One-pot Multicomponent Reaction Research Articles

Tetrahydropyrimidine Ionizable Lipids for Efficient mRNA Delivery.

Lipid nanoparticles (LNPs) have emerged as an effective and promising technology for messenger RNA (mRNA) delivery, offering a potential solution to physiological barriers and providing an alternative approach to gene therapy without the drawbacks associated with viral delivery. However, efficiently delivering mRNA remains a significant challenge in nucleic acid-based therapies due to the limitations of current LNP platforms in achieving optimal endosomal escape and mRNA release, which largely relies on finding a suitable ionizable lipid. Additionally, the synthesis of these ionizable lipids involves multiple chemical reactions, often making the process time-consuming and difficult to translate. In this study, we employed a facile, catalyst-free, and versatile one-pot multicomponent reaction (MCR) to develop a library of ionizable lipids featuring a pharmacologically significant tetrahydropyrimidine (THP) backbone, tailored for enhanced mRNA delivery. A library of 26 THP ionizable lipids was systematically synthesized in just 3 h and formulated with luciferase mRNA for initial in vitro screening. The THP LNPs exhibited tunable particle sizes, favorable ζ-potentials, and high encapsulation efficiencies. Among them, THP1 demonstrated the highest transfection efficiency both in vitro and in vivo after intramuscular administration, comparable to DLin-MC3-DMA (MC3), a conventional benchmark. Further optimization of THP1 with phospholipids significantly enhanced intramuscular mRNA delivery and showed sustained protein expression in vivo for up to 5 days. More importantly, it demonstrated successful intravenous delivery in a dose-dependent manner with minimal toxicity, as indicated by hematological, histopathological, and proinflammatory cytokine assessments. Furthermore, THP1 LNPs also demonstrated the ability to edit genes in specific liver tissues in a tdTomato transgenic mouse model, highlighting their precision and utility in targeted therapeutic applications. These findings position THP1 LNPs as promising candidates for advancing mRNA-based therapies, with significant implications for clinical translation in vaccine delivery and CRISPR/Cas9-mediated gene editing in the liver.

Visible-light-promoted one-pot synthesis of β-keto sulfones from aryldiazo tetrafluoroborate salts via aerobic multicomponent reaction

β-Keto sulfone is a useful structure in organic chemistry and pharmaceuticals. In the present study, we developed a highly efficient visible-light-promoted reaction to prepare β-keto sulfones under mild conditions. Synthesis was achieved via one-pot multi-component reaction of aryldiazo tetrafluoroborate salts, alkenes, and DABSO in the presence of air (O2) with rhodamine B serving as the photocatalyst. A variety of β-keto sulfones were obtained at high yields by this one-pot operation under aerobic atmosphere. This oxysulfonylation procedure has benefits such as mild reaction conditions, a wide tolerance of functional groups, and simplicity, making it a promising choice for preparing valuable β-keto sulfones.

Nano-reusable CuO-ZnO Catalyzed One-Pot Synthesis of 1-Amidoalkyl-2-Naphthols under Green Condition

Introduction: The Developed CuO-ZnO nanocomposite has been demonstrated as a new and environmentally friendly catalyst for one-pot multicomponent reaction between aldehydes, 2- naphthol and amides in the synthesis of 1-amidoalkyl-2-naphthols. Method: The new catalyst was synthesized by a ball-milling method by mixing a mixture of CuO and ZnO powder in various proportions and characterized by different spectroscopic methods such as powder X-ray diffraction (pXRD), Scanning Electron Microscopy (SEM), UV-Visible analysis, EDAX elemental analysis and mapping. The advantages of the devised protocol include a green approach, simple work-up procedures, avoidance of hazardous solvents, and good to excellent yields. RE Sult: Evaluation of the catalyst performance in the synthesis of some 1-amidoalkyl-2-naphthols showed presentable results. Sixteen derivatives were synthesized in desirable yield by our new method (4a-4p). CuO-ZnO nanocomposite as a safe and efficient catalyst could be reused up to 5 runs for the synthesis of naphthol derivatives without any significant decrease in its potency. Conclusion: The High purity of the products and desirable yields are other points that make the present work more attractive.

