented on three anti-viral specific chemical libraries against SARS-CoV-2 main protease (Mpro). Particularly, viewing the large-scale biological role of Mpro in the viral replication process it has been considered as a prospective anti-viral drug target. Herein, on collected 79,892 compounds, hierarchical multistep docking followed by relative binding free energy estimation has been performed. Thereafter, implying a user-defined XP-dock and MM-GBSA cut-off scores as -8.00 and -45.00 kcal/mol, chemical space has been further reduced. Exhaustive molecular binding interactions analyses and various pharmacokinetics profiles assessment suggested four compounds (ChemDiv_D658-0159, ChemDiv_F431-0433, Enamine_Z3019991843 and Asinex_LAS_51389260) as potent inhibitors/modulators of SARS-CoV-2 Mpro. In-depth protein-ligand interactions stability in the dynamic state has been evaluated by 100 ns molecular dynamics (MD) simulation studies along with MM-GBSA-based binding free energy estimations of entire simulation trajectories that have revealed strong binding affinity of all identified compounds towards Mpro. Hence, all four identified compounds might be considered as promising candidates for future drug development specifically targeting the SARS-CoV-2 Mpro; however, they also need experimental assessment for a better understanding of molecular interaction mechanisms.

Inhibition of α-, ß- and γ-carbonic anhydrases from the pathogenic bacterium Vibrio cholerae with aromatic sulphonamides and clinically licenced drugs - a joint docking/molecular dynamics study.

The binding mode of aromatic sulphonamides and clinically licenced drugs to the three carbonic anhydrase (CA, EC 4.2.1.1) isoforms from the human pathogen V. cholerae was here thouroghly characterised by a joint docking and molecular dynamics in silico protocol. In fact, VchCA, VchCAß, and VchCAγ are crucial in the pathogen life cycle and growth and represent innovative targets to fight V. cholerae proliferation overcoming the spreading chemoresistance to the available drugs. A set of 40 sulphonamides/sulfamates VchCAs inhibitors was studied using the proteins homology built 3 D models unveiling the key and stable interactions responsible for a potent CA inhibition. This study has the aim to offer insights and guidelines for the future rational design of potent and selective inhibitors targeting CA isoforms from V. cholerae or other human pathogens.

In vitro catabolism of 3',4'-dihydroxycinnamic acid by human colonic microbiota.

3',4'-Dihydroxycinnamic acid (aka caffeic acid) is a common dietary component found in a variety of plant-derived food products either in a free form or esterified as in chlorogenic acids such as 5-O-caffeoylquinic acid. The dihydroxycinnamate is produced principally by hydrolysis in the colon of 5-O-caffeoylquinic acid and other caffeoylquinic acid esters, and is catabolised by the resident microbiota prior to absorption. In the present study 3',4'-dihydroxycinnamic acid was incubated in vitro, with or without glucose, under anaerobic conditions with faecal slurries obtained from five volunteers. The main resultant catabolites to accumulate were 3-(3',4'-dihydroxyphenyl)propanoic acid (aka dihydrocaffeic acid), 3-(3'-hydroxyphenyl)propanoic acid and phenylacetic acid. Both the rate of degradation of the hydroxycinnamate substrate and the catabolite profile varied between the faecal samples from the individual volunteers. Overall there was no clear cut effect when glucose was added to incubation medium.

Green synthesized Ag decorated CeO2 nanoparticles: Efficient photocatalysts and potential antibacterial agents.

