Letters in Organic Chemistry - Online First

Pyrazole and phthalazine moieties receive special attention in the pharmaceutical and medical industries as essential ingredients in certain drugs. It is known that these substances exhibit a wide range of biological functions. A new method has been developed for the synthesis of pyridine-fused pyrazolo[1,2-b]phthalazine derivatives via a three-component reaction of phthalhydrazide, aromatic aldehydes, and 2-aminopropene-1,1,3-tricarbonitrile. This transformation presumably occurs via Knoevenagel condensation, Michael addition, cyclization and isomerization sequence of reactions. Noteworthy features of this protocol include easy isolation, a broad substrate range, non-column chromatographic separation and high product yields. Benzaldehydes containing electron-withdrawing groups, such as Br, Cl, F, CN and NO2, were found to be very reactive in the process and to provide good yields of the appropriate pyridine-fused pyrazolo[1,2-b]phthalazine derivatives. In addition, the electron-donating groups such as hydroxyl, methoxy, ethoxy and isopropyl were also favourable for the transformation. In conclusion, the current study describes a straightforward new one-pot, three-component method for the synthesis of pyridine-fused pyrazolo[1,2-b]phthalazine derivatives. The transformation requires the use of an inexpensive and readily available catalyst and does not require column chromatographic purification for isolation of products. The devised protocol's primary advantages are its straightforward experimental process, wide range of substrates, and high yields.

An efficient CuFe2O4 nanocatalyst was created using the simple and cost-effective assisted sol gel method, which has been effectively worked with as an efficient catalyst for one-pot multicomponent synthesis of pyrano[2,3-c] pyrazoles starting from aromatic aldehydes, malononitrile, ethyl acetoacetate, and hydrazine hydrate. The synthesized catalyst was characterized by using Fourier transform infrared (FT-IR), X-ray diffraction (XRD), energy dispersive X-ray (EDX), scanning electron microscopy (SEM), and transmission electron microscope (TEM) techniques. The synthesized organic compounds were examined using IR, 1H NMR, and 13C NMR spectroscopy. The yield of pyrano[2,3-c] pyrazoles was studied using various reaction parameters such as the amount of catalyst, type of solvent, reaction conditions, and time. The present work's significant advantages such as simple setup, mild reaction conditions, non-toxic solvents, high yields, simple purification, efficiency, and utilization of recovered materials after four cycles.

A straightforward and facile method for the synthesis of imidazo[1,2-a]pyridine derivatives by one-pot, three-component reaction of phenyl glyoxals, 2-aminopyridines, and barbituric acids has been developed. The synthesis was performed in a microwave reactor and under solvent-free conditions without using any catalyst. The synthesis displayed many other attractive features such as high efficiency, short reaction time, simple product purification, and environmentally benign reaction conditions. Moreover, the synthesis could be applied on a gram scale without any significant decrease in reaction yield. Eleven imidazo[1,2-a]pyridine adducts were provided in high yields (82-96%), and their structures were confirmed by NMR data. A comparison between this method and the literature report was also included. A plausible reaction mechanism involving a Knoevenagel condensation and aza-Michael addition was also suggested.

A series of 4-(((8-hydroxyquinolin-7-yl)(phenyl)methyl)amino)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one derivatives (4a–j) were synthesized via a one-pot, three-component reaction. The reaction employed benzaldehyde derivatives (1a–j), 4-aminoantipyrine (2), and 8-hydroxyquinoline (3), using titanium dioxide nanoparticles (TiO2 NPs) as a catalyst. The TiO2 NPs, synthesized through a sol–gel method, efficiently catalyzed the transformation under mild conditions, delivering high yields in just 9 minutes at room temperature. Optimization revealed that 0.010 g of catalyst in methanol was optimal, with protic solvents outperforming aprotic and non-polar ones. The reaction progress was monitored using thin-layer chromatography (TLC), and the final products were isolated via recrystallization. A systematic study of reaction parameters confirmed TiO2 NPs as an efficient, reusable, and environmentally friendly catalyst for multicomponent organic synthesis.