Two Thiophene-Functionalized Co-MOFs as Green Heterogeneous Catalysts for the Biginelli Reaction.

Two Co(II) metal-organic frameworks (Co-MOFs), namely, [Co(DMTDC)(bimb)]n (Co-MOF-1) and {[Co(DPTDC)(bimb)(H2O)]·2DMF}n (Co-MOF-2) (H2DMTDC = 3,4-dimethylthieno[2,3-b]thiophene-2,5-dicarboxylic acid, H2DPTDC = 3,4-diphenylthieno[2,3-b]thiophene-2,5-dicarboxylic acid, bimb = 1,4-bis((1H-imidazol-1-yl)methyl)benzene), were obtained by the reaction of flexible N-containing ligand bimb and two structurally related thiophene-containing ligands H2DMTDC and H2DPTDC, respectively. These Co-MOFs displayed a 3D framework and porous structure, respectively. Co-MOF-1 and the activated sample Co-MOF-2' could act as green heterogeneous catalysts for the one-pot multicomponent Biginelli reaction, specifically the dehydration condensation process involving aldehydes, acetoacetates, and urea to yield dihydropyrimidin-2(1H)-ones. The reaction has advantages such as solvent-free conditions, water as only byproduct, readily accessible starting materials, excellent functional group compatibility, and simple operation. Both catalysts exhibited a wide substrate scope and maintained significant catalytic activity over five cycles. The special catalytic performance may be ascribed to functional groups within the ligand.

Mangrove tree aerial root extract mediated green synthesis of Ag/Fe3O4/rGO nanocomposite and its application as a catalyst for one potsynthesis of 7-phenyl-6H,7H-benzo[4,5]imidazo[2,1-b]chromeno[4,3-d][1,3]thiazin-6-one derivatives.

In this study, we report the green preparation of magnetically separable Ag/Fe3O4/rGO nanocomposites using mangrove tree aerial root extract as a stabilising agent. The morphology, size, chemical composition, magnetic property and other characteristic parameters of synthesised Ag/Fe3O4/rGO nanocomposite were determined by analytical techniques like Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM),transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM). The results proved that mangrove tree aerial root extract has the ability to reduce Ag+ ions, graphene oxide (GO) to Ag nanoparticle and reduced graphene oxide (rGO), respectively. The prepared Ag/Fe3O4/rGO nanocomposite was used successfully as a prompt catalyst for synthesis of 7-phenyl-6H,7H-benzo[4,5]imidazo[2,1-b]chromeno[4,3-d][1,3]thiazin-6-one derivatives by one-pot multi-component reaction of 4-hydroxycoumarin (10mmol), 2-mercaptobenzimidazole (10mmol) and different arylaldehyde (10mmol) in the presence of ethanol (10ml) as an eco-benign solvent at reflux condition. By utilising this protocol, we have constructed 7-phenyl-6H,7H-benzo[4,5]imidazo[2,1-b]chromeno[4,3-d][1,3]thiazin-6-one derivatives in good to excellent yield of 80-90%. This synthesis involves the formation of C-C, C-N and C-S bonds. The synthesised organic heterocyclic compounds were examined for the green matrix properties such as atom economy (AE), E-factor and product mass intensity (PMI). This green protocol is of big interest due to employing simple, non-toxic heterogeneous, separable, reusable Ag/Fe3O4/rGO as an eco-safe heterogeneous catalyst and environmentally benign ethanol as a green solvent without the use of any harmful mineral acid and toxic transition metal catalyst.

