Precision in stereochemistry: the integral role of catalytic asymmetric Biginelli reaction in crafting enantiomerically pure dihydropyrimidinones.

One well-known multicomponent reaction that is helpful in the synthesis of dihydropyrimidinones (DHPMs), important molecules in organic synthesis and medicinal chemistry, is the Biginelli reaction. Because of their wide range of biological activities, DHPMs are regarded as essential chemicals. A great deal of research has been done in the last few decades to find ways to produce enantiomerically pure DHPMs because of their notable and focused target-oriented biological activities. In this reaction, numerous structural variants and catalysts have been employed in a range of solvents to yield an enormous number of Biginelli-type compounds. In the present review, the available catalysts in the literature including ionic liquids, Lewis acids, and organocatalysts for the Biginelli reaction and synthesis of a large number of asymmetric compounds since 2003 are summarized.

Dihydropyrimidinones as potent anticancer agents: Insight into the structure-activity relationship.

Cancer is a serious disease that has been around for a long time but currently has no sustainable solution. Several medications currently available offer an opportunity for the manifestation of cancer treatment; however, the "search for better" has led to the development and study of a variety of new scaffolds. Dihydropyrimidinones (DHPMs) are a privileged scaffold, prominent for their versatile range of biological activities. In recent years, the anticancer potential of these unsaturated pyrimidine ring systems has been traversed, along with their synthesis methods and the interlinked mechanisms leading to the anticancer activity. This review summarizes the structure-activity relationship of DHPMs as potential anticancer agents. This study is a short review of their synthesis, mechanism of action, and structure-activity relationships (SARs) that are answerable for the anticancer activity of DHPMs and have been thoroughly researched and assessed.

Deep eutectic solvent mediated synthesis of 3,4-dihydropyrimidin-2(1H)-ones and evaluation of biological activities targeting neurodegenerative disorders.

Substitution of hazardous and often harmful organic solvents with "green" and "sustainable" alternative reaction media is always desirous. Ionic liquids (IL) have emerged as valuable and versatile liquids that can replace most organic solvents in a variety of syntheses. However, recently new types of low melting mixtures termed as Deep Eutectic Solvents (DES) have been utilized in organic syntheses. DES are non-volatile in nature, have sufficient thermal stability, and also have the ability to be recycled and reused. Hence DES have been used as alternative reaction media to perform different organic reactions. The availability of green, inexpensive and easy to handle alternative solvents for organic synthesis is still scarce, hence our interest in DES mediated syntheses. Herein we have investigated Biginelli reaction in different DES for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. Monoamine oxidases and cholinesterases are important drug targets for the treatment of various neurological disorders such as Alzheimer's disease, Parkinson's disease, depression and anxiety. The compounds synthesized herein were evaluated for their inhibitory potential against these enzymes. Some of the compounds were found to be highly potent and selective inhibitors. Compounds 1 h and 1c were the most active monoamine oxidase A (MAO A) (IC50 = 0.31 ± 0.11 µM) and monoamine oxidase B (MAO B) (IC50 = 0.34 ± 0.04 µM) inhibitors respectively. All compounds were selective AChE inhibitors and did not inhibit BChE (<29% inhibition). Compound 1 k (IC50 = 0.13 ± 0.09 µM) was the most active AChE inhibitor.

Synthesis of new 2-aminothiazolyl/benzothiazolyl-based 3,4-dihydropyrimidinones and evaluation of their effects on adenocarcinoma gastric cell migration.

Gastric cancer is one of the malignant tumors of the gastrointestinal tract that, despite its decrease in recent years, is still the fourth most common cancer and the second leading cause of cancer-related death. Various strategies including chemotherapy are used to keep cancer cells from spreading and induce apoptotic death in them. Recent studies have shown that dihydropyrimidinones (DHPMs) are privileged structures in medicinal chemistry due to their pharmacological effects. A number of new 2-aminothiazolyl/benzothiazolyl derivatives of 3,4-DHPMs (3-8) were synthesized and structurally identified, and then their effects on the migration behavior of human AGS cells (gastric cancer cells) were investigated. Molecular docking and molecular dynamics (MD) simulations were applied to explore binding potential and realistic binding model of the assessed derivatives through identification of key amino acid residues within L5/α2/α3 allosteric site of kinesin 5 (Eg5) as a validated microtubule-dependent target for monastrol as a privileged DHPM derivative.

Synthesis and in vitro study of antiproliferative benzyloxy dihydropyrimidinones.

