Multicomponent Synthesis Research Articles

GO‐TiO2 Nanocomposite: An Efficient Catalyst for the Conventional and Ultrasonically Mediated Multicomponent Synthesis of 2, 4, 5‐Trisubstituted Imidazole Derivatives**

AbstractA flexible, reliable, and effective method for the synthesis of a wide variety of highly functionalized 2, 4, 5‐trisubstituted imidazole derivatives are reported. It involves a one‐pot, multicomponent process using a variety of aldehydes, ammonium acetate, and benzil /benzoin in the presence of non‐toxic, readily accessible, affordable, reusable and unexplored catalysts, GO‐TiO2. This one‐pot synthesis method has numerous benefits, including benign reaction conditions, a quick reaction time, low catalyst loading, efficient productivity with better atom economy and functional group tolerance, which makes this methodology realistic. TiO2 is known for its excellent catalytic activity for many organic reactions, however GO‐TiO2 nanocomposite is yet to be explored in the field of heterocyclic synthesis. In the present work GO‐TiO2 nanocomposite has been introduced as a catalyst for the synthesis of imidazole derivatives and among the TiO2 and GO‐TiO2 catalysts, GO‐TiO2 exhibited better catalytic efficiency and provided great substrate scope with α‐hydroxy ketone (benzoin) as well as 1, 2‐diketone (benzil). Both the conventional method as well as ultrasonically mediated method has been adopted to find out the best possible methodology for the synthesis of 2, 4, 5‐trisubstituted imidazole derivatives.

Advances in Isocyanide‐Based Multicomponent Synthesis of Quinoxaline Scaffolds

AbstractThe present review article includes recent advances in the synthesis of structurally and functionally diversified quinoxalines‐drug‐like small molecules with molecular complexity. We have extended our efforts to include the research work concerning the isocyanide‐based multicomponent reactions. The synthetic methods included in the present review article will provide an access for a diverse range of natural product mimetic scaffolds with the use of isocyanide‐.based combinatorial synthesis. These isocyanide based reactions will be significant for the synthesis of complex bioactive natural products and potential synthetic pharmaceuticals. The present review will contribute considerably to the organic syntheses and particularly drug discovery research including pharmaceutical and medicinal chemistry. Academically, the present review article will be interesting for the researchers engaged in design and development of isocyanide‐based organic transformations. Moreover, we hope that the isocyanide‐based multicomponent reactions will find major applications in industrially significant organic transformations and to develop new synthetic routes to facilitate the incorporation of heterocyclic substructures into pharmaceutically active molecules.

Microwave-promoted multi-component and green synthesis of thiadiazolo[3,2-a]pyrimidines under solvent-free conditions

Microwave-promoted multi-component and green synthesis of thiadiazolo[3,2-a]pyrimidines under solvent-free conditions

MgO-MgAl2O4: An Efficient Catalyst for Multicomponent Synthesis of Substituted 4H-pyran