Chlorine containing tetrahydropyrimidines: Synthesis, characterization, anticancer activity and mechanism of action

The aim of the presented research was to explore anticancer potential of eleven newly synthesized tetrahydropyrimidine derivatives. The compounds were synthesized via Biginelli multicomponent one-pot reaction using different derivatives of vanillin, ethyl 4-chloroacetoacetate and (N-methyl)urea. The cytotoxic effects of the compounds were examined on three human malignant cell lines (HeLa, K562, and MCF7), and normal lung fibroblasts MRC-5. The mechanisms of anticancer activity were examined for two compounds 4a and 4b which showed the strongest and selective cytotoxicity against chronic myelogenous leukaemia K562 cells (IC50 = 1.76 ± 0.09, and.1.66 ± 0.05, respectively). The changes of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor A (VEGFA) were investigated in the K562 cell line, as well as oncomiRNA miR-10b, miR-23a described to have both features, depending on a specific type of malignancy, and miR-34a with mostly described as a tumour suppressor.

Expeditious and selective synthesis of 2,4,5-trialkyl-1H-imdazoles and benzimidazoles via multicomponent one-pot reaction catalyzed by Schiff base dioxomolybdenum(VI) complex

Imidazoles and benzimidazoles are privileged heterocyclic compounds that can be extensively found in medicinal and materials chemistry, however, the experimental procedures for their synthesis are limited to multicomponent condensation reactions and normally are strongly dependent upon the desired substitution pattern, consequently several procedures with different conditions and catalysts are available in literature. Accordingly, the development of synthetic methodologies to afford these compounds remains a very attractive research problem. In this regard, dioxomolybdenum based catalysts are emerging as versatile and non-expensive reagents for a myriad of chemically relevant transformations. Within this context, an expedient and efficient synthesis of 2,4,5-trialkyl-1H-imidazoles and benzimidazoles from a multicomponent one-pot condensation has been developed with a tridentate Schiff base dioxomolybdenum(VI) complex, resulting in an efficient, simple and readily available catalyst to promote the aforementioned reaction. This reaction offers advantages such as good to excellent yields, good selectivity of products, low catalyst loadings and simple reaction work-up.

Environmental and Convenient Construction Strategy to Obtained New Supreme Series of Fused 1,2,4-Triazalo System Incorporating N-Acetyl Quanazole

The presentation goal is to develop new procedures for regioselective synthesis of unusual series of heterocyclic compounds (2-8) derived from N-acetyl guanazole (1) which received a great deal of attention due to it's unique properties. N-acetyl guaunazole used as active precursor to obtained two type of fused 1,2,4-triazole system. The first one including grinding for (1 min.) of a mixture consist of N-acetyl guanazole , malononitrile and substituted benzaldehlyde through direct one-pot multicomponent reaction to achieve a new series of 1,2,4-trazolo[1,5-a,4,3-a]bispyrimidine (2-7). Whereas, the second one involved firstly the conversion of N-acetyl gluanazole to the corresponding Schiff base (8-13) accelerated by microwave irradiation (MWI) for few minutes, then they will underwent intercyclization reaction with phenyl isothiocynate and also acceclerated by grinding then by microwave irradiation to afford 1,2,4-triazolo[1,5-a,4,3-a] bistriazine (14-18).

An Acid-Mediated Multicomponent Domino Reaction for the Synthesis of N-Substituted Isoindolinones

AbstractA one-pot multicomponent reaction of 2-carboxybenzaldehyde, nitriles/anilines and a nucleophile (N,N-disubstituted anilines) for the synthesis of a range of functionalized N-substituted isoindolinone derivatives is described. This metal-free intramolecular cyclization reaction furnishes the desired products in good to excellent yields. The process is environmentally friendly and offers a sustainable method for synthesizing a diverse library of N-substituted isoindolinone derivatives under acidic conditions. This cascade reaction triggers the formation of a C–C and two C–N bonds involving carbonyl and carboxyl groups in the presence of nitriles/anilines. Additionally, in the absence of a nitrogen source, 3-substituted isobenzofuran-1(3H)-ones are synthesized.

