Catalyst-free anti-Markovnikov hydroamination and hydrothiolation of vinyl heteroarenes in aqueous medium: an improved process towards centhaquine.

Catalyst-free hydroamination and hydrothiolation of alkenes have been achieved in an aqueous medium. The anti-Markovnikov addition works efficiently in suspended water at room temperature and allows straightforward access to centhaquine, a drug used for the management of hypovolemic shocks in critically ill patients, and its derivatives. Various primary and secondary amines, thiols, and hydrazides were successfully reacted with a number of heteroaryl/aryl-alkenes. The scalability of the process has been demonstrated by synthesizing centhaquine at a 19.65 g scale. A comparative analysis of the present process with previous approaches has been provided on the basis of green chemistry metrics.

American Academy of Orthopaedic Surgeons Clinical Practice Guideline Summary of Surgical Management of Osteoarthritis of the Knee.

The Surgical Management of Osteoarthritis of the Knee Evidence-Based Clinical Practice Guideline is based on a systematic review of published studies for surgical management of osteoarthritis of the knee in skeletally mature patients. This guideline contains 16 recommendations and seven options to assist orthopaedic surgeons and all qualified physicians with the surgical management of patients with osteoarthritis of the knee based on the best current available evidence. It is also intended to serve as an information resource for professional healthcare practitioners and developers of practice guidelines and recommendations. In addition to providing pragmatic practice recommendations, this guideline also highlights gaps in the literature and informs areas for future research and quality measure development.

Palladium(II)-Catalyzed Decarboxylative Difunctionalization of Alkynoic Acids To Access (E)-ß-Sulfonylacrylamides and DFT Study.

A palladium(II)-catalyzed regio- and stereoselective difunctionalization of alkynoic acids has been achieved using sodium sulfinates and isocyanides to synthesize (E)-ß-sulfonylacrylamides. The reaction proceeds via decarboxylative isocyanide addition, followed by sulfonylation. This three-component process works well with aromatic, heteroaromatic, and aliphatic alkynoic acids with good functional group tolerance and excellent regio- and stereoselectivity. DFT calculations were carried out to explain the reaction mechanism and the stereoselective formation of (E)-ß-sulfonylacrylamides.

Regioselective Synthesis of Phenanthridines via Pd(II)-Catalyzed Annulative C(sp2)-H Activation.

A robust synthesis of phenanthridines has been described via Pd(II)-catalyzed domino C(sp2)-H activation/N-arylation using oxime esters with aryl acyl peroxides in a highly regioselective manner. This protocol is compatible with acetophenone as well as benzophenone-derived oxime esters and allows modular construction of functionalized phenanthridines with wide tolerance of electronic functionality. Further transformations were conducted to synthesize key building blocks, and control experiments were performed to understand the plausible reaction mechanism.

Multiepitope glycan based laser assisted fluorescent nanocomposite with dual functionality for sensing and ablation of Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) infection is becoming a severe health hazard and needs early diagnosis with high specificity. However, the non-specific binding of a biosensor is a challenge to the current bacterial detection system. For the first time, we chemically synthesized a galactose tripod (GT) as a P. aeruginosa-specific ligand. We conjugated GT to a photothermally active fluorescent nanocomposite (Au@SiO2-TCPP). P. aeruginosa can be detected using Au@SiO2-TCPP-GT, and additionally ablated as well using synergistic photothermal and photodynamic therapy. Molecular dynamics and simulation studies suggested better binding of GT (binding energy = -6.6 kcal mol-1) with P. aeruginosa lectin than that of galactose monopod (GM) (binding energy = -5.9 kcal mol-1). Furthermore, a binding study was extended to target P. aeruginosa, which has a galactose-binding carbohydrate recognition domain receptor. The colorimetric assay confirmed a limit of detection (LOD) of 104 CFU mL-1. We also looked into the photosensitizing property of Au@SiO2-TCPP-GT, which is stimulated by laser light (630 nm) and causes photoablation of bacteria by the formation of singlet oxygen in the surrounding media. The cytocompatibility of Au@SiO2-TCPP-GT was confirmed using cytotoxicity assays on mammalian cell lines. Moreover, Au@SiO2-TCPP-GT also showed non-hemolytic activity. Considering the toxicity analysis and efficacy of the synthesized glycan nanocomposites, these can be utilized for the treatment of P. aeruginosa-infected wounds. Furthermore, the current glycan nanocomposites can be used for bacterial detection and ablation of P. aeruginosa in contaminated food and water samples as well.