Implication of natural resources for manufacturing of nanoparticles is sustainable, economical and contaminant free approach towards ecological and medical applications. Herein, CeO2 and Ag/CeO2 nanoparticles are green synthesized from Morinda tinctoria plant extract. The phase structure, surface morphology, optical identity, Ce(III) and Ce(IV) valency of the synthesized CeO2 and Ag/CeO2 nanoparticles are explored. The X-ray diffraction analysis indicated the formation of cubic phase CeO2 and cubic silver decorated CeO2 nanoparticles. Fourier transform infrared (FTIR) spectroscopy revealed the metal decoration of CeO2 nanoparticles, metal-oxygen stretching, indicating the plant molecules reduction and stabilization. UV-visible spectroscopy shown the decreased band gap owing to silver modification. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) micrographs displayed spherical morphology of the nanoparticles. Elemental composition and sample purity is assessed by energy dispersive spectroscopy (EDS). Double oxidation of Ce, double splitting energy of Ag and lattice oxygen are observed from X-ray photoelectron spectroscopy (XPS). Photocatalytic activity of Ag/CeO2 exposed the enhanced photocatalytic activity up to 94% where CeO2 nanoparticles gave 60% degradation of bromophenol blue (BB). The plasmonic decoration of silver on the ceria surface induced the charge separations and free radical reactions. Moreover, Ag/CeO2 nanoparticles are seen as superior antibacterial agents than CeO2 towards both E.coli and S.aureus. Hence, the silver decorated metal oxide photocatalyst successfully degraded the BB dye and inactivated the bacterial strains. This report established a future research in green synthesis of multipurpose metal nanoparticles.

Excellent photocatalytic and antibacterial activities of bio-activated carbon decorated magnesium oxide nanoparticles.

Green production of nanomaterials are restrict toxic substances and motivated the noxious free environment. Photocatalysis and antibacterial resistance are more promising and efficient fields for their chemical reductants and clean environment. Herein, we adopted a green and simple method for the biosynthesis of MgO NPs using Manilkara zapota as a bio source. Recently, the green synthesis of magnesium oxide nanoparticles has been a keen interest amongst researchers and scientists due to its simplicity eco-friendliness, non-toxic, inexpensive and potential to perform as an antibacterial agent. Activated carbon/Magnesium oxide (AC/MgO) photocatalyst was blended through a simple solution evaporation method. The surface electron microscopy (SEM) study reviles that AC/MgO had smooth and aggregated particles. The Fourier transform infrared (FT-IR) and x-ray diffraction (XRD) study confirms the structural formation and incorporation of nanoparticles into the AC matrix. Results confirmed the flourishing integration of MgO NPs over the activated carbon matrix. The electron movement and valency of AC/MgO photocatalyst reduced the bandgap and their findings were characterized by ultra visible diffuse reflectance spectroscopy (UV-DRS) and x-ray photoelectron spectroscopy (XPS). The blended AC/MgO photocatalyst was analyzed for photodegradation of Rhodamine- B (Rh-B) dye using a UV-visible spectrophotometer. The degradation study projects that the AC/MgO photocatalyst degrades (Rh-B) dye with 99% efficiency under simulated solar irradiation. This efficient degradation of (Rh-B) dye by AC/MgO photocatalyst is ascribed to the synergetic AC as catalytic support and adsorbent and MgO as photocatalyst. Finally, the photocatalytic material shows a better bactericidal effect in both gram-positive bacteria Escherichia coli-745 and gram-negative bacteria Staphylococcus aureus-9779. The AC/MgO photocatalyst is effectively used in bacteriocidal and photocatalytic removal of dyes and can be used for further development of water reuse and bio-medical fields. In addition, this research shows a viable method for synthesizing a cheap and effective AC/MgO for the photocatalytic destruction of organic pollutants.

Molecularly imprinted ormosil as a sorbent for targeted dispersive solid phase micro extraction of pyriproxyfen from strawberry samples.