In this study, we report on antiproliferative benzyloxy dihydropyrimidinones (DHPMs) produced by the Biginelli reaction of benzyloxy benzaldehyde, urea, and diverse 1,3-diones. The reaction was catalyzed by lanthanum triflate and completed within 1-1.5 h, with 74-97% yield. The antiproliferative assay was carried out for all synthesized dihydropyrimidinones against six human solid tumor cell lines. Six compounds showed good antiproliferative activity with GI50 values below 5 µM. Among all the synthesized compounds, the most potent derivative showed good antiproliferative activity against all cell lines with GI50 values in the range of 1.1-3.1 µM. These DHPMs comply with druglikeness. Furthermore, ADMET prediction and the effect of P-glycoprotein on the antiproliferative activity were also studied. Overall, our method allows eco-friendly access to benzyloxy DHPMs as potential anticancer drugs.

Solvothermal Synthesis of Multiple Dihydropyrimidinones at a Time as Inhibitors of Eg5.

Solvothermal synthesis of multiple dihydropyrimidinones at a time has been developed in inexpensive and green bio-based solvent lactic acid without any additional catalysts or additives. By this method, thirty new dihydropyrimidinone derivatives were synthesized in two batches and characterized. All of the compounds were screened by Eg5 motor protein ATPase assay, and the positive compounds were tested against the Caco-2 cell line, HeLa cell line, L929 cell line and T24 cell line in vitro. Among them, compound C9 exhibited the best inhibitory activity against motor protein ATPase with an IC50 value of 30.25 µM and significant cytotoxic activity in the micromolar range against the cells above. The Lineweaver-Burk plot revealed that compound C9 was a mixed-type Eg5 inhibitor. A molecular modeling study using the Discovery Studio program was performed, where compound C9 exhibited good binding interaction with Eg5 motor protein ATPase, and this was consistent with the attained experimental results.

Biochar-Based Graphitic Carbon Nitride Adorned with Ionic Liquid Containing Acidic Polymer: A Versatile, Non-Metallic Catalyst for Acid Catalyzed Reaction.

A novel biochar-based graphitic carbon nitride was prepared through calcination of Zinnia grandiflora petals and urea. To provide acidic and ionic-liquid functionalities on the prepared carbon, the resultant biochar-based graphitic carbon nitride was vinyl functionalized and polymerized with 2-acrylamido-2-methyl-1-propanesulfonic acid, acrylic acid and the as-prepared 1-vinyl-3-butylimidazolium chloride. The final catalytic system that benefits from both acidic (-COOH and -SO3H) and ionic-liquid functionalities was applied as a versatile, metal-free catalyst for promoting some model acid catalyzed reactions such as Knoevenagel condensation and Biginelli reaction in aqueous media under a very mild reaction condition. The results confirmed high activity of the catalyst. Broad substrate scope and recyclability and stability of the catalyst were other merits of the developed protocols. Comparative experiments also indicated that both acidic and ionic-liquid functionalities on the catalyst participated in the catalysis.

One Pot Synthesis of Micromolar BACE-1 Inhibitors Based on the Dihydropyrimidinone Scaffold and Their Thia and Imino Analogues.

A library of dihydropyrimidinones was synthesized via a "one-pot" three component Biginelli reaction using different aldehydes in combination with ß-dicarbonyl compounds and urea. Selected 2-thiooxo and 2-imino analogs were also obtained with the Biginelli reaction from thiourea and guanidine hydrochloride, respectively. The products were screened in vitro for their ß-secretase inhibitory activity. The majority of the compounds resulted to be active, with IC50 in the range 100 nM-50 µM.

Natural dolomitic limestone-catalyzed synthesis of benzimidazoles, dihydropyrimidinones, and highly substituted pyridines under ultrasound irradiation.

Natural dolomitic limestone (NDL) is employed as a heterogeneous green catalyst for the synthesis of medicinally valuable benzimidazoles, dihydropyrimidinones, and highly functionalized pyridines via C-N, C-C, and C-S bond formations in a mixture of ethanol and H2O under ultrasound irradiation. The catalyst is characterized by XRD, FTIR, Raman spectroscopy, SEM, and EDAX analysis. The main advantages of this methodology include the wide substrate scope, cleaner reaction profile, short reaction times, and excellent isolated yields. The products do not require chromatographic purification, and the catalyst can be reused seven times. Therefore, the catalyst is a greener alternative for the synthesis of the above N-heterocycles compared to the existing reported catalysts.

Design and synthesis of substituted dihydropyrimidinone derivatives as cytotoxic and tubulin polymerization inhibitors.

