PCy3-assisted Ag(I)-catalyzed click reaction for regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles at room temperature.

An approach towards Cu-free click chemistry has been developed in this work. Silver-catalyzed PCy3-ligand-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles at room temperature has been developed. Regioselectivity of the reaction was confirmed from the results of single-crystal X-ray diffraction (SC-XRD) of one of the products. SC-XRD of ex situ-generated Ag-PCy3 complex helped us propose a plausible mechanism for the reaction. This reaction was indicated to exhibit a catalytic activity level similar to that for the in situ-generated complex. The methodology was found to work well with benzyl azides, phenyl azides, terminal alkynes and internal alkynes in aqueous medium. The one-pot three-component reaction leading to 1,2,3-triazole synthesis also proceeded well.

Recent Advances in Metal Free Synthesis of N-unsubstituted 1,2,3-Triazoles.

1, 2, 3-triazoles display enormous applications in the extensive fields of chemistry such as pharmaceuticals, ligands, conjectures, etc. Among these classes of compounds, the N-unsubstituted triazole emerges as a potent applicant for various fields of chemistry and therefore synthetic procedures for this molecular scaffold possess certain importance. Moreover, from an environmental perspective, metal-free organic synthesis gains tremendous attention as most of the metals are persistent in nature. In this review, we are going to discuss only the metal-free synthetic routes for the construction of N-unsubstituted 1,2,3-triazoles reported during the last decade.

Room temperature ligand-free Cu2O-H2O2 catalyzed tandem oxidative synthesis of quinazoline-4(3H)-one and quinazoline derivatives.

An efficient and simple copper catalytic system has been developed for the synthesis of medicinally important 2-substituted quinazoline-4(3H)-ones from 2-aminobenzonitrile and benzyl alcohol derivatives and additionally 2-substituted quinazolines from 2-aminobenzylamine and benzaldehyde derivatives. Mild oxidant H2O2 was utilized, providing excellent product yields. The molecular structure of one of the compounds was substantiated through SC-XRD. The versatility of the protocol was demonstrated through gram-scale syntheses.

Removal of As(III)/As(V) from aqueous solution using newly developed thiosalicylic acid coated magnetite [TSA@Fe3O4] nanoparticles.

The aim of this study was to develop an affordable adsorption methodology for removal of As(III)/As(V) from contaminated water. Herein, novel adsorbent TSA@Fe3O4 nanoparticles (NPs) were synthesized by decorating thiosalicylic acid (TSA) on magnetite nanoparticles (Fe3O4 NPs) and employed for removal of As(III)/As(V) species from artificially contaminated natural water systems. TSA@Fe3O4 NPs demonstrated excellent adsorption efficiency (AE) and 98% of As(V) and 93% of As(III) was removed at optimized experimental conditions. The adsorption kinetic and equilibrium isotherm studies were conducted preferentially for As(III) adsorption. Adsorption followed the pseudo-second-order kinetic (R2 = 99%) and adsorption data fitted well in Langmuir isotherm model (R2 = 99%) and maximum adsorption capacity (Qmax = 34.1 mg/g) was calculated for 5 mg/L of As(III) by using 10 mg of TSA@Fe3O4 NPs. The effect of pH, contact time, adsorption dosages, and competitive anions was also examined to identify optimum experimental conditions. The adsorbent was characterized by advanced instrumental techniques to investigate the physicochemical properties and stability of NPs. To comprehend the interactions of As(III) species with adsorbent NPs, NPs were analyzed using XPS and Raman spectroscopy techniques. Both the techniques confirmed that As(III) and As(V) species present simultaneously on adsorbent surface. The TSA@Fe3O4 was regenerated using 0.1 M NaOH. The findings of this study suggested that TSA@Fe3O4 NPs could be considered a potential adsorbent for effective remediation of As(III) and As(V) from contaminated natural water systems.

[DDQM][HSO4]/TBHP as a Multifunctional Catalyst for the Metal Free Tandem Oxidative Synthesis of 2-Phenylquinazolin-4(3H)-ones.

