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A highly regioselective and efficient method has been developed for synthesizing novel β-amino alcohols fused with dihydropyrimidin-2-one. This method utilizes the enzyme Novozyme-435 to catalyze the reaction between epoxides and various aliphatic amines in acetonitrile. Novozyme-435 outperformed other catalysts, including Porcine Pancreatic Lipase (PPL), Pseudomonas aeruginosa lipase (PAL), and Candida rugosa lipase (CRL). This process yielded two series of β-amino alcohols (compounds 8a-h and 9a-h), whose structures were confirmed through IR, NMR (1H,13C), and HRMS analyses. The anti-inflammatory and antioxidant properties of these compounds were evaluated, revealing mild to moderate inhibition of TNF-α-induced ICAM-1 expression in primary human endothelial cells, with compounds 9a and 9c showing approximately 60% inhibition. Antioxidant activity, assessed using the DPPH (2,2-diphenyl-1-picrylhydrazyl) method, indicated that compounds 9a, 9b, 9c, and 9 g had the superior activity than others. This study highlights the potential of these β-amino alcohols fused with dihydropyrimidin-2-one as anti-inflammatory and antioxidant agents. [ABSTRACT FROM AUTHOR]

In this study, glycine-based ionic liquid ([Gly-H][OTs]) was synthesized through a reaction of glycine with ρ-toluenesulfonic acid in water. The synthesized IL was utilized for the one-pot, multi-component synthesis of 3,4-dihydropyrimidin-2(1H)-ones, 14-aryl-14H-dibenzo[a,j]xanthenes and 12-aryl-8,9,10,12-tetrahydrobenzo [a]xanthene-11-ones under solvent-free condition. The prepared IL indicates desirable catalytic activity in organic reactions under solvent-free conditions with the high reusability of four runs. The proposed protocol's main advantages are the originality of prepared [Gly-H][OTs], organic green synthesis under solvent-free conditions, high product yields, and less reaction times. [ABSTRACT FROM AUTHOR]

Herein, a solvent-free synthesis of 5-bromothiophene based 3,4-dihydropyrimidin-2-(1H)-(thi)ones was explored. The main advantages of this study are that pure products are readily obtained through an easy workup and without using any separation technique and in good yields (66-80% yield), All the synthesized products were characterized by 1H and 13C-APT NMR, IR spectroscopy and elemental analysis. A single crystal X-ray analysis of ethyl-4-(5-bromothiophen-2-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4c) was performed. All the synthesized compounds were screened for their antifungal and antibacterial assay. Among all synthesized compounds, some showed good antibacterial and antifungal activity. ADMET prediction for was carried out and calculated data show that all the compounds have a drug-like nature. [ABSTRACT FROM AUTHOR]

Imidazolium sulfonic acid chloride grafted ZrO2 nanoparticles (ZrO2-IL) were synthesized through facile post-treatment of the nanoparticles with the imidazolium-sulfonic acid chloride ionic liquid. The immobilization of the ionic liquid over the ZrO2 nanoparticles was evident from the XRD, SEM, TEM, Raman, BET, and XPS analysis. The results obtained from the XRD analysis clearly show that the catalyst has an orthorhombic structure and from the BET analysis it is evident that the surface is mesoporous with uniform pore sizes and pore distribution. Further evidence of immobilization of ionic liquid over the ZrO2 NPs was obtained from the SEM, TEM, XPS, and Raman analysis. Under mild conditions, the synthesized heterostructure was used in the acid-catalyzed esterification of different acids. The ZrO2-IL catalyst converts 99% of the acid to ester with a 98.9% yield in 1h. The material was also shown to be highly efficient as catalyst for the Biginelli reaction under solvent-free conditions, with the catalyst for dihydropyrimidin-2(1H)-one (DHPMs) in 1h with 99.2% conversion and 99% yield. The synergy between the ionic liquid catalyst and the substrates increased the catalytic efficiency and resulted in high-yield product conversion. The mechanism of both transformation reactions was investigated, as well as the synergy between ionic liquid and ZrO2 nanoparticles for better catalytic efficiency was established. [ABSTRACT FROM AUTHOR]

The synthesis of 3,4-dihydropyrimidin-2(1H)-one, -thione, and -selone derivatives by three-com-ponent condensation of aromatic aldehydes, ethyl acetoacetate, and urea (thiourea, selenourea) was catalyzed by TiO2 nanoparticles. The effect of this catalyst on the reaction time and yield was investigated. The use of TiO2 nanoparticles improved the reaction conditions to an acceptable level, and good yields of the products were obtained. [ABSTRACT FROM AUTHOR]

