Search Results (27)

The growing demand for sustainable and efficient synthetic methodologies has brought nanocatalysis to the forefront of modern organic chemistry, particularly in the construction of heterocyclic compounds through multicomponent reactions (MCRs). Among various nanocatalysts, calcium oxide nanoparticles (CaO NPs) have gained significant attention because of their strong basicity, thermal stability, low toxicity, and cost-effectiveness. This review provides a comprehensive account of the recent strategies using CaO NPs as heterogeneous catalysts for the green synthesis of nitrogen- and oxygen-containing heterocycles through MCRs. Key reactions such as Biginelli, Hantzsch, and pyran annulations are discussed in detail, with emphasis on atom economy, reaction conditions, product yields, and catalyst reusability. In many instances, CaO NPs have enabled solvent-free or aqueous protocols with high efficiency and reduced reaction times, often under mild conditions. Mechanistic aspects are analyzed to highlight the catalytic role of surface basic sites in facilitating condensation and cyclization steps. The performance of CaO NPs is also compared with other oxide nanocatalysts, showcasing their benefits from green metrics evaluation like E-factor and turnover frequency. Despite significant progress, challenges remain in areas such as asymmetric catalysis, industrial scalability, and catalytic stability under continuous use. To address these gaps, future directions involving doped CaO nanomaterials, hybrid composites, and mechanochemical approaches are proposed. This review aims to provide a focused and critical perspective on CaO NP-catalyzed MCRs, offering insights that may guide further innovations in sustainable heterocyclic synthesis. Full article

In this work, eco-friendly ceric ammonium nitrate (CAN) and ferric chloride hexahydrate catalysts in ethanol/acetonitrile systems were used to efficiently synthesize novel dihydropyrimidinone (-thione) derivatives via the Biginelli reaction. The obtained compounds with phenolic fragments at the C4 position demonstrated enhanced antioxidant properties. Significant structure–activity relationships were indicated by three complementary assays (PFRAP, ABTS, and AAPH-induced DNA oxidation): oxo-derivatives demonstrated superior ferric ion reduction (PFRAP), while thio-substituted analogs consistently outperformed their carbonyl counterparts in radical scavenging. Remarkably, all compounds surpassed the reference antioxidant BHT, demonstrating the potential of synthesized dihydropyrimidine structures as multifunctional antioxidants for therapeutic applications. The study also shows the relationship between the catalyst–solvent system and its effect on product yields, using ceric ammonium nitrate and ferric chloride hexahydrate. Full article

Background: Heterocyclic compounds represent a key class of compounds in medicinal chemistry. Both benzimidazoles and pyrimidines are essential heterocycles in medicinal chemistry, with various therapeutic properties. Recent literature presents a series of hybrid heterocyclic compounds, as their medicinal properties are generally improved compared to those of single heterocyclic rings. Methods: A literature search was conducted across relevant scientific literature from peer-reviewed sources, using keywords, including “benzimidazole”, “pyrimidine”, “Biginelli”, “benzimidazole-pyrimidine hybrids”, “anticancer”, “antiviral”, “antimicrobial”, and “anti-inflammatory”. Results: In this review, benzimidazole–pyrimidine hybrids are reported as anticancer, antimicrobial, antiviral, anti-inflammatory, analgesic, antiulcer, antidepressant, anti-Alzheimer’s, or antioxidant agents, with activities even better than those of existing drugs. The IC₅₀ values for these anticancer hybrids are in the nanomolar range, which signifies potent anticancer agents. It can be mentioned here that the anticancer hybrid Abemaciclib, as a CDK4/6 inhibitor for the treatment of certain types of breast cancer, was approved in 2017. The antimicrobial activity of these hybrids proved especially potent against a broad variety of infections, with MIC values in the range of µM or even nM. Moreover, these hybrids exhibited good antiviral properties against SARS-CoV-2, HIV-1, and the hepatitis C virus. The hybrids also functioned as JAK3 inhibitors, COX-1 inhibitors, and MAO-A inhibitors. Conclusions: This review presents synthesis methods of benzimidazole–pyrimidine hybrids, their medicinal properties, and SAR studies reported in the last 20 years. For almost every therapeutic activity, SAR studies have revealed the essential presence of a substituent on the aromatic rings or between the two benzimidazole and pyrimidine nuclei. Full article