An operationally simple Biginelli protocol was employed for the synthesis of new C6-carbon based aryl α-haloacrylamide-linked dihydropyrimidinone derivatives. The synthesized compounds were appraised for their in vitro antiproliferative potential against a selected panel of human cancer cell lines especially MCF-7 (human breast cancer), MDA-MB-231 (human breast cancer), HCT-116 (human colon cancer), HCT-15 (human colorectal adenocarcinoma), HT-29 (human colon adenocarcinoma) and DU145 (human prostate cancer) along with normal lung fibroblasts (HFL-1). Preferably, compounds containing α-haloacrylamide (10a-g) functionality were found to exhibit most significant cytotoxicity (IC50 value 0.54 ±â€¯0.12 to 8.35 ±â€¯0.82 µM) against the listed cancer cell lines, particularly towards breast cancer cell lines MCF-7 and MDA-MB-231 (IC50 value 0.54 ±â€¯0.12 to 3.70 ±â€¯0.24 µM). In the seam of synthesized compounds, compound 10f exhibited potent antiproliferative activity against breast cancer cell lines namely MCF-7 (IC50 value 0.54 ±â€¯0.12 µM) and MDA-MB-231 (IC50 value 1.18 ±â€¯0.32 µM). Further to understand the underlying apoptosis mechanisms, different staining techniques such as AO/EB, DCFDA, and DAPI staining were performed. To know the extent of apoptosis and loss of mitochondrial membrane potential in MCF-7 cell lines, annexin V-FITC/PI and JC-1 were performed. Cell cycle analysis revealed that compound 10f arrested the cells at G2/M phase in a dose-dependent manner. The compound 10f also found to exhibit significant inhibition of tubulin polymerization (IC50 of 6.91 ±â€¯0.43 µM) with microtubule destabilizing properties. Molecular docking studies also revealed that compound 10f efficiently interacted with critical catalytically active residues Ser178, Val238, and Val318 of the α/ß-tubulin by a hydrogen bond.

Synthesis and in vitro antiviral evaluation of 4-substituted 3,4-dihydropyrimidinones.

A series of 4-substituted 3,4-dihydropyrimidine-2-ones (DHPM) was synthesized, characterized by IR, 1H NMR, 13C NMR and HRMS spectra. The compounds were evaluated in vitro for their antiviral activity against a broad range of DNA and RNA viruses, along with assessment for potential cytotoxicity in diverse mammalian cell lines. Compound 4m, which possesses a long lipophilic side chain, was found to be a potent and selective inhibitor of Punta Toro virus, a member of the Bunyaviridae. For Rift Valley fever virus, which is another Bunyavirus, the activity of 4m was negligible. DHPMs with a C-4 aryl moiety bearing halogen substitution (4b, 4c and 4d) were found to be cytotoxic in MT4 cells.

An Efficient One-Pot Protocol for the Synthesis of Substituted 3,4-Dihydropyrimidin-2(1H)-ones Using Metallophthalocyanines (MPcs) as Potent Heterogeneous Catalysts: Synthesis, Characterization, Aggregation and Antimicrobial Activity.

In this study, novel phthalonitrile 3 and their corresponding metal-free 4 and metallophthalocyanine derivatives 5-7 bearing 2-isopropenyl-4-methoxy-1-methylbenzene groups were synthesized and characterized. 3,4-Dihydropyrimidinones have been synthesized by a modified Biginelli-type reaction with various metallophthalocyanines 5-7 as catalysts. Compared to the classical Biginielli reaction, the new method has the advantages of good yield and short reaction time. Among the various metallophthalocyanines studied, cobalt (II)-phthalocyanine was found to be most active for this transformation. The newly prepared compounds were characterized using elemental analyses, MS, IR, ¹H/13C-NMR and UV-Vis spectroscopy. In addition; the 3,4-dihydropyrimidinones (DHPMs) 8-12 were investigated for antimicrobial activities and revealed good activity. The minimum inhibitory concentration (MIC) was determined by the microdilution technique in Mueller-Hinton broth. The MICs were recorded after 24 hours of incubation at 37 °C. These results are promising, showing these compounds are biologically active.

FeCl3∙6H2O/TMSBr-Catalyzed Rapid Synthesis of Dihydropyrimidinones and Dihydropyrimidinethiones under Microwave Irradiation.

