Secondary amine-initiated three-component synthesis of 3,4-dihydropyrimidinones and thiones involving alkynes, aldehydes and thiourea/urea

Wan, Jie‐Ping; Lin, Yunfang; Hu, Kaikai; Liu, Yunyun

doi:10.3762/bjoc.10.25

Cited by 24 publications

(7 citation statements)

References 40 publications

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“…We successfully synthesized five compounds based on 3,4-dihydropyrimidinone and found their specific structure according to our previous work ( Wan and Pan, 2009 ; Wan et al, 2014 ). The formula and the molecular weight are showed as follows ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

“…Compounds 1 and 2 were synthesized following literature procedure reported by Pan et al ( Wan and Pan, 2009 ). Compounds 3 and 4 were synthesized following literature procedure reported by Wan et al ( Wan et al, 2014 ). Compound 5 was synthesized following a modified procedure based on literature process reported by Pan et al ( Wan and Pan, 2009 ).…”

Section: Methodsmentioning

confidence: 99%

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Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative

et al. 2021

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative

et al. 2021

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“…The results are shown in Table 1. [34]. None of the Lewis acids used in previous syntheses favored exclusively some of the reactions that developed, and presented different behaviors among them, although they presented the same by-products.…”

Section: Chemistrymentioning

confidence: 97%

Understanding the Lack of Reactivity of 2,4-Dihydroxybenzaldehyde Towards the Biginelli Adduct Using Density Functional Theory Molecular Modeling

et al. 2019

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The Biginelli reaction is a multicomponent reaction for obtaining dihydropyrimidinthiones quickly, with multiple substitution patterns. The reaction mechanism remains unclear. Three possible pathways proposed for the reaction are the iminium route, an enamine intermediate, and the Knoevenagel pathway. However, when thiourea was used, no theoretical calculations were reported. Thus, based on the literature, the iminium pathway was used to obtain evidence explaining the lack of reactivity of 2,4-dihydroxybenzaldehyde towards the Biginelli adduct, compared with 4-hydroxybenzaldehyde. This computational study, carried out using the B3LYP/6-31++G(d,p) level of theory, showed an increment of 150 kJ/mol in the activation energy of the slowest pathway, due to the presence of a hydroxyl group in position 2 (ortho) of the aromatic aldehyde, decreasing its reactivity. Natural bond orbital (NBO) calculations suggest that the determinant steps are simultaneous, i.e., the polarization of the carbonyl group and its corresponding protonation by the hydrogen of the SH fragment of the thiourea tautomer. The activation enthalpy values suggest that the nucleophile attack takes place later on the compound 2,4-dihydroxybenzaldehyde compared to 4-hydroxybenzaldehyde-TS, confirming that the OH group in position 2 hinders the condensation reaction.

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“…In 2014, we reported the secondary amine catalyzed three‐component reactions of aldehydes 16 , alkyl propiolates 36 , and ureas/thioureas 24 for the synthesis of 6‐unsubstituted DHPMs 37 . The reactions were run under the promotion of acid additives (TMSCl/ p ‐TSA) and exhibited satisfactory tolerance to the aryl/alkyl aldehydes, (N‐substituted) ureas/thioureas, and different alkyl propiolates 27. Although several similar compounds had been reported by using N ‐methylurea with harsh heating conditions before this work,28 our work was the first example allowing the general synthesis of these compounds using conventional starting materials corresponding to each component, including NH‐ and N‐substituted ureas/thioureas.…”

Section: Reactions Based On the Catalytic In Situ Generation Of Electmentioning

confidence: 99%

Domino Reactions Based on Combinatorial Bond Transformations in Electron-Deficient Tertiary Enamines

Wan

Gao

2016

The Chemical Record

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Electron-deficient enamines such as enaminones and enaminoesters are moieties showing widespread application in organic synthesis. Among the various available electron-deficient enamines, the N,N-disubstituted amino-functionalized ones (tertiary enamines) represent a class of special enamines with distinct properties and important applications. Based on our longstanding interest in exploring novel synthetic methods using electron-deficient tertiary enamines, we present herein the research advances in organic synthesis via domino reactions making use of the combinatorial C-N, C=C, C-H, and other bond transformations of electron-deficient tertiary enamines.

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Secondary amine-initiated three-component synthesis of 3,4-dihydropyrimidinones and thiones involving alkynes, aldehydes and thiourea/urea

Cited by 24 publications

References 40 publications

Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative

Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative

Understanding the Lack of Reactivity of 2,4-Dihydroxybenzaldehyde Towards the Biginelli Adduct Using Density Functional Theory Molecular Modeling

Domino Reactions Based on Combinatorial Bond Transformations in Electron-Deficient Tertiary Enamines

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