Background: The 4H-pyran compounds are an important class of heterocyclic compounds due to their diverse biological and pharmaceutical properties. Moreover, 4H-pyran is a crucial structural component commonly encountered in the pharmaceutical industry. Thus, it has recently gained significant attention from industry researchers and academic organizations. Herein, we report an efficient and eco-friendly one-pot strategy to synthesize bioactive compounds containing 4H-pyran motifs via a multicomponent reaction. This reaction occurs by reacting equimolar amounts of ethyl acetoacetate, malononitrile, and substituted aldehyde under mild conditions in the presence of a solid catalyst, MgO-MgAl2O4. This latter, was obtained by heat treatment, at 800°C, of a layered double hydroxide with the metal cation ratio of Mg2+/Al3+ = 3:1, and it was characterized by some techniques including XRD, TG-DTA, FT-IR and N2 adsorption-desorption. Therefore, bioactive compounds containing the pyran unit may possess intriguing biological properties. The synthetic protocol offers advantages such as a simple procedure, good to excellent yields, and easy catalyst separation from the reaction mixture. Methods: Substituted 4H-pyran derivatives were prepared by the condensation reaction of substituted aldehydes, ethyl acetoacetate and malononitrile using MgO-MgAl2O4 catalyst under mild conditions. This study aims to develop an efficient methodology for synthesizing 4H-pyran heterocyclic compounds that have potential applications in biological sciences. The study utilizes MgO-MgAl2O4 as a highly effective heterogeneous catalyst. Results: The present research details the synthesis of 4H-pyran bioactive compounds using sustainable reaction conditions, which resulted in high yields and facilitated the easy separation of the catalyst from the reaction mixture. Conclusion: In summary, the MgO-MgAl2O4 spinel nanostructure has been successfully prepared and fully characterized by using different physicochemical techniques such as XRD, TG-DTA, FT-IR and N2 adsorption-desorption. Afterwards, its catalytic activity was investigated through the one-pot condensation of aryl aldehyde, malononitrile and ethyl acetoacetate. Moreover, it exhibits good catalytic activity for the synthesis of 4H-pyran derivatives under green conditions. These latter have many benefits, such as simple procedure, good to excellent yields and easy separation of the catalyst from the reaction mixture.

Design‐Expert a Powerful Tool for Optimizing Organic Synthesis: A Green and Facile Multicomponent Synthesis of New 2‐Pyridone‐pyrimidine Derivatives by p‐Toluene Sulfonic Acid in Water

AbstractAn efficient synthesis of a novel series of 2‐pyridone‐pyrimidine derivatives via multicomponent reaction of different 4‐hydroxy‐6‐methylpyridine‐2‐ones, aromatic aldehydes, and barbituric acid or 6‐aminouracil in the presence of p‐toluene sulfonic acid in water has been reported. At first, the modified conditions to afford the best yield of a sample product were obtained (100 °C, one hour, and 100 mole % of p‐TSA) and then used for the others. The significant point of this report is to use Design‐Expert software for optimizing conditions. This reaction addition to having all the advantages of a green approach for synthesizing potentially bioactive compounds, such as eco‐compatibility, high yield of products, simple operation, and so, due to the using the methodic and pre‐calculated statistical optimization process, has high precision and accuracy. This approach can show a new path in optimizing the synthetic procedures of organic compounds.

One‐pot Multicomponent Synthesis of Novel Chromene Derivatives Using New Organic Phosphate Salt Catalysts

AbstractA new method for synthesizing chromene derivatives as an essential class of heterocyclic compounds has been reported. This research described synthesizing and identifying three new organic salt catalysts based on phosphate moieties. Among the synthesized new phosphate‐based organic salt catalysts, disodium ethyl (phenyl) amino phosphate (DSEAP) plays an essential role and reusable catalyst for the preparation of chromene derivatives under different reaction conditions following the principles of green chemistry. Cost‐effectiveness, non‐toxicity and easy availability are among the salient features of this environmentally friendly catalyst. Furthermore, the catalyst was satisfactorily recycled up to four times without significant performance degradation in the yield of synthesized chromenes. X‐ray diffraction (XRD), infrared spectroscopy (FT‐IR), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were employed to illustrate the structural and morphologic characteristics of the catalysts. Some synthesized chromene derivatives, including 4I and 4P, showed good antibacterial and biological antioxidant activity compared to the standard drug, respectively. In this research, DSEAP was used as a heterogeneous catalyst in performing one‐pot 3MCRs of aryl aldehyde, an active methylene group e. g. ethyl acetoacetate or diethyl malonate and 5,5‐dimethyl‐1,3‐cyclohexanedione.

