A novel multicomponent one-pot expeditious synthesis of highly functionalized and pharmaceutically fascinated pyranopyrazoles has been developed. This reaction occurs via tandem Knoevenagel condensation reaction of methyl aryl derivatives, 3-methyl pyrazolone and malononitrile in the presence of urea hydrogen peroxide under the physical grinding method. The present methodology offers several benefits such as available green and cheap starting materials, solvent-free, mild reaction conditions, high atom economy, eco-friendly standards, excellent yields and easy isolation of the products without column chromatographic separation.
Graphic abstractNumerical simulations are performed to investigate the breakup of air bubble in flow focusing configuration; the CLSVOF (coupled level set with volume of fluid) method is employed to track the interface, which allows a better identification of the liquid–gas interface via a function called level set. The CFD simulations showed that the velocity ratio, the interfacial tension, the outer channel diameter, the continuous phase viscosity, the orifice width and length play an important role in the determination of the air bubble’s size and shape. However, at low capillary number, increasing the flow velocity ratio gives a smaller bubble size in shorter time, while the increase in interfacial tension leads to a bigger bubble. Moreover, the carrier fluid is found to slightly affect the bubbling mechanism, while the smallest bubbles were obtained with the smallest orifice size. In addition, three breakup regimes are observed in this device: disc-bubble (DB), elongated bubble (EB) and the slug bubble (SB) regime flows. This work also demonstrates that the CLSVOF is an effective method to simulate the bubbles breakup in flow focusing geometry. In addition, a comparison of our computational simulations with available experimental results reveals reasonably good agreement.
Graphic abstractFukuyama reaction for the synthesis of multifunctional aldehydes, secondary amines and ketones has gained considerable importance in synthetic organic chemistry because of mild reaction conditions. The use of thioesters in both Fukuyama aldehydes and ketones synthesis is highly attractive for organic chemists as they are easily accessible from corresponding carboxylic acids. Fukuyama–Mitsunobu reaction utilizes 2-nitrobenzenesulfonyl (Ns) for the protection/activation/deprotection of primary amines to afford secondary amines in good yields and high enantioselectivities. This review presents recent synthetic developments and applications of Fukuyama reaction for the synthesis of aldehydes, secondary amines and ketones.
Graphic abstractThe c-Met tyrosine kinase plays an important role in human cancers. Preclinical studies demonstrated that c-Met is over-expressed, mutated and amplified in a variety of human tumor types and design of more potent c-Met inhibitors is a priority. In this study, 14 molecular dynamics simulations of potent type II c-Met inhibitors were run to resolve the critical interactions responsible for high affinity of ligands towards c-Met considering the essential flexibility of protein–ligand interactions. Residues Phe1223 and Tyr1159, involved in pi-pi interactions were recognized as the most effective residues in the ligand binding in terms of binding free energies. Hydrogen bond interaction with Met1160 was also found necessary for effective type II ligand binding to c-Met.
Graphic abstractThe azomethine ylides are generally used in 1,3-dipolar cycloadditions with various dipolarophiles. In this work, a new and diverse route has been developed for the azomethine ylides, for synthesis of novel pyrrole derivatives. The azomethine ylide, produced via C–H activation of unreactive C(sp3)–H bond of 2-methylquinoline, by molecular iodine, in the presence of pyridine. Herein, we represent novel pyrrole derivatives, synthesized from the reaction of pyridinium ylide with olefins, which formed via a reaction of isatin, dialkyl acetylenedicarboxylate derivatives and pyridine as a base in moderate to excellent yields. Various features of this cyclization, discussed.
Graphic abstractMerocyanine dye based fluorescent organic compound has been synthesized for the detection of glutamine. The probe showed remarkable fluorescent intensity with glutamine through ICT (Intermolecular Charge Transfer Mechanism). Hence, it is tested for the detection of glutamine using colorimetric and fluorimetric techniques in physiological and neutral pH (7.2). Under optimized experimental conditions, the probe detects glutamine selectively among other interfering biomolecules. The probe has showed a LOD (lower limit of detection) of 9.6?×?10–8 mol/L at the linear range 0–180 µM towards glutamine. The practical application of the probe is successfully tested in human biofluids.
Graphical abstractA new series of (?±)-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)(phenyl)methanones were efficiently synthesized starting from 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol 1, acetyl acetone 2, various aromatic and heterocyclic aldehydes 3 and phenacyl bromides 4. All the newly synthesized compounds were tested for their antiviral and antitumoral activity. It was shown that subtle structural variations on the phenyl moiety allowed to tune biological properties toward antiviral or antitumoral activity. Mode-of-action studies revealed that the antitumoral activity was due to inhibition of tubulin polymerization.