Synthesis of dicholesteryl organogelator as a green sorbent nanomaterial for oil spill remediation

In the field of global water purification, the issue of marine oil spills represents a significant challenge. The use of phase-selective organogelators (PSOGs) as sorbent materials in oil spill remediation is a promising solution due to their environmental adaptability and high absorption capacity. However, there are limited reports on PSOGs that can be used in powder form for rapid phase-selective gelation of crude oils. In this context, the development of innovative dicholesteryl derivatives as low-molecular-weight organogelators (LMOGs) offers a promising solution in powder form. These gelators are synthesized through a one-pot multi-component reaction as green synthesis method, which ensures high purity and eliminates the need for harsh conditions. The incorporation of cholesterol into the gelator structure demonstrate environmental adaptability. The exceptional sorption capacity was attributed to the structured 2D/3D networks observed through scanning electron microscopy (SEM). The hydrophobic properties of these gelators, as evidenced by a water contact angle of 118 degrees, enable them to efficiently gel various organic solvents at low concentrations (1% w/v) at ambient temperatures, without the need for heating–cooling cycles or co-solvents. The eco-friendly nature and efficient oil–water separation capabilities of these gelators in powder form represent a significant advancement in global water purification efforts.

Ni-Fe2O3@SiO2-Pr-DBU: A novel efficient magnetically retrievable catalyst for one-pot synthesis of dihydropyrano [3,2-c] chromene

In the present work, Ni-Fe2O3@SiO2-Pr-DBU was synthesized as a novel magnetically separable nano-catalyst and characterized by various techniques like Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), Scanning electron microscopy (SEM), Vibrating-sample magnetometry (VSM), Transmission electron microscopy (TEM) and Elemental analysis by energy dispersive X-ray (EDX). The catalytic efficiency of NiFe2O3@SiO2-Pr-DBU was explored in the synthesis of dihydropyrano[3,2-c] chromenes through a one-pot multicomponent reaction of 4-hydroxycoumarin, malononitrile, and aryl aldehydes in aqueous solution at ambient temperature condition. An external magnet easily removed the nano-sized magnetic core catalyst from the synthesized reaction mixture. It was recycled for five successive runs while maintaining its potential and adhering to our green synthesis approach. We used dihydropyrano chromene, a highly biologically active commercial compound, to prepare some novel derivatives.

Anticancer Activity of 4-Aryl-1,4-Dihydropyridines

We have synthesized 22 symmetric and asymmetric 4-aryl-1,4-dihydropyridines (1,4-DHPs) by a “green” microwave-assisted one-pot multicomponent Hantzsch reaction and evaluated their cytotoxicity to three human cancer cell lines regarding U-251MG (human glioblastoma), HeLa 229 (human cervical adenocarcinoma), and MCF-7 (human breast carcinoma). None of the 1,4-DHPs were cytotoxic to U-251MG cells. Most of the 1,4-DHPs did not affect HeLa 229 or MCF-7 cell viability. On the other hand, symmetric 1,4-DHPs 18 (diethyl 4-(4-benzyloxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate), 19 (diethyl 4-(4-bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate), and 20 (diethyl 4-(3-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate) reduced the HeLa (IC50 = 3.6, 2.3, and 4.1 µM, respectively) and MCF-7 (IC50 = 5.2, 5.7, and 11.9 µM, respectively) cell viability. These 1,4-DHPs were more cytotoxic to the HeLa and MCF-7 cells than to the GM07492 (normal human fibroblast) cells, as evidenced by their selectivity indexes. Therefore,1,4-DHPs 18, 19, and 20 may serve as novel lead compounds to discover other 1,4-DHP derivatives with improved anticancer potency and selectivity.

Facile one-pot synthesis of N-pyridinylaminonaphthol derivatives and their antibacterial evaluation against multidrug-resistant Staphylococcus aureus.