A One-pot Multi-component Synthesis of some New Dihydropyrimidine Derivatives via Biginelli Condensations

A One-pot Multi-component Synthesis of some New Dihydropyrimidine Derivatives via Biginelli Condensations

Preparation and characterization of MWCNTs/CONHBu and investigation of its catalytic effect in the multi component synthesis of 2-amino-4H-chromenes under green conditions

A facile, efficient and environmentally-friendly method for the synthesis of 2-amino-4H-chromenes via the multicomponent reaction in the presence of modified multiwalled carbon nanotubes (MWCNTs/CONHBu) as a green and reusable solid base catalysts is presented. All of products were synthesized in short times with high to excellent yields under green conditions and were identified using FTIR and 1H NMR techniques. The remarkable aspects of this method are including the mild reaction conditions, simple workup, heterogeneous catalyst, green process, and high to excellent yield of products. The solid base catalyst was characterized using SEM, XRD, TEM, Raman and FT-IR spectroscopy.

Multicomponent Synthesis, Characterization of Novel Pyrimidine Derivatives with Anti-cancer Potential

Multicomponent Synthesis, Characterization of Novel Pyrimidine Derivatives with Anti-cancer Potential

Multicomponent Synthesis of the SARS-CoV-2 Main Protease Inhibitor Nirmatrelvir.

In the wake of the Covid-19 pandemic, it has become clear that global access to efficacious antiviral drugs will be critical to combat future outbreaks of SARS-CoV-2 or related viruses. The orally available SARS-CoV-2 main protease inhibitor nirmatrelvir has proven an effective treatment option for Covid-19, especially in compromised patients. We report a new synthesis of nirmatrelvir featuring a highly enantioselective biocatalytic desymmetrization (>99% ee) and a highly diastereoselective multicomponent reaction (>25:1 dr) as the key steps. Our route avoids the use of transition metals and peptide coupling reagents, resulting in an overall highly efficient and atom-economic process.

Multicomponent synthesis of 2-amino-3-cyano pyridines catalyzed by Nano-[Fe-4BSP]Cl2 as a new Schiff base complex and catalyst

Multicomponent synthesis of 2-amino-3-cyano pyridines catalyzed by Nano-[Fe-4BSP]Cl2 as a new Schiff base complex and catalyst

Multicomponent synthesis and photophysical study of novel α,β-unsaturated carbonyl depsipeptides and peptoids.

Multicomponent reactions were performed to develop novel α,β-unsaturated carbonyl depsipeptides and peptoids incorporating various chromophores such as cinnamic, coumarin, and quinolines. Thus, through the Passerini and Ugi multicomponent reactions (P-3CR and U-4CR), we obtained thirteen depsipeptides and peptoids in moderate to high yield following the established protocol and fundamentally varying the electron-rich carboxylic acid as reactants. UV/Vis spectroscopy was utilized to study the photophysical properties of the newly synthesized compounds. Differences between the carbonyl-substituted chromophores cause differences in electron delocalization that can be captured in the spectra. The near UV regions of all the compounds exhibited strong absorption bands. Compounds P2, P5, U2, U5, and U7 displayed absorption bands in the range of 250-350nm, absorbing radiation in this broad region of the electromagnetic spectrum. A photostability study for U5 showed that its molecular structure does not change after exposure to UV radiation. Fluorescence analysis showed an incipient emission of U5, while U6 showed blue fluorescence under UV radiation. The photophysical properties and electronic structure were also determined by TD-DFT theoretical study.

A Sustainable synthesis, eco-safe approach efficiency and DFT study of novel 5,6,7,8-Tetrahyroquinazolin-2(1H)-one derivatives as antioxidant reagents