A bifunctional ionic liquid (IL) [DDQM][HSO4] has been designed and explored as a three-way catalyst for the synthesis of 2-phenylquinazolin-4(3H)-ones from anthranilamide and benzyl alcohol in 3.5 min incorporating microwave irradiation. Photochemically the reaction proceeds for 4 h at room temperature and thermally for 8 h at 120 °C. Further IL-assisted metal, solvent, and base free in situ oxidation of benzyl alcohols to aldehydes shows its task specificity. The multifunctionality of the IL was reestablished with the synthesis of two Wnt pathway antagonists.

Design and Synthesis of Quinazolinone-Triazole Hybrids as Potent Anti-Tubercular Agents.

A straightforward and convenient methodology has been developed for the reaction of 2-aminobenzamide and carbonyls affording 2,3-dihydroquinazolin-4(1H)-ones using aqueous solution of [C12Py][FeCl3Br]. The developed methodology was applied for the synthesis of 25 quinazolinone-triazole hybrids followed by evaluation of their in vitro anti-tubercular (TB) activity. The results revealed that 8 quinazolinone-triazole hybrids displayed promising activity having MIC values of 0.78-12.5 µg/mL. The compound 3if with MIC 0.78 µg/mL was found to be the lead nominee among the series, better than Ethambutol, a first line anti-TB drug and comparable with Rifampicin. The active compounds with MIC values ≤ 6.25 µg/mL were subjected to in vitro cytotoxicity and found nontoxic. In drug-drug interaction, compounds 3ia and 3ii interacted synergistically with all the three anti-TB drugs, INH, RFM, and EMB. Other 3 compounds interacted either in synergistic or additive manners. Important information on the binding interaction of the target compounds with the active sites of 1DQY Antigen 85C from Mycobacterium tuberculosis and Enoyl acyl carrier protein reductase (InhA) enzymes was obtained from molecular docking studies. Screening of the drug-likeness properties and bioactivity score indicates that synthesized molecules could be projected as potential drug candidates. Based on the current study, quinazolinone-triazole hybrids framework can be useful in drug development for TB.

Preparation of a novel environmentally friendly hydrophobic deep eutectic solvent ChCl-THY and its application in removal of hexavalent chromium from aqueous solution.

A liquid-liquid extraction methodology was developed for the removal of Cr(VI) from contaminated water using a novel green hydrophobic deep eutectic solvent (DES) as an efficient sole extracting agent. The hydrophobic DES was obtained by mixing choline chloride and thymol in 1:4 molar ratio at 70°C for 10 min and was denoted as ChCl-THY(1:4). The ChCl-THY(1:4) works efficiently for removal of high (20 mg/L) and low (500 µg/L) concentration of Cr(VI) from artificially contaminated natural water with >95% extraction efficiency (E%) at optimized reaction conditions (pH 2-6, 40°C). The DES was characterized by 1 H NMR and FTIR spectroscopy, and the data suggest that interaction occurs between Cl- ion of choline chloride and H atoms of thymol molecules. Physicochemical properties such as density, melting point, moisture, and solubility were studied and discussed. Herein, no sharp melting point was observed for ChCl-THY(1:4) in DSC curve. DES was regenerated using 0.1 M NaOH as stripping agent, and 50%-60% extraction efficiency could be attained in the next cycle. A plausible mechanism of interaction between Cr(VI) species and DES was also explored with the help of FTIR spectroscopy. PRACTITIONER POINTS: A novel hydrophobic DES (ChCl-THY) is prepared by mixing choline chloride and thymol at 1:4 molar ratio. ChCl-THY(1:4) is employed for the first time as sole extracting agent to remove the Cr(VI) from contaminated aqueous solution. >95% extraction efficiency was achieved by ChCl-THY(1:4) in natural water conditions at µg/L and mg/L level of contamination. Both the component used to prepare the DES are naturally abundant; hence, DES is not toxic for biota. The element present in natural water did not show any interference with extraction of Cr(VI).