A series novel dihydropyrimidinone (DHPM) containing 1,2,3-triazole moiety have been designed and synthesized using Cu(I) catalysed azide-alkyne cycloaddition (CuAAC) method. All synthesized derivatives have been characterised by IR, 1H and 13C NMR, and mass spectra. The new chemical entities (NCEs) have been tested for in vitro antibacterial and anticancer activity. The novel 1,2,3-triazole derivatives have been also subjected to molecular properties prediction, drug likeness by using Molinspiration (Molinspiration-2017) and MolSoft (MolSoft-2017) tools. [ABSTRACT FROM AUTHOR]

A novel caffeine-based acidic ionic liquid was synthesized, characterized, and utilized as an efficient and green catalyst for synthesizing DHPMs, xanthenediones, and acridinediones under solvent-free conditions. The prepared IL showed notable catalytic activity in organic reactions under solvent-free conditions with good reusability of four runs. The advantage of the present protocol is underlined by the originality of the prepared ionic liquid, absence of toxic solvents, high yields of products, and short reaction times. [ABSTRACT FROM AUTHOR]

The synthesis of 5-acetyl-6-methyl-4-(1,3-diphenyl-1H-pyrazol-4-yl)-3,4-dihydropyrmidin-2(1H)-thione was achieved by one-pot three-component synthesis using CaCl2 in refluxing EtOH. The starting compound was utilized to synthesize a new series of 5-pyrazolyl; isoxazolyl; pyrimidinyl derivatives via the synthesized chalcone. Also, fused isoxazolo [5,4-d]pyrimidine and pyrazolo[3,4-d]pyrimidine were obtained by the treatment of 5-acetyl derivative with hydroxyl amine and/ or hydrazine hydrate. Also, the thiosemicarbazide derivative was prepared and utilized to synthesize other new thiazole derivatives. The structures of all compounds have been established on the basis of their analytical and spectral data. All compounds was also evaluated for their antibacterial and antifungal activity against various strains of bacteria and fungi. Also, the anti-inflammatory activity of some of synthesized compounds was evaluated using the carrageenan induced paw oedema test in rats using indomethacin as the reference drug. [ABSTRACT FROM AUTHOR]

Background: Toll-like receptor 4 (TLR4) initiates both innate and adaptive immune responses, which plays an important protective role in self-defense mechanisms. Excessive or inappropriate TLR4 activation causes the development of many autoimmune diseases. Dihydropyrimidinone derivatives are medicinally important molecules with diverse pharmacological activities, including anti-inflammatory activity. The present study focused on novel synthesized 3,4-dihydropyrimidinone derivatives and evaluated their inhibitory effects on TLR4.Methods: A series of 3,4-dihydropyrimidinone derivatives were recently synthesized and evaluated for their TLR4 inhibition activities and cytotoxic on HEK-BlueTM hTLR4 cells with the help of QUANTI-Blue assay and MTS assay. Selected compound 3 was analyzed for its molecular docking with TLR4 by using Autodock vina 1.1.2. Its effect on the TLR4 pathway related cytokines was also evaluated in THP-1 cells and human peripheral blood mononuclear cells by using real-time PCR, ELISA and western blot.Results: Five compounds were synthesized and characterized for effectiveness based on 3,4-dihydropyrimidinone. Compound 3 was found to be the potent hybrid among the synthesized compounds, with high TLR4 inhibition activities and low cytotoxic activities against HEK-BlueTM hTLR4 cells. Molecular docking analysis showed that two hydrogen bonds between compound 3 and residues Asp209(TLR4) and Asp99(MD-2) mainly contribute to the TLR4 inhibition. In addition, compound 3 suppressed LPS-induced of the mRNA expression of TLR4, IP-10, TNF-α, IL-6, IL-12A, and IL-12B, the protein expression of pIRF3 and pNFκB and the secretion of IP-10, TNF-α in THP-1 cell line. Compound 3 also inhibited LPS-induced expression of TNF-α, IL-6, and IL-1β but increased IP-10 at mRNA levels in human peripheral blood mononuclear cells.Conclusion: Our study reveals compound 3, a novel 3,4-dihydropyrimidinone derivative, is a potential TLR4 antagonist, which opens up new research avenues for the development of promising therapeutic agents for inflammatory and autoimmune diseases.