The escalating severity of the menace posed by bacterial resistance has rendered the existing antibiotics less effective, thus necessitating the discovery of new antibacterial agents. The current study reports the exploration of substituted N-pyridinylaminonaphthols produced by a straightforward, one-pot multicomponent reaction process as antibacterial agents. The synthesized derivatives were assessed in vitro for their antibacterial properties against a panel of bacterial pathogens. The analogs 4b, 4g, 4h, 4i, 4j, 4l, 4r, and 4t exhibited potent inhibitory activity with minimum inhibitory concentration (MIC) values of 1-2 µg/mL. Notably, 4b, 4l, and 4t displayed an excellent selectivity index. Additionally, they were active against the multidrug-resistant bacterial strains, with 4l exhibiting the best activity against methicillin-resistant Staphylococcus aureus and vancomycin resistant staphylococcus aureus with a MIC of 1 µg/mL. 4l showed synergism with gentamycin and showed bactericidal property in a concentration-dependent manner. Furthermore, the molecule 4l inhibited the DNA gyrase supercoiling activity. Absorption, distribution, metabolism, excretion/toxicity parameters and pharmacokinetic properties were assessed via in silico techniques, which elucidate the potential mode of action. These findings demonstrate the potential of the N-pyridinylaminonaphthol derivatives as antibacterial agents against multidrug-resistant S. aureus.

Green Chemistry and In silico Techniques for Synthesis of Novel Pyranopyrazole and Pyrazolo-pyrano-pyrimidine Derivatives as Promising Antifungal Agents.

Every year Invasive Fungal Infections (IFI) are globally affecting millions of people. Candida albicans and Aspergillus niger have been reported as the most infectious and mortality-inducing fungal strains among all pathogenic fungi. To tackle this problem in the current study Pyranopyrazoles and Pyrazolopyrano- pyrimidine derivatives were developed using molecular hybridization, green chemistry and one-pot multicomponent reaction. In the present work, New Chemical entities (NCE's) were developed on the basis of Structure activity relationship. All designed NCE's were screened for ADMET studies using the QikProp module of Schrodinger software. NCE's with zero violations were further docked on the crystal structure of 14α demethylase, cytochrome P450 and thymidine synthase (PDB ID: 5V5Z, 7SHI, 1BID). Selected molecules were synthesized using green chemistry techniques and evaluated for in vitro antifungal activity against Candida albicans and Aspergillus niger. Designed NCE's (B1-12 and C1-11) showed favorable results in ADMET studies. In the docking study six compounds from series-B and five molecules from series- C showed good dock score and binding interaction when compared with the standard drugs. Compounds B-3 and C-4 showed the highest zone of inhibition activity against Candida albicans, where as B-1 and C-3 had shown highest zone of inhibition activity against Aspergillus niger. Bicyclic ring (series B) showed better activity as compare to fused tricyclic ring (series C).

WITHDRAWN: Green Synthesis and Evaluation of the Biological Activity of New Dihydropyridine Derivatives

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Enhanced Catalytic Activity of Binuclear Oxidovanadium(IV) Bisbenzimidazole Linked Porphyrin Dimer for the Generation of Biologically Active 3,4-Dihydropyrimidinones and Their Corresponding Thiones.

Binuclear vanadyl(IV) porphyrin (V2BP), where two vanadium(IV) porphyrin macrocycles are linked through benzimidazole units at the β-positions, has been prepared and characterized with various techniques, such as UV-vis, Fourier transform-infrared, electron paramagnetic resonance, cyclic voltammetry, density functional transform calculations, and mass spectrometry. V2BP exhibits a red shift (Δλmax = 10 nm) in the Soret band as compared with unsubstituted parent vanadyl(IV) meso-tetraphenylporphyrin (VP). The synthesized binuclear vanadyl(IV) porphyrin (V2BP) has further been studied as a catalyst to explore a single-pot multicomponent Biginelli reaction producing biologically active 3,4-dihydropyrimidin-2-(1H)-one (DHPM)-based biomolecules and the corresponding thiones under solvent-free conditions and its catalytic activity has been compared with vanadyl(IV) meso-tetraphenylporphyrin (VP). Several reaction conditions, such as the amount of catalyst, time, solvent, and temperature, have been optimized to obtain the maximum yield of DHPMs or thiones. The synthesized β-functionalized V2BP porphyrin dimer manifests much higher conversion (84-95% yield) of DHPMs or the corresponding thiones under the optimized reaction conditions with high TON (4454-5037) and TOF (1113-1259 h-1) values for the one-pot multicomponent Biginelli reaction as compared to the literature. The catalyst exhibited excellent recyclability up to 10 cycles.