Stereodivergent Synthesis of (Z)-/(E)-ß-Sulfonylacrylamides via Tandem Difunctionalization of Alkynes with Sulfinates and Isocyanides.

Stereoselective difunctionalizations of the terminal and internal alkynes with various sulfinates and isocyanides have been achieved to prepare (Z)-/(E)-ß-sulfonylacrylamides. The (Z)-ß-sulfonylacrylamides were generated via a one-pot process that involves the reaction of terminal alkynes with sulfinates and isocyanides in the presence of iodine in sequential manner. The (E)-ß-sulfonylacrylamides were prepared in a two-step synthesis via palladium(II)-catalyzed addition of isocyanide to (E)-ß-iodovinylsulfones synthesized from alkynes.

Regioselective Synthesis of Functionalized Pyrrolo[1,2-a]pyrazine-3,6(2H,4H)-diones via Tandem Post-Ugi Cyclization and Gold(I)-Catalyzed Annulation.

A convenient synthesis of less explored pyrrolo[1,2-a]pyrazine-3,6(2H,4H)-diones is described in two steps from Ugi adducts. The method involves acid-mediated cyclization of Ugi adducts to form dihydropyrazinones followed by gold(I)-catalyzed regioselective annulation. The generality of the transformation was established by reacting a variety of substituted dihydropyrazinones under the optimized reaction conditions to form densely functionalized pyrrolo[1,2-a]pyrazine-3,6(2H,4H)-diones in good-to-excellent yields. It was also observed some of the acetone-derived Ugi adducts furnish 7-acyl-pyrroloimidazolones as a byproduct during TFA-mediated cyclization via alkyne-carbonyl metathesis and condensation.

Discovery of 2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one derivatives as possible antileishmanial agents.

A series of uniquely functionalized 2,3,-dihydro-1H-pyyrolo[3,4-b]quinolin-1-one derivatives were synthesized in one to two steps by utilizing a post-Ugi modification strategy and were evaluated for antileishmanial efficacy against visceral leishmaniasis (VL). Among the library compounds, compound 5m exhibited potential in vitro antileishmanial activity (CC50 = 65.11 µM, SI = 7.79, anti-amastigote IC50 = 8.36 µM). In vivo antileishmanial evaluation of 5m demonstrated 56.2% inhibition in liver and 61.1% inhibition in spleen parasite burden in infected Balb/c mice (12.5 mg kg-1, i.p.). In vitro pharmacokinetic study ascertained the stability of 5m in both simulated gastric fluid and simulated intestinal fluid. All the active compounds passed the PAINS filter and showed no toxicity in in silico predictions.

Copper-Catalyzed Oxidative [3 + 2]-Annulation of Quinoxalin-2(1H)-one with Oxime Esters toward Functionalized Pyrazolo[1,5-a]quinoxalin-4(5H)-ones as Opioid Receptor Modulators.

Pyrazolo[1,5-a]quinoxalin-4(5H)-one derivatives as novel opioid receptor modulators have been synthesized via copper-catalyzed oxidative [3 + 2]-annulation of quinoxalin-2(1H)-one and oxime-O-acetates. This hydrazine-free C-C and N-N bond formation strategy starts with the generation of C2N1 synthon using oxime acetate, which reacts in a [3 + 2] manner with quinoxalin-2(1H)-one, followed by oxidative aromatization. The synthesized compounds were tested against opioid receptors, of which eight compounds exhibited an antagonistic effect with EC50 < 5 µM at various opioid receptors. Molecular docking studies were performed to identify the binding of active pyrazolo[1,5-a]quinoxalin-4(5H)-one ligands with hKOR protein. Docking results indicated that compounds 3d and 3g participate in hydrogen bonding with the hydroxyl group of T111 of the active site pocket residue.