1-Butyl-3-methylimidazolium hydrogen sulfate ([BMIM][HSO4]) as a non-halogenated ionic liquid (IL) was used for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones or 2-selenoxo DHPMs in a Biginelli type multi-component reaction. By using this ionic liquid, the reaction time was significantly reduced and the products were obtained in good to high yields. Also, in this method, the synthesis of novel 2-selenoxo DHPMs is introduced in the presence of this ionic liquid and their structures were determined by 1H and 13C NMR, FT-IR, and Elemental analysis. [ABSTRACT FROM AUTHOR]

5-Carboxanilide-dihydropyrimidinone derivatives were prepared by three-component Biginelli reaction of acetoacetanilide, aromatic aldehydes and thiourea in the presence of CeCl3 as an expedient catalyst and used as key intermediates for the highly efficient and eco-friendly synthesis of new and densely functionalized thiazolo[3,2-a]pyrimidin derivatives with use of dimethyl and diethyl acetylenedicarboxylate in ethanol at ambient temperature (conventional magnetic stirring). [ABSTRACT FROM AUTHOR]

This article studies a digital hydraulic servo drive driven by a variable speed electric servomotor. Digital displacement control is implemented by using a two-port digital hydraulic power management system having six pistons and 18 on/off control valves. The first port of the digital hydraulic power management system controls the cylinder speed, while the second port is connected to a hydraulic accumulator. The peak power is taken from the accumulator, and the electric servomotor supplies only the average power into the system. An experimentally validated simulation model is used, and the results show a combination of adequate controllability and excellent energy efficiency. The estimated reduction in the size of the electric motor is 57%. [ABSTRACT FROM AUTHOR]

• Multicomponent reactions helps to swiftly synthesize and evaluate for activity. • This review covers synthesis of dihydropyrimidines and their biological activities. • Novel dihydropyrimidines can be potential anticancer therapeutics. • This review reports all the patented and marketed dihydropyrimidines as drugs. • This review reports future perspectives of dihydropyrimidines in drug discovery. One of the largest classes of organic molecules are dihydropyrimidines and its derivatives. They are widely used in a variety of pharmacological and industrial applications. Their biological and pharmacological activities include antihypertensive, antidiabetic, anti-inflammatory, antibacterial, antifungal, anticancer, and antiviral activities. The presence of pyrimidine and pyrimidine-containing rings in the substructures of therapeutically effective drugs has drawn considerable interest amongst the scientific fraternity. The potential therapeutic use of these heterocycles has prompted medicinal chemists to synthesize drugs that contain these heterocycles. Against this backdrop, this review examines the one-pot multicomponent reaction, that is, the Biginelli reaction and its mechanism. Also, we reviewed various synthetic approaches for the synthesis of dihydropyrimidines and their diverse pharmacological activities reported in the last two decades. We highlight different marketed drugs with dihydropyrimidine as a pharmacophore as well as patented dihydropyrimidines in the recent past. [Display omitted] [ABSTRACT FROM AUTHOR]

We investigated a novel catalytic application of nickel-doped zinc oxide (Ni-ZnO) nanoparticles and zinc oxide (ZnO) nanoflakes at room temperature in an aqueous hydrotropic solution for the synthesis of biologically active dihydropyrimidones (DHPMs). Ni-ZnO is a stable, recyclable, green, efficient heterogeneous catalyst which shows maximum yield in a shorter reaction time than ZnO nanoflakes in very mild conditions of hydrotropic aqueous medium for DHPMs syntheses. [ABSTRACT FROM AUTHOR]

Dihydropyrimidin-2(1H)-ones/thiones (DHPMs) are important heterocyclic compounds owing to their excellent biological activities and have been widely utilized in pharmaceutical applications. Recently, numerous DHPM derivatives have been prepared. This review covers the synthesis of DHPMs and improved procedures for the preparation of DHPMs from 1995 to 2016. [ABSTRACT FROM AUTHOR]

The three-component reactions of aldehydes, electron deficient alkynes and ureas/thioureas have been smoothly performed to yield a class of unprecedented 3,4-dihydropyrimidinones and thiones (DHPMs). The reactions are initiated by the key transformation of an enamine-type activation involving the addition of a secondary amine to an alkyne, which enables the subsequent incorporation of aldehydes and ureas/thioureas. This protocol tolerates a broad range of aryl- or alkylaldehydes, N-substituted and unsubstituted ureas/thioureas and alkynes to yield the corresponding DHPMs with specific regioselectivity.