Novel molecularly imprinted organically modified silica was prepared by reacting acrylamide and 3-(tri-methoxysilyl) propyl methacrylate followed by condensation and hydrolysis with tetraethyl ortho-silicate for the determination of pyriproxyfen. The sorbent proved to be highly selective for the template molecule, pyriproxyfen. The characterization of sorbent was carried out using SEM, BET and TGA. The prominent peaks in FTIR at 3700 cm-1 and 1071 cm-1 confirmed the stretching of amide group's N-H and Si-O-Si bond linkage of MIOrmosil. The pseudo-first-order model (R2 0.99) described the adsorption kinetics of the MIOrmosil, whereas among adsorption isotherms, Freundlich model showed the best fit (R2 0.99). The molecularly imprinted silica was applied for the determination of target analytes from strawberries sample using dispersive solid-phase micro extraction (DSPME) followed by high-performance liquid chromatography (HPLC). The LOD (4.93 x10-5 µg mL-1) and LOQ (1.49 x10-4 µg m-1) values were calculated by signal to noise ratio through HPLC. Results show that the maximum binding capacity and percentage recovery values of MIOrmosil were 13 mg g-1 (n = 5) and 97.3% respectively.

Design, synthesis and evaluation of novel enzalutamide analogues as potential anticancer agents.

The androgen receptor inhibitor, Enzalutamide, proved effective against castration resistance prostate cancer, has demonstrated clinical benefits and increased survival rate in men. However, AR mutation (F876L) converts Enzalutamide from antagonist to agonist indicating a rapid evolution of resistance. Hence, our goal is to overcome this resistance mechanism by designing and developing novel Enzalutamide analogues. We designed a dataset of Enzalutamide derivatives using Enzalutamide's shape and electrostatic features to match with pharmacophoric features essential for tight binding with the androgen receptor. Based on this design strategy ten novel derivatives were selected including 5,5-dimethyl-3-(6-substituted benzo[d]thia/oxazol-2-yl)-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl)imidazolidin-4-one (6a-j) for synthesis. All the compounds were evaluated in-vitro on prostate cancer cell lines DU-145, LNCaP and PC3. Interestingly, two compounds 3-(6-hydroxybenzo[d]thiazol-2-yl)-5,5-dimethyl-2-thioxo-1-(4-(trifluoromethyl)pyridin-2-yl) imidazolidin-4-one (6c, IC50 - 18.26 to 20.31µM) and 3-(6-hydroxybenzo[d]oxazol-2-yl)-5,5-dimethyl -2-thioxo- 1- (4-(trifluoromethyl) pyridin-2-yl)imidazolidin-4-one (6h, IC50 - 18.26 to 20.31µM) were successful with promising in-vitro antiproliferative activity against prostate cancer cell lines. The binding mechanism of potential androgen receptor inhibitors was further studied by molecular docking, molecular dynamics simulations and MM-GBSA binding free energy calculations and found in agreement with the in vitro studies. It provided strong theoretical support to our hypothesis.

Matairesinol, an active constituent of HC9 polyherbal formulation, exhibits HDAC8 inhibitory and anticancer activity.

Histone deacetylase 8 (HDAC8) has emerged as a promising drug target for cancer therapeutics development. HDAC8 has been reported to regulate cancer cell proliferation, invasion and promote metastasis through modulation of cell cycle associated proteins. Of late, phytocompounds have been demonstrated to exhibit anticancer and anti-HDAC8 activity. Here, we have shown the HDAC8 inhibitory potential of an active phytocompound from HC9 (herbal composition-9), a polyherbal anticancer formulation based on the traditional Ayurvedic drug, Stanya Shodhan Kashaya. HC9 was recently reported to exhibit anticancer activity against breast cancer cells through induction of cell cycle arrest, decrease in migration and invasion as well as regulation of inflammation and chromatin modulators. In silico studies such as molecular docking, molecular dynamics (MD) simulation and binding free energy analyses showed greater binding energy values and interaction stability of MA with HDAC8 compared to other phytocompounds of HC9. Interestingly, in vitro validation confirmed the anti-HDAC8 activity of MA. Further, in vitro studies showed that MA significantly decreased the viability of breast and prostate cancer cell lines, thereby confirming its anticancer potential.