Graphic abstractRapid and onsite detection of nitroaromatic explosive 2,4,6-trinitrotoluene (TNT) is very crucial for the safety and security of human life as well as for the environment. In this present work, we demonstrate the feasibility for employing Folic Acid (FA) as a fluorescent as well as a colorimetric probe for the detection of TNT. This probe was synthesized by a simple one-step process. The developed probe shows an emission maximum at 490 nm upon excitation at 420 nm. On adding TNT, the fluorescence of the FA probe is quenched. Also, it shows a good selectivity towards TNT over other similar organic compounds such as 4-nitrophenol (4-NP), 2,4-dinitrophenol (2,4-DNP) and picric acid (PA). The limit of detection (LoD) of TNT was found to be 1.9398 µM. Colorimetric detection was conducted and paper strip assay was developed for the practical applications.
Graphical AbstractFluorescent carbon dots (CDs) have acquired growing interest from different areas over decades. Their fascinating property of tunable fluorescence by changing the excitation wavelength has attracted researchers worldwide. Understanding the mechanisms behind fluorescence is of great importance, as they help with the synthesis and applications, significantly when narrowed down to applications with color-tunable mechanisms. But, due to a lack of practical and theoretical information, the fluorescence mechanisms of CDs remain unknown, preventing the production of CDs with desired optical qualities. This review focuses on the PL mechanisms of carbon dots. The quantum confinement effect determined the carbon core, the surface and edge states determined by various surface defects and the connected functional/chemical groups on the surface/edges, the molecular state solely determined the fluorophores in the interior or surface of the CDs, and the Crosslink Enhanced Emission Effect are the currently confirmed PL mechanisms.
Graphic AbstractIn the current scenario, flow chemistry is emerging as a significant technology in the field of organic synthesis. This miniaturized protocol including microreactors facilitates excellent heat transfer, low solvent wastage, lesser reaction time, a safer environment for reagent handling and appreciable yields of desired products. Thus, this “enabling technology” has a great scope in the synthesis and preparation of a variety of heterocycles that require toxic reagents as starting materials. This review discusses the recent advances (2020–2021) in continuous flow strategy for synthesis and derivatization of variety of heterocyclic entities, of different ring size, using different approaches. This also highlights the advantages of different combined techniques like Microwave assisted heating, electrochemical flow cell, LED light source, NMR and FT-IR analysis, etc., that enables utilization of various mechanisms and real-time monitoring of reactions leading to improved results.
Graphic abstractThe present study aimed to develop a carbon dots-based fluorescence (FL) sensor that can detect more than one pollutant simultaneously in the same aqueous solution. The carbon dots-based FL sensor has been prepared by employing a facile hydrothermal method using citric acid and ethylenediamine as precursors. The as-synthesized CDs displayed excellent hydrophilicity, good photostability and blue fluorescence under UV light. They have been used as an efficient “turn-off” FL sensor for dual sensing of Fe3+ and Hg2+ ions in an aqueous medium with high sensitivity and selectivity through a static quenching mechanism. The lowest limit of detection (LOD) for Fe3+ and Hg2+ ions was found to be 0.406 µM and 0.934 µM, respectively over the concentration range of 0-50 µM. Therefore, the present work provides an effective strategy to monitor the concentration of Fe3+ and Hg2+ ions simultaneously in an aqueous medium using environment-friendly CDs.
Graphical AbstractIn this study, water extract of Spinacia oleracea leaves was used for the synthesis of Fe3O4/TiO2/MWCNTs magnetic nanocomposites and high performance of this catalyst was confirmed by employing it in the solvent-free multicomponent reactions of anilines, oxalyl chloride, diamines or hydroxyamines, electron-deficient acetylenic ester, α-haloketones and Et3N at room temperature for the generation of new spiropyrroloindoles in high yields. This catalyst could be utilized several times and has a significant role in the yield of product. The synthesized spiropyrroloindoles have NH and OH group in their structure and for this reason have good antioxidant activity. Also, by employing Gram-positive and Gram-negative bacteria and the disk diffusion procedure confirmed the antimicrobial effect of some spiropyrroloindole derivatives. The results showed that synthesized spiropyrroloindoles prevented the bacterial growth. This used process for preparation of new spiropyrroloindoles has some improvements such as low reaction time, product with high yields, and simple separation of catalyst and products.