This study introduces an efficient and sustainable catalytic system utilizing cobalt ferrite nanoparticles (CoFe₂O₄-NPs) for the synthesis of valuable 6-amino-2-oxo-4-phenyl (or 4-chlorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives. Recognizing the limitations of traditional methods for the Biginelli reaction, we thoroughly characterized CoFe₂O₄-NPs, alongside individual iron oxide nanoparticles (Fe₂O₃-NPs) and cobalt oxide nanoparticles (CoO-NPs), using FTIR, XRD, TEM, SEM, XPS, TGA, and BET analysis. These characterizations revealed the unique structural, morphological, and physicochemical properties of CoFe₂O₄-NPs, including an optimized porous structure and significant bimetallic synergy between Fe and Co ions. Catalytic studies demonstrated that CoFe₂O₄-NPs significantly outperformed individual Fe₂O₃-NPs and CoO-NPs under mild conditions. While the latter only catalyzed the Knoevenagel condensation, CoFe₂O₄-NPs uniquely facilitated the complete Biginelli reaction. This superior performance is attributed to the synergistic electronic environment within CoFe₂O₄-NPs, which enhances reactant activation, intermediate stabilization, and proton transfer during the multi-step reaction. This work highlights the potential of CoFe₂O₄-NPs as highly efficient and selective nanocatalysts for synthesizing biologically relevant 1,2,3,4-tetrahydropyrimidines, offering a greener synthetic route in organic chemistry. Full article

In this study, we present the highly efficient and rapid synthesis of substituted dihydropyrimidinone derivatives through an ultrasound-accelerated approach. We utilize copper ferrite (CuFe₂O₄) magnetic nanoparticles as heterogeneous catalysts, employing the well-known Biginelli reaction, under solvent-free conditions. The impact of the solvent, catalyst amount, and catalyst type on the reaction performance is thoroughly investigated. Our method offers several notable advantages, including facile catalyst separation, catalyst reusability for up to three cycles with the minimal loss of activity, a straightforward procedure, mild reaction conditions, and impressive yields, ranging from 79% to 95%, within short reaction times of 20 to 40 min. Furthermore, in the context of fighting COVID-19, we explore the potential of substituted dihydropyrimidinone derivatives as inhibitors of three crucial SARS-CoV-2 proteins. These proteins, glycoproteins, and proteases play pivotal roles in the entry, replication, and spread of the virus. Peptides and antiviral drugs targeting these proteins hold great promise in the development of effective treatments. Through theoretical molecular docking studies, we compare the binding properties of the synthesized dihydropyrimidinone derivatives with the widely used hydroxychloroquine molecule as a reference. Our findings reveal that some of the tested molecules exhibit superior binding characteristics compared to hydroxychloroquine, while others demonstrate comparable results. These results highlight the potential of our synthesized derivatives as effective inhibitors in the fight against SARS-CoV-2. Full article

Bioactive dihydropyrimidinones (DHPs) were designed and synthesized by a multicomponent Biginelli reaction. The reaction was catalyzed by the polarized surface of nano-zirconium dioxide with partial positive charge of 0.52e at the Zr center and a negative charge of −0.23e at the oxygen center. There was good corroboration between the computed and experimental ZrO₂ cell parameters and bond distances as determined by in silico and in vitro experimental methods. Since DHPs were found to target the peroxisome proliferator-activated receptor (PPAR)-γ, we tested these ligands toward MCF-7 cell toxicity, which revealed that the compounds 4d [ethyl-4-(4′-fluoro-[1,1′-biphenyl]-4-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate] and 4e [ethyl-4-(3′-methoxy-[1,1′-biphenyl]-4-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate] inhibited proliferation with IC₅₀ values of 11.8 and 15.8 μM, respectively. Further, our bioinformatic analysis found that the active molecule 4d, fit into the enzyme’s catalytic site, almost in the same position as rosiglitazone, which was buried deep inside the cavity. In conclusion, we herein report novel DHPs which could be better structures to help explore a new class of synthetic PPAR-γ ligands. Full article