Nanoglycocluster based diagnostic platform for colorimetric detection of bacteria; A comparative study analysing the effect of AuNPs size, linker length, and glycan diversity.

Nanoglycoclusters, an upcoming class of functional nanomaterial are known to drive various processes like detection, imaging, targeting proteins, cells, and bacteria. Nanoglycoclusters are a type of nanomaterial functionalized with various glycans. The array of glycan in multiple copies enhances binding affinity with proteins. Selective and sensitive bacteria/lectin interactions using nanomaterials are an emerging area of research. The measurement of different ligand receptor interactions require sophisticated analytical tools that limit the application in biosensor domain. Recently, colorimetric biosensors gained importance in the field of the biosensor for the detection of bacteria/lectins. Herein we have demonstrated that different size of gold nanoparticles (AuNPs) along with various polyethylene glycol (PEG) linkers, functionalized with synthesized monopod and tripod of mannose and galactose that have different bacteria/lectins specificity. The newly synthesized nanoglycoclusters were able to discriminate between different lectins and bacteria. The aggregation of specific nanoglycocluster upon interaction with specific bacteria/lectins revealed that mannose monopod (MM) and mannose tripod (MT) are specific to Escherichia coli and concanavalin A (ConA) lectin, while galactose monopod (GM) and galactose tripod (GT) are specific to Pseudomonas aeruginosa and Peanut agglutinin (PNA) lectin. Further, the binding events depict the affinity of tripod glycans is more with respect to its corresponding monopod glycans. Our findings explored the potential of colorimetric sensing depending upon the size of AuNPs, linker length, specificity, along with glycans density to develop user friendly diagnostic system for the detection of bacteria.

Phase III, Randomized, Double-blind, Placebo controlled trial of Efficacy, Safety and Tolerability of Antiviral drug Umifenovir vs Standard care of therapy in non-severe COVID-19 patients.

OBJECTIVE: To test efficacy, safety and tolerability of Umifenovir in non-severe COVID-19 adult patients. METHODS: We carried out randomized, double-blind, placebo-controlled, multicenter, phase III trials involving adult (18-75 years), non-severe COVID19 patients, randomized 1:1 on placebo or Umifenovir (800 mg BID, maximum 14 days) respectively along with standard-of-care. The primary endpoint for Asymptotic-mild patients was time to nasopharyngeal swab RT-PCR test negativity. For Moderate patients, the average change in the ordinal scale from the baseline scores on the eight-point WHO ordinal scale was assessed. RESULTS: 132 patients were recruited between 3rd October to 28th April 2021, of which 9 discontinued due to various reasons. In Mild-asymptomatic patients (n=82), we found that 73% patients in the Umifenovir arm were RT-PCR negative, while 40% patients in the placebo arm were negative (P=0.004) on day 5. However, in the moderate group (n=41), the WHO scores for the Umifenovir arm was not statistically significant (P=0.125 on day 3), while it was statistically significant in the Mild-asymptomatic group (P=0.019 on day 5). CONCLUSION: Umifenovir meets the primary and secondary endpoint criteria and exhibits statistically significant efficacy for Mild-asymptomatic patients. It is efficacious, safe and well-tolerated at the tested dosage of 800mg BID, maximum 14 days.

[3 + 2]-Dipolar Cycloaddition of Aldehyde-Tethered Alkynamides and Trimethylsilyl Amino Esters: A Gateway to Uniquely Functionalized Polycyclic N-Heterocycles via Post-Ugi Functionalization.

An efficient method for the generation of uniquely functionalized pyrrolo-pyrrolizinones, pyrido-pyrrolizinones, and azepino-pyrrolizinones via [3 + 2]-dipolar cycloaddition is described. The method involves the synthesis of tethered alkynamides using Ugi condensation and oxidation that were subsequently subjected to a dipolar cycloaddition reaction with trimethylsilyl amino esters. Further transformations to demonstrate the utility of these scaffolds were also investigated.