Green and Convenient Synthesis of Pharmaceutically Active Mono and Bis-dihydroquinazolines via a One-pot Multicomponent Reaction Under Sulfamic Acid Catalysis

Introduction: Multicomponent reactions (MCRs) and green chemistry are essential criteria for the development of efficient chemical syntheses for valuable organic compounds. Method: The design, synthesis, and development of sustainable procedures for the production of novel biological and pharmaceutical molecules have gained high importance. Herein, an environmentally benign synthesis of mono- and bis-2,3-dihydroquinazolin-4(1H)-ones as pharmaceutically active compounds was carried out in good to high yields of 80-99% within 45-120 minutes. Result: The desired products were synthesized via three-component and pseudo five-component condensations of isatoic anhydride, a primary amine (aniline or ammonium acetate), and an aldehyde/dialdehyde using sulfamic acid (20%) as a solid acidic catalyst under the solvent-free condition at 100°C. Conclusion: The easy work-up procedure, metal-free and environmentally benign catalyst, green reaction conditions for performing MCRs, and high yields of pure products are some advantages of the presented protocol.

Ultrasound Assisted and SO4-2/SnO2-Catalyzed One-Pot Multicomponent Reaction for the Synthesis of 1,2,3,4,6-Pentasubstituted Piperidines

Ultrasound Assisted and SO4-2/SnO2-Catalyzed One-Pot Multicomponent Reaction for the Synthesis of 1,2,3,4,6-Pentasubstituted Piperidines

Synthesis of Polysubstituted Pyridines via Nitrogen-doped Graphene Catalyzed One-Pot Multicomponent Reaction under Solvent-Free Conditions

Abstract: Polysubstituted pyridine derivatives were produced with high to excellent yields in the presence of nitrogen-doped graphene (NDG) as a dual acid-based catalyst. NDG efficiently catalyzes the multicomponent reaction between arylaldehydes, diethyl-acetylene dicarboxylates, malononitrile, and ammonium acetate under solvent-free conditions at 80°C to afford the polysubstituted pyridines in short reaction times. The structures of the synthesized pyridines were established by Ft-IR, 1H, and 13C NMR spectroscopic analysis. The advantages of this method include the in-situ oxidation of prepared 1,4-dihydropyridines, one-pot procedure, solventless system, operational simplicity, and no column chromatography. Additionally, neither toxic solvents nor catalysts are needed, and the procedure can be very reliable among the reported methodologies. The yields and reaction times in the presence of four times recycled catalyst are in comparable to the fresh catalyst.

Synthesis and biological evaluation of new 2-Amino-7-hydroxy-8-methyl-4-aryl-4H-chromene-3-carbonitrile derivatives

A series of new 2-amino-7-hydroxy-8-methyl-4-aryl-4H-chromene-3-carbonitrile derivatives (4a-4g) have been synthesized by a one-pot multicomponent reaction of 2-methylresorcinol (1) and malononitrile (2) with various aldehydes (3). All the synthesised compounds (4a-4g) have been characterised using FT-IR, 1H NMR, 13C NMR, HR-MS and evaluated for swarming behaviour, biofilm formation, biofilm disruption and urease activity against P. mirabilis (MTCC-425). Among all the synthesized compounds, compounds 4a, 4b and 4g showed slightly inhibited swarming behaviour and compounds 4f and 4g inhibited biofilm formation with increasing concentration. SEM (Scanning Electron Microscope) imaging shows that compound 4e effectively disrupts the preformed biofilm. Also, compounds 4d and 4e showed 40% reduction in urease activity. The SAR studies of synthesized compounds are elaborated in detail to provide key structural features. Furthermore, molecular docking studies against urease could provide a mechanistic basis for the inhibition. The per-residue interaction analysis suggested the involvement of non-bonded and bonded interactions with the active site of urease. Hence, the aim of the below study was to synthesize new chromene derivatives and study their biological activities.