Versatile precursor-dependent copper sulfide nanoparticles as a multifunctional catalyst for the photocatalytic removal of water pollutants and the synthesis of aromatic aldehydes and NH-triazoles.

A series of copper sulfide (CS) nanoparticles (NPs) were synthesized just by varying the amount of the sulfur precursor and have been explored for the first time as a three-way heterogeneous catalyst in the photocatalytic oxidation of a number of aromatic alcohols, photocatalytic degradation and the reduction of water pollutants, and the facile synthesis of pharmaceutically important moiety 4-aryl-NH-1,2,3-triazoles. The green and novel protocol was successfully developed for the synthesis of covellite (CuS, Cu2+) and the covellite-villamaninite (CuS-CuS2) (copper in Cu2+, Cu1+) phases of copper sulfide, employing EDTA both as the chelating and capping agent via a simple precipitation method at room temperature using water as the solvent. A blue shift in the absorption spectra and band gap in the range of 2.02-2.07 eV prompted the investigation of the as-synthesized CS nanoparticles as the photocatalyst under visible light irradiation. In the absence of any oxidizing or reducing agent, covellite CuS nanoparticles showed the highest photocatalytic efficiency for the degradation of methylene blue (MB) and the reduction of carcinogenic and mutagenic Cr(vi) to non-toxic Cr(iii). Interestingly, the mixed phase of CS (CuS-CuS2), where Cu is present in both +1 and +2 oxidation states, was found to be the most efficient catalyst compared to CuS toward the visible light-mediated selective oxidation of various benzyl alcohols to their corresponding aldehydes. However, in the synthesis of substituted NH-1,2,3-triazoles, single-phase CS nanoparticles (i.e., CuS) provided the best catalytic result. This significant outcome certainly opens up the scope for realizing the present demand of low-cost multifunctional semiconductor nano-materials, which will have a huge impact on the economy and environment when they show more than two potential applications.

Advances in developing small molecule SARS 3CLpro inhibitors as potential remedy for corona virus infection.

Originated in China, coronavirus disease 2019 (COVID-19)- the highly contagious and fatal respiratory disease caused by SARS-CoV-2 has already infected more than 29 million people worldwide with a mortality rate of 3.15% (according to World Health Organization's (WHO's) report, September 2020) and the number is exponentially increasing with no remedy whatsoever discovered till date. But it is not the first time this infectious viral disease has appeared, in 2002 SARS-CoV infected more than 8000 individuals of which 9.6% patients died and in 2012 approximately 35% of MERS-CoV infected patients have died. Literature reports indicate that a chymotripsin-like cystein protease (3CLpro) is responsible for the replication of the virus inside the host cell. Therefore, design and synthesis of 3CLpro inhibitor molecules play a great impact in drug development against this COVID-19 pandemic. In this review, we are discussing the anti-SARS effect of some small molecule 3CLpro inhibitors with their various binding modes of interactions to the target protein.

A Simple Work-Up-free, Solvent-free Approach to Novel Amino Acid Linked 1,4-Disubstituted 1,2,3-Triazoles as Potent Antituberculosis Agents.

An efficient, green strategy for synthesis of 1,4-disubstituted-1,2,3-triazole has been developed using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) acetate ionic liquid (200 µL) under a solvent- and external base-free condition. This protocol is further applied for the synthesis of novel amino acid containing 1,2,3-triazole molecules, which were then evaluated for potential antitubercular and antibacterial activities. Cytotoxicity assay of the compounds was also performed. In silico analysis of the promising compounds selected through experimental analysis was thereafter performed for visualizing molecular interactions and predicting binding affinities between our synthesized molecules, which exhibited good activity in experimental studies and the DprE1 target protein of Mycobacterium tuberculosis. Durg-likeness studies also show potential of the synthesized molecules as drug candidates.

Recent advances in the synthesis of Quinazoline analogues as Anti-TB agents.