Autocatalytic reaction represents an appealing approach in organic chemistry and life sciences. The development of a novel autocatalytic mode for aza-6π electrocyclization reactions represents a promising protocol for the efficient construction of aromatic N-heterocycles. Drawing inspiration from natural biosynthetic pathways for aromatic heterocycles, a wide variety of bioactive natural products can be synthesized efficiently using a biomimetic aza-6π electrocyclization strategy. However, conventional thermal catalysis inevitably suffers from a limited substrate scope and diversity. The photochemical protocol is considered a promising approach in elegant organic synthesis, but the application of photocatalysis in 6π electrocyclization has been rarely explored. In this context, we hypothesized that the aza-hexatriene system of phenanthridine precursor might cyclize with the intermediate imine, which could be formed in situ from the reaction of 2-arylaniline and aldehyde source, respectively. Subsequently, the aza-hexatriene is excited by the corresponding phenanthridine via energy transfer under visible light. The final intramolecular cyclization could generate the substituted phenanthridines. Herein, a novel visible light-induced autocatalytic aza-6π electrocyclization method was reported for the synthesis of diverse phenanthridines. A broad spectrum of 2-arylaniline and (hetero)aryl aldehydes could be well tolerated under metal- and oxidant-free conditions, affording the corresponding phenanthridines in moderate to good yields. This newly developed method represents a highly efficient and cost-effective synthetic protocol. The late-stage functionalization of celecoxib and bromopride derivatives also demonstrated the practical value of this method.

A growing number of applications in the fields of biotechnology, biomedicine, catalysis, and energy storage have resulted from the development of gold nanoparticles (AuNPs), which have garnered considerable attention in recent years due to their unique biochemical, optical, electronic, and catalytic properties. However, the traditional approaches to creating AuNPs, like chemical reduction and physical procedures, frequently call for the use of toxic solvents, dangerous compounds, and large energy inputs, raising questions about environmental sustainability and public health. In recent years, there has been a growing interest in the development of environmentally friendly and sustainable approaches to synthesize AuNPs, often referred to as “green synthesis” or “biogenic synthesis”. Green synthesis of AuNPs involves the use of biocompatible agents, such as plants, microorganisms, and biomolecules, to reduce gold ions and form AuNPs in a single step. Compared to conventional approaches, this strategy has a number of benefits, such as a reduced adverse effect on the environment, cheaper production costs, and better scalability. In this review, we will provide an overview of the current state of green synthesis of AuNPs, highlighting the various biogenic agents and characterization methods that have been employed to date. Furthermore, we shed light on the role of plant-derived biomolecules in the reduction mechanism and stabilization processes. Our review provides researchers with a standard reference for future studies.

The study aims to work on Computational Studies to Optimize Pyrazole Derivatives for Antibacterial Activity. A dataset of 28 Pyrazole derivatives having antibacterial activities was used to generate a pharmacophore hypothesis and a 3D-QSAR model. The established pharmacophore model (DHRRR_1) features three hydrogen bond donors (D), hydrophobic (H), and aromatic ring (R) features, exhibiting favorable parameters (R² = 0.9031; Q² = 0.9004). Hypothesis validation, enrichment analysis, and contour plot analysis were conducted, followed by virtual screening of the ChEMBL database using the optimized pharmacophore model and filtering based on the Lipinski rule of five. Docking was done with PDB ID 3G75 targeting DNA gyrase using Schrodinger software, further Desmond module of Schrodinger 2024-2 was used for MD simulations. The QSAR model was validated along with standard parameters. A library of NCE’s was designed with hypothesis DHRRR_1. Compounds that showed no violations in ADMET studies were further analysed for their interactions in the docking study. Eight compounds have shown zero violations in ADMET and have shown greater binding affinity in comparison to the standard Metronidazole. Further in the MD simulation results, instability of the complex 3G75-Comp D1 was analysed for 100 ns. This study provides a comprehensive approach for identifying novel Pyrazole-based antibacterial agents, highlighting compound D1 as a promising lead. Most promising compound D1 has indicated the role of the Hydroxy group, Pyrazole, and pyrrole ring for good antibacterial activity.