A series of novel chiral 4-styryldihydropyrimidin-2-thiones were prepared with high yields and enantioselective by a Biginelli reaction. In the condensation reaction, substituted cinnamaldehyde, thiourea, and β-ketoester were organocatalyzed to afford 4-styryldihydropyrimidin-2-thiones 4a- v using self-assembled methanoproline-thiourea as catalysts. Anti-proliferative activity of these 4-styryldihydropyrimidin-2-thiones was tested against the HepG2 and PC-3 cells. Among all the tested compounds, 4e, 4k, and 4s bearing CF- groups at styryl group displayed moderate anti-proliferative activity with IC ranged between 29.3-38.5 μM. The structure-activity relationship showed that substituents (R) on the C-4 styryl ring of 4-styryldihydropyrimidin-2-thiones and R at ester group affected the anti-proliferative activity, yet R at C-6 position had little influence for anti-proliferative activity. [ABSTRACT FROM AUTHOR]

This report describes the development of six acidic composites of Y-zeolite with 1,3-disulfoimidazolium trifluoroacetate [Dsim][CFCOO] ionic liquid (IL) and displays the gradual increase of acidic IL mediated dealumination within zeolite framework with increasing loading in Powder XRD and IR studies. The structural changes of modified framework of zeolite were analyzed by SEM-EDX, TEM, TGA, BET and UV-Vis techniques. Out of the six composites, the more acidic [Dsim][CFCOO]/NaY = 20% (e) composite was evaluated as heterogeneous catalyst for multicomponent synthesis of 3,4-dihydropyrimidinones (DHPMs) under neat condition at various temperature. Graphical Abstract: [ABSTRACT FROM AUTHOR]

Abstract: Preparative nanoZnO and ZnO have been found as reusable catalysts for either condensation or dissociation of urea to ammonia and controllable selectivity in the Biginelli and Hantzsch reactions. The feasibility of urea dissociation to ammonia and switching of the selectivity of heterocyclization for DHPMs to DHPs over various metal oxides has been comparatively investigated. In the presence of nanoZnO and ZnO, direction of the MCR reaction in either Biginelli or Hantzsch way is possible by choice of the reaction conditions. Biginelli reaction occurs at 60°C under solvent-free conditions, while Hantzsch reaction occurs in water at ∼120–140°C or under microwave irradiation using 5mol% nanoZnO or 10mol% ZnO. [Copyright &y& Elsevier]

Abstract: An efficient one-pot method to synthesize thiazolo[3,2-a]pyrimidine derivatives has been developed. The method involves the temperature controlled functionalization-annulation of 5-ethoxycarbonyl-6-methyl-4-aryl-3,4-dihydro-2(1H)-pyrimidin-2-thione (DHPM) derivatives with in-situ generated bromo-ketones received by reaction of different α-H carbonyl compounds with bromine. [Copyright &y& Elsevier]

Abstract: Here we demonstrate on the synthesis of 3,4-dihydropyrimidin-2-ones (DHPMs) and their derivatives through a three-component condensation reactions of aldehyde, β-ketoester and urea or thiourea using mesoporous aluminosilicate (AlKIT-5) nanocage as catalyst and acetonitrile as solvent under reflux conditions. The catalyst was found to be highly active and selective, affording a high yield of DHPMs. Compared to the classical Biginelli reaction conditions, this new approach consistently has the advantage of excellent yields (80–96%) and short reaction times, 3.0–4.0h. The effect of the acidity and the concentration of the catalyst on the above process was investigated. We also demonstrate the synthesis of various multifunctional Biginelli compounds using the highly active AlKIT-5 catalysts. [Copyright &y& Elsevier]

Dihydropyrimidinones (DHPMs) are heterocycles obtained by the multicomponent Biginelli reaction. Recently, new synthetic protocols have allowed us to explore functionalisation at less explored positions of DHPMs, such as the N1 position. In this context, a full literature survey of N1- substituted DHPMs was performed. We analysed 27 papers and identified 379 compounds with substituents at the N1 position, most of them with alkyl groups, and a total of 28% compounds with aromatic substituents attached at the N1 position. N1-substituted DHPMs were explored mainly due to their effects on cancer cell proliferation via numerous targets, such as kinesin Eg5, heat shock protein 70, heat shock protein 90, and the epidermal growth factor receptor. Similarity analyses were performed using the data of 379 DHPMs from different cheminformatic approaches, i.e., chemical property correlations, principal component analysis, similarity networks, and compound clustering., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A zeolite-catalyzed, simple, one-pot, solvent-free, cost effective, and environmentally benign process for the synthesis of dihydropyrimidones is described. This reaction is scaleable to multigram scale and the catalyst is recyclable. This methodology has resulted in an efficient synthesis of monastrol, a potent inhibitor of kinesin Eg5.