Quinazoline analogues are one of the important nitrogen containing heterocycles that have significant bioactivity as well as found in a plethora of natural products. Tuberculosis is one of the serious universal health threats caused by Mycobacteriumtuberculosis (MTB) and primarily affects the lungs. Due to their significant bioactivity and natural occurrences of quinazolines, researchers are trying to synthesize new quinazoline analogues which may have significant potency against tuberculosis. This particular review summarizes recent development of different types of quinazoline bearing analogues as anti-tubercular (anti-TB) agents and their synthesis with structure-activity relationship.

Tetraamminecopper(II) Sulfate Monohydrate in Oxidative Azide-olefin Cyclo-addition and Three-component Click Reaction.

INTRODUCTION: An effective Cu-complex, [Cu(NH3)4SO4 • H2O] was prepared conveniently from the inexpensive and easily available starting reagents in a simple route. MATERIALS AND METHODS: Excellent reactivity of the catalyst was observed towards two competent clickcycloadditions: (a) oxidative cycloaddition of azides with electron-poor olefins and (b) one-pot cycloaddition of alkynes with boronic acid and sodium azide under "click-appropriate" conditions. RESULTS: No external oxidant, short reaction time, high product yield, wide substrate scope, and aqueous solvent media make the azide-olefin cycloaddition approach a greener route in contrast to the reported methods. CONCLUSION: The newly developed mild, green, and rapid three-component strategy shows product diversity with superb yields at room temperature by reducing the synthetic process time and using only 1 mol % of the synthesized copper complex.

A Low-Cost, Well-Designed Catalytic System Derived from Household Waste "Egg Shell": Applications in Organic Transformations.

A waste feedstock-derived economical basic alternative catalyst is described in this review. Eggshell is one of the household wastes created in tons of weight daily. Therefore, in order to reduce the environmental pollution-related problems, its use in heterogeneous catalysis can be attributed as a great contribution for the chemical and material science society to carry out several known reactions and for the much-needed energy alternative biodiesel production as low-cost catalytic system. Keeping green chemistry in mind, industrial use of these catalysts may also reduce the use of other traditionally used high-cost chemical catalytic systems.

Synthesis and biological evaluation of novel 1,2,3-triazole derivatives as anti-tubercular agents.

A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular 'click chemistry' approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78µg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages). Molecular docking of the target compounds into the active site of DprE1 (Decaprenylphosphoryl-ß-d-ribose-2'-epimerase) enzyme revealed noteworthy information on the plausible binding interactions.

Identification of novel human renin inhibitors through a combined approach of pharmacophore modelling, molecular DFT analysis and in silico screening.

Renin is an aspartyl protease of the renin-angiotensin system (RAS) and the first enzyme of the biochemical pathway for the generation of angiotensin II - a potent vasoconstrictor involved in the maintenance of cardiovascular homeostasis and the regulation of blood pressure. High enzymatic specificity of renin and its involvement in the catalysis of the rate-limiting step of the RAS hormone system qualify it as a good target for inhibition of hypertension and other associated diseases. Ligand-based pharmacophore model (Hypo1) was generated from a training set of 24 compounds with renin inhibitory activity. The best hypothesis consisted of one Hydrogen Bond Acceptor (HBA), three Hydrophobic Aliphatic (HY-Al) and one Ring Aromatic (AR) features. This well-validated pharmacophore hypothesis (correlation coefficient 0.95) was further utilized as a 3D query to screen database compounds, which included structures from two natural product repositories. These screened compounds were further analyzed for drug-likeness and ADMET studies. The compounds which satisfied the qualifying criteria were then subjected to molecular docking and Density Functional Theory (DFT) analysis in order to discern their atomic level interactions at the active site of the 3D structure of rennin. The pharmacophore-based modelling that has been used to generate the novel findings of the present study would be an avant-garde approach towards the development of potent inhibitors of renin.

Novel butyrylcholinesterase inhibitors through pharmacophore modeling, virtual screening and DFT-based approaches along-with design of bioisosterism-based analogues.