By employing a catalytic proportion of Co-Al2O3-SO3H in a three-component Biginelli-type condensation, combining various aromatic aldehydes, 1,3-cyclohexadione, and urea, practical one-pot synthesis of hexahydroquinazolinone was accomplished. This method yielded hexahydroquinazolinones in good yields, which were further enhanced under reflux conditions. This approach offers several significant advantages, including high efficiency, straightforward reaction conditions, simple workup, reusable catalysts, superior yields, and shorter reaction times. The structure of the produced heterogeneous catalyst Co-Al2O3-SO3H was analyzed using Brunauer-Emmett-Teller (BET) analysis, X-ray diffraction (XRD), and Scanning Electron Microscopy (SEM).

A new series of low molar mass mesogens having double lateral substituents were prepared and characterized with the objective to explore the effect of structure modification on the mesomorphic behavior. The molecular structure has three aromatic rings at the centre core system, which is connected by an imine linking group, two flexible alkyloxy chains at both sides of molecules and two lateral methyl groups attached to the core system. This low molar mass mesogen is known as bis(4-alkyloxybenzylidene)-2,5-dimethyl-1,4-phenylenediamine with different numbers of carbon (n) at the alkyloxy chain. Molecular structures were confirmed via infrared and nuclear magnetic resonance spectroscopic and mass spectrometric methods. Phase transition studies were conducted using a differential scanning calorimeter. Whereas, mesophase characterization was determined by polarizing optical microscopy and the temperature was varied with a temperature controller. The current core system of benzylidene-1,4-phenylenediamine showed good potential of exhibiting liquid crystal as all compounds were found to exhibit a nematic phase. Double lateral methyl atoms at the central mesogenic core had broadened the molecular width. This has caused a reduction in the overall lateral intermolecular attraction, and therefore, it exhibited a nematic phase. As the number of carbons at the alkyloxy chain increased, the clearing temperatures were observed to show a descending trend. A comparison of thermal properties was made between the current compounds with analogous compounds that do not possess any lateral substituent or have a single lateral substituent attached to the mesogenic core.

Steroidal saponins are natural compounds known to have anticancer activity by inducing apoptosis through inhibition of Bcl-2. This study was carried out on the potency, mechanism, and binding affinity of steroidal saponins present from Hoya verticillata var. verticillata as Bcl-2 inhibitor of colorectal cancer in silico using molecular docking and molecular dynamics simulation. All steroidal saponins exhibited hydrogen bonds in molecular docking, Van der Waals, and hydrophobic interactions. The binding potentials of steroidal saponins collected in previous studies and a reference compound, navitoclax, as target protein 6GL8 of BCL-2 inhibitor of colorectal cancer, were examined using molecular docking. The results showed the binding stabilities as -8.28, -8.87, -9.29, -11.09, -11.16, and -8.34 kcal/mol, respectively. Given the limited in-silico studies on pregnane saponins, we considered the extensive interest in these compounds. So, molecular dynamics studies were carried out to better comprehend the dynamics of ligands within the binding pocket of the target protein. Molecular dynamics simulation revealed that the binding of parasiticoside B to the 6GL8 receptor was stable and strong, based on their RMSD, RMSF, and the number of hydrogen bonds throughout the simulation. From the molecular interaction analysis derived from molecular dynamic trajectories of each ligand-bound complex, these interacting amino acids might be determined to play a crucial role in binding with the ligands of the 6GL8 active site. Parasiticoside B could be a good candidate for new inhibitors of anti-apoptotic BCL-2 proteins in colorectal cancer.