Synthesis of ß- and γ-lactam fused dihydropyrazinones from Ugi adducts via a sequential ring construction strategy.

A modular approach for the construction of ß- and γ-lactam fused dihydropyrazinones from the readily available Ugi adducts has been described. The sequential construction of rings through base-mediated cycloisomerization followed by acid-mediated cyclization yielded ß-lactam fused dihydropyrazinones. However, the Ugi-derived dihydropyrazinones afforded γ-lactam fused dihydropyrazinones under base-mediated cycloisomerization. The regioselectivity in the cycloisomerization reactions is explained on the basis of ring-strain. Substrate scope, limitations and mechanistic investigations through DFT-calculations have been explored.

Indirect Carbon Emissions and Energy Consumption Model for Electric Vehicles: Indian Scenario.

The environment-friendly nature of E-vehicles (electric vehicles) coupled with higher energy efficiency has increased their popularity in the automotive industry. A detailed study has been conducted in this article to evaluate the role of the energy mix for electricity generation at the charging locations in secondary C emissions from E-vehicles. The E-vehicle market is booming in India. Evaluation of indirect C emissions was conducted for 3 energy mix scenarios in India, and the results showed that in the present energy mix scenario, E-vehicle emissions will be more than that of conventional-fuel-based vehicles. An energy consumption model for the E-vehicle was also developed in this article using MATLAB Simulink, by considering road slope and driving conditions as input parameters. The developed model was tested for 3 driving conditions, namely (i) Flat road at a constant speed, (ii) Extra Urban Driving Cycle (EUDC), and (iii) Real-time driving condition, to estimate the relation between the energy consumption pattern and the driving range with road slope. Simulation results showed variation in the driving range of the E-vehicles regarding input parameters like road slope and vehicle speed. Therefore, this model could serve as an effective tool for establishing charging stations at strategic locations. Integr Environ Assess Manag 2020;16:998-1007. © 2020 SETAC.

Construction of Highly Functionalized Piperazinones via Post-Ugi Cyclization and Diastereoselective Nucleophilic Addition.

A novel method for the generation of uniquely functionalized piperazinones by utilizing post-Ugi functionalization is described. The method involves an Ugi reaction with aminoacetaldehyde dimethyl acetal, followed by acid-mediated cyclization to generate the iminium precursor that was subjected to nucleophilic addition in a diastereoselective manner. The method was also employed to synthesize trans-dragmacidine C and praziquantel-like molecules.

Impact of Electric Vehicles on Indirect Carbon Emissions and the Role of Engine Posttreatment Emission Control Strategies.

Electricity generation in developing countries is dependent on fossil fuel-based thermal power plants, and the introduction of electric vehicles will only shift the threat of emissions from the operation stage to the energy generation stage. India is one of the developing countries in South Asia where fossil fuel-based power plants make major contributions to electricity generation. In this paper, a detailed review of the challenges faced by electric vehicles is discussed, and an analysis was conducted on the equivalent C emissions from electric vehicles by considering 3 scenarios in India: 1) current electricity generation, 2) power generation considering the installed capacity, and 3) Vision 2022. Based on these 3 scenarios, the main objectives of this work are to understand the potential of electric vehicles to reduce the overall C emissions after considering the indirect C emissions from electricity generation and to highlight the importance of emission control techniques. Experimental investigations of the conversion efficiency of diesel oxidation catalysis (DOC) systems have been conducted for comparative studies. The results of the analysis showed that the indirect C emissions from electric vehicles are higher than the C emissions from internal combustion engines for scenarios 1 and 2. In scenario 3, the C emissions from electric and fossil fuel-powered vehicles are found to be in the same range. The DOC system had an average conversion efficiency of 56% for hydrocarbons and 59% for particle number emissions. The posttreatment emission control systems in internal combustion engines will be the best possible solution, compared to electric vehicles, for reducing overall vehicular emissions until renewable energy sources have a major share in electricity generation. Integr Environ Assess Manag 2020;16:234-244. © 2019 SETAC.