Ligand and structure-based pharmacophore models were used to identify the important chemical features of butyrylcholinesterase (BChE) inhibitors. A training set of 16 known structurally diverse compounds with a wide range of inhibitory activity against BChE was used to develop a quantitative ligand-based pharmacophore (Hypo1) model to identify novel BChE inhibitors in virtual screening databases. A structure-based pharmacophore hypothesis (Phar1) was also developed with the ligand-binding site of BChE in consideration. Further, the models were validated using test set, Fisher's Randomization and Leave-one-out validation methods. Well-validated pharmacophore hypotheses were further used as 3D queries in virtual screening and 430 compounds were finally selected for molecular docking analysis. Subsequently, ADMET, DFT and chemical similarity search were employed to narrow down on seven compounds as potential drug candidates. Analogues of the best hit were further developed through a bioisosterism-guided approach to further generate a library of potential BChE inhibitors.

3D pharmacophore-based virtual screening, docking and density functional theory approach towards the discovery of novel human epidermal growth factor receptor-2 (HER2) inhibitors.

Human epidermal growth factor receptor 2 (HER2) is one of the four members of the epidermal growth factor receptor (EGFR) family and is expressed to facilitate cellular proliferation across various tissue types. Therapies targeting HER2, which is a transmembrane glycoprotein with tyrosine kinase activity, offer promising prospects especially in breast and gastric/gastroesophageal cancer patients. Persistence of both primary and acquired resistance to various routine drugs/antibodies is a disappointing outcome in the treatment of many HER2 positive cancer patients and is a challenge that requires formulation of new and improved strategies to overcome the same. Identification of novel HER2 inhibitors with improved therapeutics index was performed with a highly correlating (r=0.975) ligand-based pharmacophore model (Hypo1) in this study. Hypo1 was generated from a training set of 22 compounds with HER2 inhibitory activity and this well-validated hypothesis was subsequently used as a 3D query to screen compounds in a total of four databases of which two were natural product databases. Further, these compounds were analyzed for compliance with Veber's drug-likeness rule and optimum ADMET parameters. The selected compounds were then subjected to molecular docking and Density Functional Theory (DFT) analysis to discern their molecular interactions at the active site of HER2. The findings thus presented would be an important starting point towards the development of novel HER2 inhibitors using well-validated computational techniques.

An In Silico Approach for Identification of Potential Anti-Mycobacterial Targets of Vasicine and Related Chemical Compounds.

Tuberculosis (TB) is known to mankind as one of the most pervasive and persistent of diseases since the early days of civilization. The growing resistance of the causative pathogen Mycobacterium tuberculosis to the standard drug regimen for TB poses further difficulty in its treatment and control. Screening of novel plant-derived compounds with promising anti-tubercular activity has been cited as a prospective route for new anti-tubercular drug discovery and design. Justicia adhatoda L. is a perennial evergreen shrub which is widely mentioned in scientific literature on account of its potent anti-mycobacterial properties. In the present study, we have employed a series of computational methodologies to reveal the probable molecular interactions of vasicine, the principal alkaloid of Justicia adhatoda L., and two of its close natural derivatives- vasicinone and deoxyvasicine, with certain biological targets in M. tuberculosis. Targets were identified from literature and through a reverse Pharmacophore-based approach. Subsequent comparative molecular docking to identify the best ligand-target interactions revealed Antigen 85C of M. tuberculosis as the most potent biological target of vasicine on the basis of optimum molecular docking values. A chemogenomics approach was also employed to validate the molecular interactions between the same class of chemical compounds as vasicine and Antigen 85C. Further, a library of structural analogs of vasicine was created by bioiosterism-based drug design to identify structural analogs with better inhibitory potential against Antigen 85C.

Pd(OAc)2 in WERSA: a novel green catalytic system for Suzuki-Miyaura cross-coupling reactions at room temperature.

A recyclable/reusable Pd(OAc)2 catalysed Suzuki-Miyaura cross-coupling reaction condition in neat "Water Extract of Rice Straw Ash" (WERSA) at room temperature was developed. This is a ligand/base/promoter/additive/organic media free protocol.