Biological Activities of In-House Developed Haloxylon griffithii Plant Extract Formulations.

The therapeutic potential of whitish glaucous sub-shrub Haloxylon griffithii (H. griffithii), abundantly present in southern regions of South Asia, has been neglected. The current study aimed to assess the phytochemicals and pharmacological potential of native and gemm forms of H. griffithii. Results of antimicrobial activity revealed that all tested bacteria were susceptible at concentrations ≤50 µg/mL, while tested fungal species were susceptible at ≤25 µg/mL. The values of minimum bactericidal concentrations (MBCs) ranged between 10.75 ± 0.20 to 44.25 ± 0.42 µg/mL, 8.25 ± 0.02 to 28.20 ± 0.80 µg/mL. The value of minimum inhibitory concentration (MIC) of all microbial species was ≤100 µg/mL and the antibiotic mechanism showed that both extracts were highly bactericidal and fungicidal. Results of average log reduction of viable cell count in time kill assay indicated that Pseudomonas aeruginosa (P. aeruginosa) NCTC 1662, Candida albicans (C. albicans) IBL-01, Candidakrusei (C. krusei) ATCC 6258, and Aspergillus flavus (A. flavus) QC 6158 were the most susceptible microbial species. High performance liquid chromatography (HPLC)-based quantification confirmed the presence of gallic acid p.coumeric acid catechin, vanillin, ellagic acid, and salicylic acid, while in native extract only gallic acid. Native and gemm extracts exhibited excellent radical scavenging potential measured by 1,1-diphenyl-2-picryl-hydrazyl radical scavenging assay. Significant thrombolytic activity was found in both extracts with negligible haemolytic activity. Highest percent (%) clot lysis was observed with gemm extracts (87.9 ± 0.85% clot lysis). In summary, we infer that valuable evidence congregated can be exploited for better understanding of gemm H. griffithii's health benefits, further, to increase its utility with enriching dietary sources of health-promoting compounds.

Ex vivo fecal fermentation of human ileal fluid collected after raspberry consumption modifies (poly)phenolics and modulates genoprotective effects in colonic epithelial cells.

Diets rich in fruit and vegetables are associated with a decreased incidence of colorectal cancer (CRC) due, in part, to the bioactive (poly)phenolic components and their microbiota-mediated metabolites. This study investigated how such compounds, derived from ingested raspberries in the gastrointestinal tract, may exert protective effects by reducing DNA damage. Ileal fluids collected pre- and post-consumption of 300 g of raspberries by ileostomists (n = 11) were subjected to 24 h ex vivo fermentation with fecal inoculum to simulate interaction with colonic microbiota. The impact of fermentation on (poly)phenolics in ileal fluid was determined and the bioactivity of ileal fluids pre- and post fermentation investigated. (Poly)phenolic compounds including sanguiin H-6, sanguiin H-10 and cyanidin-3-O-sophoroside decreased significantly during fermentation while, in contrast, microbial catabolites, including 3-(3'-hydroxyphenyl)propanoic acid, 3-hydroxybenzoic acid and benzoic acid increased significantly. The post-raspberry ileal fermentate from 9 of the 11 ileostomates significantly decreased DNA damage (~30%) in the CCD 841 CoN normal cell line using an oxidative challenge COMET assay. The raspberry ileal fermentates also modulated gene expression of the nuclear factor 2-antioxidant responsive element (Nrf2-ARE) pathway involved in oxidative stress cytoprotection, namely Nrf2, NAD(P)H dehydrogenase, quinone-1 and heme oxygenase-1. Four of the phenolic catabolites were assessed individually, each significantly reducing DNA damage from an oxidative challenge over a physiologically relevant 10-100 µM range. They also induced a differential pattern of expression of key genes in the Nrf2-ARE pathway in CCD 841 CoN cells. The study indicates that the colon-available raspberry (poly)phenols and their microbial-derived catabolites may play a role in protection against CRC in vivo.