An efficient and practical protocol has been developed to synthesize dihydropyrimidinones and dihydropyrimidinethiones through FeCl3∙6H2O/TMSBr-catalyzed three-component cyclocondensation under microwave irradiation. This approach features high yields, broad substrate scope, short reaction time, mild reaction conditions, operational simplicity and easy work-up, thus affording a versatile method for the synthesis of dihydropyrimidinones and dihydropyrimidinethiones.

Towards Enzyme-like, Sustainable Catalysis: Switchable, Highly Efficient Asymmetric Synthesis of Enantiopure Biginelli Dihydropyrimidinones or Hexahydropyrimidinones.

Organocatalysts displaying a network of cooperative hydrogen bonds (NCHB) have been employed in an enzyme-like manner for a direct, switchable synthesis of enantiopure hexahydropyrimidinones (HHPMs) or dihydropyrimidinones (DHPMs), which starts at a common, easily accessible α-ureidosulfone stage. The NCHB organocatalyst exploits all its potential as a pure hydrogen-bond biomimetic catalyst even in the presence of organic bases. This one-pot, diastereo- and enantioselective synthetic procedure has been proven to be robust, scalable, highly efficient, and environmentally benign. A straightforward and truly practical entry to enantiopure HHPMs is reported for the first time.

Synthesis and evaluation of dihydropyrimidinone-derived selenoesters as multi-targeted directed compounds against Alzheimer's disease.

This paper describes the synthesis and evaluation of new dihydropyrimidinone (DHPM)-derived selenoesters as potential multi-targeted agents for the treatment of Alzheimer's disease. A series of DHPM-derived selenoesters were obtained with high structural diversity through a short and modular synthetic route. The antioxidant activity was evaluated by TBARS and iron chelation assays. These compounds were also evaluated as acetylcholinesterase inhibitors (AChEi). The compounds demonstrated good antioxidant activity, since they presented excellent lipid peroxidation inhibition and good iron chelation activity. In addition, they showed acetylcholinesterase inhibition activity and some of them presented activity superior to that of the standard drug galantamine. The in silico predictions showed that the compound 1h may present a good pharmacokinetic profile. Therefore, the series of DHPM-derived selenoesters described herein displayed good potential for the development of antioxidant and anticholinesterasic agents in the search for new multi-targeted therapeutics for the treatment of Alzheimer's disease.

Organocatalysis by Networks of Cooperative Hydrogen Bonds: Enantioselective Direct Mannich Addition to Preformed Arylideneureas.

The concept of noncovalent organocatalysis by means of networks of cooperative hydrogen bonds (NCHB organocatalysis) has been explored. Arylideneureas were chosen as ideal substrates because of their powerful donor-acceptor properties. We have examined their uncatalyzed, direct Mannich reaction with acetoacetates in comparison with that catalyzed by a number of salan derivatives capable of providing a network of cooperative hydrogen bonds. Catalyst D [(R,R)-N,N'-bis(salicyl)cyclohexane-1,2-diamine] was found to drive the above direct Mannich reaction in an enantioselective manner, thereby allowing the synthesis of several Biginelli dihydropyrimidinones with high enantioselectivity. DFT calculations (B3LYP-D-PCM/6-31+G*//B3LYP/6-31+G*) revealed that the NCHB organocatalyst lowers the energy barrier of the reaction. The NCHB organocatalysts appear to function as biomimetic catalysts.

Graphite catalyzed solvent free synthesis of dihydropyrimidin-2(1H)-ones/thiones and their antidiabetic activity.

A solvent free three component condensation reaction between an aldehyde, ethyl acetoacetate and urea catalyzed by graphite, a green catalyst is described for the synthesis of dihydropyrimidin-2(1H)-ones. This protocol is scalable and the catalyst is reusable. This method is also applied for the synthesis of dihydropyrimidin-2(1H)-thiones. α-Amylase, a key enzyme in carbohydrate metabolism is generally targeted for management of type 2 diabetes. The therapeutic potential of the dihydropyrimidinones and dihydropyrimidinthiones to inhibit α-amylase activity was evaluated by in vitro assay. Of the synthesized compounds 3,4-dihydropyrimidin-2(1H)-thione (1k) demonstrated highest inhibition of α-amylase activity.

Reaction Optimization of Strontium Perchlorate Catalyzed Novel Protocol for Stereoselective Synthesis of Dihydropyrimidinones.