Graphical abstractA novel nitrogen doped and surface functionalized fluorescent CDs (T1) was synthesized by one-step and green hydrothermal method, which exhibits a satisfactory fluorescence quantum yield and a series of admirable features such as good aqueous solubility, narrow particle size distribution, resistance to photobleaching as well as excitation-dependent behavior. Benefitting from above merits, T1 can be employed to serve as an outstanding sensing platform for sensitive and accurate detection of ClO– by remarkable fluorescence “on–off” process with rapid and anti-interference. More notably, the good biocompatibility and photostability can ensure enormous bioimaging potential and successful application of T1 in monitoring of exogenous ClO– in MG-63 cells. Meanwhile, T1 can also be regarded as a filter paper sensor providing a convenient and efficient analyzing technology for monitoring of free residual chlorine in practical environmental samples. All these results demonstrate that there exists promising possibility for practical applications of T1 in bioimaging systems and environmental monitoring.
Graphical abstractThe deeper understanding of metastasis phenomenon and detection of drug targets could be a potential approach to minimize cancer mortality. In this study, attempts were taken to unmask novel therapeutics to prevent metastasis and cancer progression. Initially, we explored the physiochemical, structural and functional insights of three metastasis tumor antigens (MTAs) and evaluated some plant-based bioactive compounds as potent MTA inhibitors. From 50 plant metabolites screened, isoflavone, gingerol, citronellal and asiatic acid showed maximum binding affinity with all three MTA proteins. The ADME analysis detected no undesirable toxicity that could reduce the drug likeness properties of top plant metabolites. Moreover, molecular dynamics studies revealed that the complexes were stable and showed minimum fluctuation at molecular level. We further performed ligand-based virtual screening to identify similar drug molecules using a large collection of 376,342 compounds from DrugBank. The results suggested that several structural analogs (e.g., tramadol, nabumetone, DGLA and hydrocortisone) may act as agonist to block the MTA proteins and inhibit cancer progression at early stage. The study could be useful to develop effective medications against cancer metastasis in future. Due to encouraging results, we highly recommend further in vitro and in vivo trials for the experimental validation of the findings.
Graphic abstractA series of amino acid-based Schiff bases have been synthesized using a facile condensation between benzil (a diketone) and amino acid in the presence of a base. The formation of Schiff base compounds has been ensured by elemental analysis, FT-IR, 1H-NMR, 13C-NMR and UV–Vis. spectra. Density Functional Theory (DFT) calculations have been explored in order to get intuition into the molecular structure and chemical reactivity of the compounds. The DFT, optimized structure of the compounds, has been used to attain the molecular docking studies with DNA structure to find the favorable mode of interaction. In silico ADME/Tox profile of the compounds has been predicted using pkCSM web tools, exhibiting suitable values of absorption, distribution, and metabolism. These obtained parameters are connected to bioavailability. In addition, toxicity, skin sensitization and cardiotoxicity (hERG) analysis have been performed for evaluating the drug-like character of the prepared Schiff bases. The findings obtained from this study may find applications in the field focusing on the production of efficient and harmless pharmacological drugs.
Graphical abstractThe novel coronavirus disease (COVID-19), which emerged in Wuhan, China, is continuously spreading worldwide, creating a huge burden on public health and economy. Ayurveda, the oldest healing schema of Traditional Indian Medicinal (TIM) system, is considered as a promising CAM therapy to combat various diseases/ disorders. To explore the regulatory mechanisms of 3038 Ayurvedic herbs (AHs) against SARS-CoV-2, in this study, multi-targeting and synergistic actions of constituent 34,472 phytochemicals (APCs) are investigated using a comprehensive approach comprising of network pharmacology and molecular docking. Immunomodulatory prospects of antiviral drug-alike potentially effective phytochemicals (PEPs) are presented as a special case study, highlighting the importance of 6 AHs in eliciting the antiviral immunity. By evaluating binding affinity of 292 PEPs against 24 SARS-CoV-2 proteins, we develop and analyze a high-confidence “bi-regulatory network” of 115 PEPs having ability to regulate protein targets in both virus and its host human system. Furthermore, mechanistic actions of PEPs against cardiovascular complications, diabetes mellitus and hypertension are also investigated to address the regulatory potential of AHs in dealing with COVID-19-associated metabolic comorbidities. The study further reports 12 PEPs as promising source of COVID-19 comorbidity regulators.