5,6,7,8-Tetrahydroquinazolin-2-(thio)-ones (THQ) fits the class of N-heterocycles as a structural core in numerous bioactive compounds. They promptly extended previous decades. They were significantly recognized in combinatorial chemistry and materials science to determine the drug discovery, antioxidants, and pharmaceuticals fields. In the present work, one-pot multicomponent sustainable synthesis of THQ with easily accessible starting materials, i.e., cyclohexanone, different aromatic aldehydes and (thio)urea, has been performed to determine the proposed Biginelli mechanism that is supported by DFT. It is found that the THQs are synthesized by a mechano-chemical (grinding) tool to achieve a yield of 85.2% within 3.5 min, i.e., YE (% yield/time) 24.34 differs from the conventional method in which lower % yield (YE = 0.72) of THQ was achieved. This confirmed that in the green chemistry principle, the determination of % yield according to saving reaction time must be considered. Moreover, DFT-based antioxidant properties of the THQ were also studied in which the most potent antioxidant compounds were 7b > 6d > 2f. Softness (σ, eV−1) and hardness (η, eV mol−1) can approve the soft molecule that stays more reactive as a result of decreasing the energy gap along heterocyclic with values 0.1491 > 0.1300 > 0.1168 eV−1 one-to-one with the efficiency of antioxidant.

One pot multicomponent synthesis of highly substituted imidazoles using tetrabutylammonium peroxy disulfate as a catalyst

One pot multicomponent synthesis of highly substituted imidazoles using tetrabutylammonium peroxy disulfate as a catalyst

Ultrasound Promoted One-Pot Multicomponent Synthesis of Highly Functionalized Tetrahydropyridine Derivatives

The N-methyl pyridinium tosylate (NMPyTs) ionic liquid is used as an efficient, homogeneous, and recyclable catalyst for the synthesis of tetrahydropyridine derivatives via one-pot multi-component condensation of aromatic aldehyde, anilines, and β-ketoesters under ultrasonic irradiations. This protocol was successfully pertinent to a wide range of structurally diverse aromatic aldehydes, substituted anilines, and β-ketoesters. The major characteristics of this technique include operational simplicity, short reaction times, mild reaction conditions, and high yield. Importantly, NMPyTs can undergo up to three recycle runs without any noticeable loss of catalytic activity.

Multicomponent diastereoselective synthesis of tetrahydropyridines as α-amylase and α-glucosidase enzymes inhibitors.

Background: Researchers seeking new drug candidates to treat diabetes mellitus have beenexploring bioactive molecules found in nature, particularly tetrahydropyridines (THPs). Methods: A library of THPs (1-31) were synthesized via a one-pot multicomponent reaction and investigated for their inhibition potential against α-glucosidase and α-amylase enzymes. Results: A nitrophenyl-substituted compound 5 with IC50 values of 0.15±0.01 and1.10±0.04μM, and a Km value of 1.30mg/ml was identified as the most significant α-glucosidase and α-amylase inhibitor, respectively. Kinetic studies revealed the competitive mode of inhibition, and docking studies revealed that compound 5 binds to the enzyme by establishing hydrophobic and hydrophilic interactions and a salt bridge interaction with His279. Conclusion: These molecules may be a potential drug candidate for diabetes in the future.

Preparation of GO/Cys-Cu(II) as a novel, effective and recoverable catalyst for the multi component synthesis of spirooxindoles under mild conditions

Modified graphene oxide (GO/CPTES/Cys-Cu(II)) was prepared as a reusable catalyst and characterized by various analytical and spectroscopic methods, including Fourier transform spectroscopy (FTIR), X-ray diffraction (XRD), energy dispersive X-ray (EDX), scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and inductively coupled plasma (ICP) techniques. Obtained results from demonstrated the existence of cystein/Cu(II) on the MWCNTs surfaces. EDX and ICP analysis shown about 11% Cu (II) and about 8.5% of N element in the catalyst structure. Also, other characterization data confirmed the successfully preparation of synthesized catalyst. The efficiency of this novel catalyst was evaluated through the green synthesis of two variety of spirooxindole derivatives in a One-pot multi component reaction in ethanol as a green solvent. The catalyst showed high efficiency in this process and all of spirooxindoles were obtained after short time (18 min) in high to excellent yields (89–95%). The structure of all obtained products was assigned with hydrogen and carbon nuclear magnetic resonance (1H and 13C NMR) and FTIR. Furthermore, the catalyst could be easily recovered and directly reused at least five times without a notable reduction in activity. The other advantages of the presented methodology are high yields of products without the formation of by-products, simple and clean process, mild reaction conditions and agreement with green chemistry protocols.