Background: Toll-like receptor 4 (TLR4) initiates both innate and adaptive immune responses, which plays an important protective role in self-defense mechanisms. Excessive or inappropriate TLR4 activation causes the development of many autoimmune diseases. Dihydropyrimidinone derivatives are medicinally important molecules with diverse pharmacological activities, including anti-inflammatory activity. The present study focused on novel synthesized 3,4-dihydropyrimidinone derivatives and evaluated their inhibitory effects on TLR4. Methods: A series of 3,4-dihydropyrimidinone derivatives were recently synthesized and evaluated for their TLR4 inhibition activities and cytotoxic on HEK-BlueTM hTLR4 cells with the help of QUANTI-Blue assay and MTS assay. Selected compound 3 was analyzed for its molecular docking with TLR4 by using Autodock vina 1.1.2. Its effect on the TLR4 pathway related cytokines was also evaluated in THP-1 cells and human peripheral blood mononuclear cells by using real-time PCR, ELISA and western blot. Results: Five compounds were synthesized and characterized for effectiveness based on 3,4-dihydropyrimidinone. Compound 3 was found to be the potent hybrid among the synthesized compounds, with high TLR4 inhibition activities and low cytotoxic activities against HEK-BlueTM hTLR4 cells. Molecular docking analysis showed that two hydrogen bonds between compound 3 and residues Asp209(TLR4) and Asp99(MD-2) mainly contribute to the TLR4 inhibition. In addition, compound 3 suppressed LPS-induced of the mRNA expression of TLR4, IP-10, TNF-α, IL-6, IL-12A, and IL-12B, the protein expression of pIRF3 and pNFκB and the secretion of IP-10, TNF-α in THP-1 cell line. Compound 3 also inhibited LPS-induced expression of TNF-α, IL-6, and IL-1β but increased IP-10 at mRNA levels in human peripheral blood mononuclear cells. Conclusion: Our study reveals compound 3, a novel 3,4-dihydropyrimidinone derivative, is a potential TLR4 antagonist, which opens up new research avenues for the development of promising therapeutic agents for inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]

The present work describes the one-pot multicomponent synthesis of heterocyclic 3,4-dihydropyrimidin-2-(1H)-ones and thiones (DHPMs) under solvent-free conditions by Sr 2 As 2 O 7 nanocatalyst. Sr 2 As 2 O 7 nanocatalyst was synthesized by solvothermal reactions at stoichiometric molar ratio. The characterizations of the as-prepared nanomaterials were performed by X-ray powder diffraction (XRPD) and fourier-transform infrared (FTIR) techniques. According to Rietveld analysis data, it was found that reaction time had a considerable effect on crystal phase change from monoclinic to tetragonal crystal system. Field emission scanning electron microscope (FESEM) images showed that the morphology of the obtained materials was changed by increasing the reaction time, from 24 to 120 h, from long-length rods to multigonal plates. Catalytic activity of the nanomaterials was investigated in Biginelli reactions for the synthesis of heterocyclic DHPMs compounds. The synthesis yields at optimum conditions were 94% and 96% for S 1 and S 5 , respectively. Langmuir–Hinshelwood kinetic model revealed that the reactions followed a pseudo-first order kinetic model. Image 1 • Ultrasonic assisted solvothermal method was used for the first time to synthesize of Sr 2 As 2 O 7. • Monoclinic and tetragonal crystal systems were achieved by changing the reaction condition. • High efficient catalytic performance was obtained to synthesize of DHPMs in Biginelli reactions. • Langmuir–Hinshelwood (L–H) kinetic model was used to study the kinetic behavior of the catalyst. [ABSTRACT FROM AUTHOR]

Abstract: Dowex-50W ion exchange resin-promoted solvent-free heating of an intimate mixture of an aldehyde, an active methylene compound and N,N′-dimethylurea furnished the title compounds in moderate to good yields. [Copyright &y& Elsevier]

The three-component reactions of aldehydes, electron deficient alkynes and ureas/thioureas have been smoothly performed to yield a class of unprecedented 3,4-dihydropyrimidinones and thiones (DHPMs). The reactions are initiated by the key transformation of an enamine-type activation involving the addition of a secondary amine to an alkyne, which enables the subsequent incorporation of aldehydes and ureas/thioureas. This protocol tolerates a broad range of aryl- or alkylaldehydes, N-substituted and unsubstituted ureas/thioureas and alkynes to yield the corresponding DHPMs with specific regioselectivity.

A zeolite-catalyzed, simple, one-pot, solvent-free, cost effective, and environmentally benign process for the synthesis of dihydropyrimidones is described. This reaction is scaleable to multigram scale and the catalyst is recyclable. This methodology has resulted in an efficient synthesis of monastrol, a potent inhibitor of kinesin Eg5.