Graphical abstractOptimization and re-optimization of bioactive molecules using in silico methods have found application in the design of more active ones. Herein, we applied a pharmacophore modeling approach to screen potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) aimed at Alzheimer's disease (AD) treatment. The investigation entails molecular dynamics simulation, docking, pharmacophore modeling, drug-like screening, and binding energy analysis. We prepared a pharmacophore model from approved inhibitors of AChE and BuChE to predict the crucial moieties required for optimum molecular interaction with these proteins. The obtained pharmacophore model, used for database screening via some critical criteria, showed 229 hit molecules. Further analyses showed 42 likely dual inhibitors of AChE/BuChE with drug-like and pharmacokinetics properties the same as the approved cholinesterase inhibitors. Finally, we identified 14 dual molecules with improved potentials over the existing inhibitors and simulated ZINC92385797 bound to human AChE and BuChE structure after noticing that these 14 molecules are similar. The selected compound maintained relative stability at the active sites of both proteins over 120 ns simulation. Our integrated protocols showed the pertinent recipes of anti-AD drug design through the in silico pipeline.
Graphical abstractThe bioreductive enzymes typically upregulated in hypoxic tumor cells can be targeted for developing diagnostic and drug delivery applications. In this study, a new fluorescent probe 4?(6?nitro?1,3?dioxo?1H?benzo[de]isoquinolin?2(3H)?yl)benzaldehyde (NIB) based on a nitronaphthalimide skeleton that could respond to nitroreductase (NTR) overexpressed in hypoxic tumors is designed and its application in imaging tumor hypoxia is demonstrated. The docking studies revealed favourable interactions of NIB with the binding pocket of NTR-Escherichia coli. NIB, which is synthesized through a simple and single step imidation of 4?nitro?1,8?naphthalic anhydride displayed excellent reducible capacity under hypoxic conditions as evidenced from cyclic voltammetry investigations. The fluorescence measurements confirmed the formation of identical products (NIB-red) during chemical as well as NTR?aided enzymatic reduction in the presence of NADH. The potential fluorescence imaging of hypoxia based on NTR-mediated reduction of NIB is confirmed using in-vitro cell culture experiments using human breast cancer (MCF?7) cells, which displayed a significant change in the fluorescence colour and intensity at low NIB concentration within a short incubation period in hypoxic conditions.
Graphical abstractNonionic surfactant vesicles (Niosomes) were prepared using polyoxyethylene alkyl ether (Brij 58).The impact of variation of the Brij: cholesterol molar ratio on the niosomal structure was studied. Fluorescence studies performed with the membrane probe 1,6-Diphenyl-1,3,5-triene (DPH) gave important insight on the bilayer integrity of the niosomes in response to environmental perturbations. The aim of the work being assessment of the efficacy of the niosomes as “drug release vehicles”, release studies were performed with a xanthene dye Carboxyfluorescein (CF). Further, the vesicles were used as nanoreactors for the synthesis of gold nanoparticles (GNPs) as it is often useful to house nanoparticles in biological /biomimicking environments. Stable, spherical GNPs of diameter 6–10 nm were formed in these vesicles. As the vesicular bilayer mimics the cell membrane, the present work is relevant to the use of the GNPs for diagnostic and therapeutic purpose. It has also been established that fluorescence resonance energy transfer (FRET) effectively occurs between DPH and CF in the niosomes. The FRET studies provide important insight on the location of dyes within the vesicles thus indicating the prospective applications of this fluorescence technique for tracking the location of probes in biomimicking systems which maybe extrapolated to in vivo biological systems in future.
Graphical AbstractWe have demonstrated a unique approach to alter the aqueous pool size of an AOT/n-heptane/water reverse micellar system. A positively charged dye Rhodamine B (RhB) and negatively charged Rose Bengal (RB) were incorporated in the reverse micellar pool to investigate the effect of electrostatic interactions and stacking effects among the dye molecules on the AOT/n-heptane/water interface. Dynamic light scattering revealed increase in reverse micellar pool size in presence of positively charged dye aggregates at the oil–water interface. However, less expansion was observed in presence of negatively charged dye aggregates (RB). This confirms the role of electrostatic interaction in modulating the hydrodynamic radius. A head-to-tail type of stacking of RhB molecules at the interface favors this expansion. The differences in stacking of the two dyes inside the reverse micelles and their torsional mobility indicated the role of the reverse micellar interface and H-bonding ability of the microenvironment on dye aggregation. Conductivity measurements demonstrated a significant drop in percolation temperature of the reverse micellar system in presence of dye aggregates. This confirms the effect of dye aggregation and electrostatic interaction on such expansion. This strategy can be exploited for solubilizing greater amounts and a wider variety of drug molecules in microemulsions.
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