In-vitro anticancer evaluation of newly designed and characterized tri/tetra-substituted imidazole congeners- maternal embryonic leucine zipper kinase inhibitors: Molecular docking and MD simulation approaches

Our cascading attempt to develop new potent molecules now involves designing a series of imidazole derivatives and synthesizing two sets of 2,4,5- tri-substituted (4a–4d) and 1,2,4,5-tetra-substituted (6a–6d) imidazole by the principle of Debus-Radziszewski multicomponent synthesis reaction. The structures of the obtained compounds were confirmed by 1H/13C NMR, FT-IR, elemental analysis, purity and the retention time was analyzed by HPLC. Based upon the binding affinity in the molecular docking studies, we have synthesized different imidazole derivatives from which compound 6c have been found to show more anti-proliferative activity by inducing apoptosis at a higher rate than the other compounds corroborating the in-silico prediction. The structure and crystallinity of compound 4d have been confirmed by single XRD analysis. The synthesized molecules were screened for their in vitro anti-cancer properties in triple negative breast cancer cell line (MDA-MB-231), pancreatic cancer cell lines (MIA PaCa-2) and oral squamous cell carcinoma cell line (H357) and results indicated that all the compounds inhibited the cell proliferation in a concentration-dependent manner at different time points. The compounds 4b and 6d were found to be effective against the S. aureus bacterial strain whereas only compound 4d fairly inhibited the fungal strain of T. rubrum with a MIC 12.5 μg/mL. Molecular docking study reveals good interaction of the synthesized compounds with known target MELK involved in oncogenesis having high binding profiles. The lead compound 6c was further analyzed by the detailed molecular dynamics study to establish the stability of the ligand–enzyme complex.

Rational Design and Multicomponent Synthesis of Lipid-Peptoid Nanocomposites towards a Customized Drug Delivery System Assembly.

Nanotechnology has assumed a significant role over the last decade in the development of various technologies applied to health sciences. This becomes even more evident with its application in controlled drug delivery systems. In this context, peptoids are a promising class of compounds for application as nanocarriers in drug delivery systems. These compounds can be obtained efficiently and with highly functionalized structural diversity via the Ugi 4-component reaction (U-4CR). Herein, we report the design of the process control strategy for the future development of lipid-peptoid-based customized drug delivery system assemblies. Over 20 lipid-peptoid nanocomposites were synthesized via the U-4CR in good to excellent yields. These products were successfully submitted to the nanoparticle formation by the emulsification-evaporation process from lipophilic solution and analyzed via Dynamic Light Scattering (DLS). Several molecules generated nanoparticles with a size ≤200 nm, making them good candidates for drug delivery systems, such as in cancer treatment.

Discovery of Novel 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine Histone Deacetylase Inhibitors for Efficient Treatment of Hepatocellular Carcinoma.

The development of histone deacetylase (HDAC) inhibitors for treating hematologic malignancies has been widely investigated, while their role in hepatocellular carcinoma (HCC) remains unexplored. In this study, we employed a scaffold-hopping design and a multicomponent synthesis approach to develop a novel series of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridines as HDAC inhibitors. There were a total of 29 compounds achieved with flexible linkers and zinc-binding groups, wherein compound 12k was identified as a promising candidate with good HDAC inhibitory activity, pharmacokinetic profiles, and potency. It exhibited significant therapeutic efficacy in HCC cell lines (IC50 = 30 nM for Bel-7402) and xenograft models (76% inhibition for Bel-7402 xenografts, P.O. at 20 mg/kg, QOD, for 14 days) and was found to upregulate the acetylation of histone H3 and α-tubulin, leading to apoptosis and autophagy in HCC models. Molecular docking studies indicated a unique T-shaped conformation of 12k with the catalytic domain of HDAC1. Therefore, this work provides a new structure design for HDAC inhibitors and also offers a promising treatment for HCC.