A Comparative Synthetic Strategy Perspective on α-Amino Acid- and Non-Amino Acid-Derived Synthons towards Total Syntheses of Selected Natural Macrolides.

Macrocyclic alkaloids (macrolides) and cyclopeptides have an immense range of applications in drug discovery research because of their natural abundance and potential biological and physicochemical properties. Presently, more than 100 approved drugs or clinical drug candidates contain macrocyclic scaffolds as the biologically active component. This review provides an interesting perspective about the use of amino acid-derived chiral pools versus other methods derived from miscellaneous synthons towards the total synthesis of non-peptidic macrolides. The synthetic routes and the key strategies involved in the total syntheses of ten natural macrolides have been discussed. Both the amino acid-derived and non-amino acid-derived synthetic routes have been illustrated to present a comparative study between the two approaches.

Green synthesis of enantiopure quinoxaline alcohols using Daucus carota.

Green chemistry comprises a new approach in the synthesis of biologically active compounds using biocatalysts, thus diminishing the hazards for human health and environmental pollution. Asymmetric bioreduction is one of the most widely employed strategies in chemoenzymatic synthesis to produce enantiomerically pure chiral alcohols. The present study highlights the use biocatalyst Daucus carota for selective bioreduction of quinoxaline ketones 1a-6a to their corresponding optically pure alcohols 1b-6b in high yields (up to 84%) and good enantioselectivity (up to 98%). The absolute configuration of the chiral product (R)-1-(3-methyl 7-nitroquinoxalin-2-yl) ethan-1-ol 2b was confirmed by X-ray crystallography studies. The chiral R-configuration of the products obtained was confirmed by absolute configuration studies and was assigned following anti-Prelogs rule. Quinoxaline pharmacophores form a part of well-known potent drug molecules; hence, the chiral products were studied for determination of their molecular properties using SwissADME property analyser. All the chiral products show no Lipinski rule violations and are expected to have good oral bioavailability. As per the molecular properties prediction studies, the compound 6b (R)-1-(6,7-dichloro-3- methylquinoxalin-2-yl) ethanol is observed to show the best physicochemical properties to be a good lead molecule. Thus, the sustainable methodology was developed, and it confirms the synthesis of novel quinoxaline chiral alcohols in a simple, inexpensive, and eco-friendly condition using D carota.

An Efficient One-Pot Synthesis of Densely Functionalized Fused-Quinolines via Sequential Ugi4CC and Acid-Mediated Povarov-Type Reaction.

A divergent synthesis of fused-quinolines has been explored by performing Ugi four-component condensation and sulfuric acid promoted deprotection/Povarov-type reaction in one-pot. The process involves Ugi condensation of propiolic acids, aldehydes/ketones, aminoaldehyde acetals and isocyanides followed by sulfuric acid promoted deprotection and Povarov-type reaction with anilines in ethanol. This method enables straightforward access to the structurally diverse 2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-ones (DHPQ), 3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-ones (DHBN), and 2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinolin-1-ones (THAQ), starting from readily available starting materials.

BET inhibitors in cancer therapeutics: a patent review.

INTRODUCTION: Inhibition of Bromodomain and Extra Terminal (BET) proteins is an emerging approach for developing advanced cancer therapeutics. In 2015, at least thirty patents have been published for developing cancer chemotherapeutics by targeting BET. Currently there are seven small molecule BET inhibitors in various stages of clinical trials for the development of anti-cancer drugs. AREAS COVERED: Important patents focusing on development of BET inhibitors as potential cancer therapeutics published in 2015 have been covered. The reports are presented together with a review of the related structural chemical space. This review mainly focuses on the therapeutic applications, chemical class and structural modifications along with the molecules currently in clinical trials. EXPERT OPINION: BET sub-family proteins are one of the emerging targets to develop anti-cancer agents. Although many research groups have demonstrated the rationality of BET inhibition to combat cancer, a detailed molecular study needs to be performed to investigate the affected biological pathways. Selectivity among BET proteins should be kept in mind while developing BET inhibitors. In-silico molecular modelling studies can also provide valuable information for designing selective BET inhibitors towards anti-cancer drug discovery and development.