BACKGROUND: Hydrated strontium perchlorate [Sr(ClO4)2.3H2O] acts as a very strong oxidizing and dehydrating agent. Until now, it could not be reported as a catalyst in dehydration mechanism-based organic synthetic reactions. Therefore, it is important to find whether it could be an effective catalyst for one-pot multicomponent reactions (MCRs). OBJECTIVE: The main objective of the present work is the development of a novel process for the synthesis of 1,4-dihydropyrimidinones through the one-pot multicomponent strategy using hydrated Sr(ClO4)2 as a catalyst. Furthermore, it includes process optimization, stereoselectivity, and spectroscopic characterization of the synthesized compounds. METHODS: Conventional and microwave-supported synthesis of 1,4-dihydropyrimidinones using 20 mol % of hydrated Sr(ClO4)2 catalyst via the one-pot solvent-free reaction was discovered as a new catalytic MCR methodology. The box-Behnken design approach and advanced analytical techniques were used for process optimization and reaction analysis. RESULTS: The results confirmed that hydrated Sr(ClO4)2; works as an efficient catalyst for one-pot multicomponent organic synthesis under both conventional and microwave heating. It is an effective catalyst for laboratory synthesis of 1,4-dihydropyrimidinones stereoselectively with moderate to excellent yield without any undesirable effect. Microwave heating provided the desired product within 1-4 minutes. Moreover, this method provides easy isolation of the pure products simply by recrystallization, and without the use of a chromatographic purification method. CONCLUSION: The simplicity and neutrality of reaction conditions, easy post-reaction workup, higher satisfactory to excellent yield, effectiveness, the diversity of substrates, etc. render the hydrated Sr(ClO4)2 catalyst-based protocol for the stereoselective synthesis of 1,4-dihydropyrimidinones as a highly efficient method. Furthermore, it has been found to be safe un-der laboratory reaction conditions and no undesirable issues have been faced during the process.

Halloysite Nanotubes as Bimodal Lewis/Brønsted Acid Heterogeneous Catalysts for the Synthesis of Heterocyclic Compounds.

Halloysite nanotubes can be used for the preparation of solid catalysts. Owing to their natural availability at low-cost as well as to their large and easy-to-functionalize surface, they can be conveniently activated with mineral acids or derivatized with acidic groups. Nevertheless, the use of HNTs as catalysts in complex transformations is still limited. Herein, we report two strategies to utilize HNT-based materials as solid acidic catalysts for the Biginelli reaction. To this aim, two methods for increasing the number of acidic sites on the HNTs were explored: (i) the treatment with piranha solution (Pir-HNTs) and (ii) the functionalization with phenylboronic acid (in particular with benzene-1,4-diboronic acid: the sample is denoted as HNT-BOA). Interestingly, both strategies enhance the performance of the multicomponent reaction. Pir-HNTs and HNT-BOA show an increased reactivity (72% and 89% yield, respectively) in comparison with pristine HNTs (52%). Additionally, Pir-HNTs can be reused up to five times without significant performance loss. Moreover, the method also displays good reaction scope, as demonstrated by the preparation of 12 different 3,4-dihydropyrimidinones in up to 71% yield. Therefore, the described strategies are promising for enhancing the acidity of the HNTs as catalysts for the organic reaction.

LaSOM 335, active against bladder cancer cells, interferes with Let-60 (hRas) and reduces CD73 expression/activity.

Bladder cancer is the fourth most common malignancy in men. It can present along the entire continuum of severity, from mild to well-differentiated disease to extremely malignant tumors with low survival rates. Human RAS genes are the most frequently mutated oncogenes in human cancers, and the critical role of aberrant Ras protein function in carcinogenesis is well established. Therefore, considerable efforts have been devoted to the development of anti-Ras inhibitors for cancer treatment. This study presents the biphenyl dihydropyrimidinone LaSOM 335 with high activity against T24 bladder cancer cells (IC50 = 10.73 ± 0.53 µM) and selectivity of cytotoxicity for this cancer cell line compared to two non-cancer cell lines investigated. Furthermore, we also show that this compound reduced vulvar development in the mutant let-60 gene of Caenorhabditis elegans. Let-60 is a homolog of the mammalian Ras gene. In addition, we observed that LaSOM 335 inhibits the enzymatic activity of CD73 and decreases CD73 expression. Possibly, this expression decrease is due to downstream EGFR signaling via the Ras-Raf-ERK pathway, that directly regulates CD73 expression via ERK1/2. Evidence suggests that non-immunomodulating functions of CD73 play an equally important role for cancer cell survival, progression, and migration. Regarding we also notice that LaSOM 335 was safe in the in vivo model of C. elegans. The set of these findings makes this biphenyl dihydropyrimidinone a promising candidate for further investigations in the bladder cancer field.