Hypertension and cardiovascular diseases related to it remain the leading medical challenges globally. Several drugs have been synthesized and commercialized to manage hypertension. Some of these drugs have a dihydropyrimidine skeleton structure, act as efficient calcium channel blockers, and affect the calcium ions’ intake in vascular smooth muscle, hence managing hypertension. The synthesis of such moieties is crucial, and documenting their structure–activity relationship, their evolved and advanced synthetic procedures, and future opportunities in this area is currently a priority. Tremendous efforts have been made after the discovery of the Biginelli condensation reaction in the synthesis of dihydropyrimidines. From the specific selection of Biginelli adducts to the variation in the formed intermediates to achieve target compounds containing heterocylic rings, aldehydes, a variety of ketones, halogens, and many other desired functionalities, extensive studies have been carried out. Several substitutions at the C3, C4, and C5 positions of dihydropyrimidines have been explored, aiming to produce feasible derivatives with acceptable yields as well as antihypertensive activity. The current review aims to cover this requirement in detail. Full article

Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software. Full article

The interest in 3,4-dihydropyrimidine-2(1H)-(thio)ones is increasing every day, mainly due to their paramount biological relevance. The Biginelli reaction is the classical approach to reaching these scaffolds, although the product diversity suffers from some limitations. In order to overcome these restrictions, two main approaches have been devised. The first one involves the modification of the conventional components of the Biginelli reaction and the second one refers to the postmodification of the Biginelli products. Both strategies have been extensively revised in this manuscript. Regarding the first one, initially, the modification of one of the components was covered. Although examples of modifications of the three of them were described, by far the modification of the keto ester counterpart was the most popular approach, and a wide variety of different enolizable carbonylic compounds were used; moreover, changes in two or the three components were also described, broadening the substitution of the final dihydropyrimidines. Together with these modifications, the use of Biginelli adducts as a starting point for further modification was also a very useful strategy to decorate the final heterocyclic structure. Full article

As a solid acid, zeolite has been widely used in many fields such as tail gas treatment, petrochemical engineering, and the fine chemical industry. F⁻ has been widely used in the synthesis of pure silica or high silica zeolites. To balance the charge of organic structure directing agents (OSDA), F⁻ is often found located at the center of the double-4-rings (d4r) of the as-made zeolites. During calcination, fluorine ion is removed with the OSDA. We screened a series of composition building units and found that d4r is capable to retain F⁻ in zeolite structure. We introduce the F⁻ back after the calcination to create an unprecedented type of acid site, i.e., F⁻@d4r in pure silica zeolites ITQ-12. The F⁻@d4r species is thermal stable up to 300 °C. ITQ-12 with F⁻@d4r shows substantial catalytic activity in Biginelli reaction. Furthermore, the catalytic performance is proved to be positive correlated with the presence of F⁻@d4r, indicating the mild acid catalytic property of F⁻@d4r. Full article

Dihydrouracil presents a crucial intermediate in the catabolism of uracil. The vital importance of uracil and its nucleoside, uridine, encourages scientists to synthesize novel dihydrouracils. In this paper, we present an innovative, fast, and effective method for the synthesis of dihydrouracils. Hence, under mild conditions, 3-chloroperbenzoic acid was used to cleave the carbon–sulfur bond of the Biginelli hybrids 5,6-dihydropyrimidin-4(3H)-ones. This approach led to thirteen novel dihydrouracils synthesized in moderate-to-high yields (32–99%). Full article

Some new pyrimidine derivatives comprising arylsulfonylhydrazino, ethoxycarbonylhydrazino, thiocarbamoylhydrazino and substituted hydrazone and thiosemicarbazide functionalities were prepared from Biginelli-derived pyrimidine precursors. Heterocyclic ring systems such as pyrazole, pyrazolidinedione, thiazoline and thiazolidinone ring systems were also incorporated into the designed pyrimidine core. Furthermore, fused triazolopyrimidine and pyrimidotriazine ring systems were prepared. The synthesized compounds were evaluated for their calcium channel blocking activity as potential hypotensive agents. Compounds 2, 3a, 3b, 4, 11 and 13 showed the highest ex vivo calcium channel blocking activities compared with the reference drug nifedipine. Compounds 2 and 11 were selected for further biological evaluation. They revealed good hypotensive activities following intravenous administration in dogs. Furthermore, 2 and 11 displayed drug-like in silico ADME parameters. A ligand-based pharmacophore model was developed to provide adequate information about the binding mode of the newly synthesized active compounds 2, 3a, 3b, 4, 11 and 13. This may also serve as a reliable basis for designing new active pyrimidine-based calcium channel blockers. Full article

A Brönsted acidic ionic solid pyridinium-functionalized organosilica network (PMO-Py-IL) was demonstrated to efficiently catalyse one-pot Biginelli condensation reaction. The green synthesis of 3,4-dihydro-2(H)-pyrimidinones (DHPMs) with high yield was carried out via one-pot three component condensation of β- dicarbonyls, aldehydes, and urea in the presence of a catalytic amount of PMO-Py-IL nanomaterial as an efficient nanocatalyst under solvent free conditions. Furthermore, the catalyst showed outstanding stability and could be easily separated and reused for at least ten reaction runs without significant loss of activity and product selectivity. The green protocol features simple set-up, cost-effectiveness, easy work-up, eco-friendly and mild reaction conditions. Full article

Antimicrobial resistance was one of the top priorities for global public health before the start of the 2019 coronavirus pandemic (COVID-19). Moreover, in this changing medical landscape due to COVID-19, finding new organic structures with antimicrobial and antiviral properties is a priority in current research. The Biginelli synthesis that mediates the production of pyrimidine compounds has been intensively studied in recent decades, especially due to the therapeutic properties of the resulting compounds, such as calcium channel blockers, anticancer, antiviral, antimicrobial, anti-inflammatory or antioxidant compounds. In this review we aim to review the Biginelli syntheses reported recently in the literature that mediates the synthesis of antimicrobial compounds, the spectrum of their medicinal properties, and the structure–activity relationship in the studied compounds. Full article

The availability and application of direct, functional group-compatible C–H activation methods for late-stage modification of small-molecule bioactives and other valuable materials remains an ongoing challenge in organic synthesis. In the current study, we demonstrate that a LED-activated, photoredox-mediated, Pd(OAc)₂-catalyzed C–H arylation, employing a phenyldiazonium aryl source and either tris(2,2′-bipyridine)ruthenium(II) or (2,2′-bipyridine)bis[3,5-di-fluoro-2-[5-(trifluoromethyl)-2-pyridinyl-kN][phenyl-kC]iridium(III) as photoredox initiator, may successfully produce unprecedented mono- and bis-phenyl derivatives of functionality-rich 2,6-diphenylpyrimidine substrates at room temperature. The series of 19 substrates employed herein, which share the biologically-relevant 4-methyl-2,6-diphenylpyrimidine-5-carboxylate scaffold, were generated via a synthetic route involving (3-component) Biginelli condensation, oxidative dehydrogenation of the obtained 3,4-dihydropyrimidin-2(1H)-one to 2-hydroxypyrimidine, O-sulfonylation, and Suzuki-Miyaura C–C cross-coupling. Submission of these substrates to pyrimidine-N-atom-directed C–H arylation conditions led to regioselective phenylation at the ortho site(s) of the pyrimidine-C2-connected phenyl ring, revealing substituent-dependent electronic and steric effects. A focused library of 18 mono- and 10 bis-phenyl derivatives was generated. Its members exhibit interesting 3D and peripheral substitution features that render them promising for evaluation in drug discovery efforts. Full article