Dihydropyrimidinone Research Articles

Studying the Effects of Curd as a Biocatalyst in Multicomponent Biginelli Reaction

Introduction: Dihydropyrimidinone (DHPM) is a very useful moiety with a wide range of applications. Synthesis of this moiety with environmentally friendly methods is the demand of the era. Method: In recent research, the optimisation of curd as a biocatalyst has been studied. It has been reported that it can be used directly in the multicomponent Biginelli synthesis of ethyl 6-methyl-2- oxo-4-benzyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates under mild reaction conditions. Result: The chemical structures of synthesized compounds were characterized by physicochemical and analytical methods (1H NMR, IR and LC-MS methods) and it was found that curd is suitable for a vast variety of aromatic aldehydes to obtain the corresponding DHPMs. Conclusion: This new eco-friendly approach can be implemented to synthesize DHPMs for different applications.

Post-Biginelli Ugi reaction towards synthesis of novel bisamides of dihydropyrimidinones: Substrate scope, modification and mechanism

A Biginelli, hydrolysis and Ugi four component reaction sequence was developed for the synthesis of novel dihydropyrimidinone (DHPM) bisamides in which an unprecedented but moderate 1,6 asymmetric induction was observed for this compound class. A detailed study is carried out to understand effects of various substitutions on the diastereoselectivity. Steric congestion led to sluggish Mumm rearrangement in some examples allowing the trapping of imidate intermediate by methanol. This unprecedented trapping confirms that slow Mumm rearrangement can lead to side products formation in Ugi reaction.

Design, synthesis, and in silico-in vitro antimalarial evaluation of 1,2,3-triazole-linked dihydropyrimidinone quinoline hybrids

In response to the malaria parasite’s resistance towards quinoline-based antimalarial drugs, we have employed quinoline-containing compounds in combination with dihydropyrimidinone (DHPM) analogues as resistance reversal agents (RAs) and investigated their antimalarial activities based on DHPM’s resistance reversal abilities. The present study employed click chemistry to link DHPM and quinoline compounds which offered several synthetic advantages over the previously used amide coupling for the same hybrids. Among the synthesised compounds, 4 hybrids with the 7-chloroquinoline moiety showed antimalarial activity below 1 µM while compounds with the mefloquine moiety showed lower antimalarial activity than chloroquine (CQ) and the 7-chloroquinoline hybrids. Among the tested hybrids for the IC50 determination, four compounds displayed good antimalarial activity with increased sensitivity against the CQ-resistant K1 strain between 421 and 567 nM and showed higher activity between 138 and 245 nM against the NF54 CQ-sensitive strain, while three compounds have IC50 values greater than 5 µM. Additionally, in silico molecular docking and molecular dynamics studies were conducted to investigate the binding affinities of all the synthesised compounds as glutathione reductase protein competitive inhibitors. Further optimisation of the compound with the highest binding affinity generated 16 compounds with higher binding affinities than the flavine adenine dinucleotide (FAD) cofactor.

Bioactivity of dihydropyrimidinone derivatives as inhibitors of cyclooxygenase-2 (COX-2): an in silico approach.

Cyclooxygenase-2 (COX-2) is an enzyme involved in inflammation. The overexpression of COX-2 causes chronic inflammation, which can be prevented by COX-2 inhibitors. Generally, COX-2 inhibitors possess a carboxyl group and an aromatic ring in their molecular structure. These moieties are involved in the interaction with the active site of COX-2, thus playing a pivotal role in the inhibitory activity. Regarding the requisite molecular structure of COX-2 inhibitors, derivatives of dihydropyrimidinone (DHPM) are ideal candidates to be explored as COX-2 inhibitors, due to the ease of synthesis and their versatility to be transformed chemically. In this study, we prepared a novel small library consisting of 288 designed DHPM derivatives by varying the constituent components. The selection criteria of potential candidates for the COX-2 inhibitor of the data bank involve in silico studies via molecular docking investigations, prediction of ADMET and druglikeness, as well as molecular dynamics (MD) simulations. Molecular docking served as the initial step of selection, based on the comparison of grid score, docking pose, and interactions with those of lumiracoxib (LUR) as the original ligand of COX-2. The next criteria of selection were scores obtained from the ADMET and druglikeness by comparing the designed candidates with COX-2 inhibitors that were already marketed. Compound RDUE2 and SDT29 were the most potential candidates, which were further analyzed using the MD simulation. The results of the MD simulation indicated that RDUE2 and SDT29 interacted stably with amino acid residues on the active site of COX-2. The estimation of binding free energy indicated that SDT29 exhibited an inhibitory activity comparable to that of LUR, whereas RDUE2 showed a lower inhibitory activity than that of SDT29 and LUR.

QSAR Study, Molecular Docking, and Pharmacokinetic Analysis of Substituted Dihydropyrimidinone as ErbB2 Inhibitors

ErbB2 is considered to be the preferred dimerization partner among the ErbB receptor tyrosine kinase (RTK) family. They are implicated in the development and progression of several cancer types, majorly breast cancer-related maladies. In the current study, quantitative structure-activity relationship (QSAR), molecular docking approaches and prediction of pharmacokinetic properties were utilized to identify promising ErbB2 inhibitors from a series of dihydropyrimidinone (DHPM) derivatives. The results indicated that the QSAR models of ErbB2 inhibitory activity is robust and has a very good prediction capacity, as exhibited by the value of R which is 0.9194. Furthermore, 6 compounds were shortlisted with potentially high biological activity. These compounds were subjected to drug likeliness, molecular docking and pharmacokinetic evaluations which indicated that the compounds are orally bioavailable and exhibit suitable proficiency as ErbB2 antagonists.

Biocatalytic Kinetic Resolution to Access Enantiomerically Enriched Dihydropyrimidinone/Thiones through Recognition of a Remote Stereocentre

AbstractThe Biginelli synthesis is a classic tricomponent reaction known to result in polyfunctionalized dihydropyrimidinone (DHPM) derivatives. Herein, we described a chemo‐enzymatic strategy for obtaining enantiomerically enriched hydroxy‐DHPMs. These compounds were previously esterified with butyric or acetic anhydride and were later submitted to hydrolysis reactions catalysed by lipase B from Candida antarctica. Although the stereogenic centre is far from the reaction site (4–5 bonds), moderate to excellent enantiomeric excess values were obtained (up to 99 %). Docking studies were performed in parallel to elucidate the binding modes of some molecules with the CALB active site, and were able to provide information on the enantiospecificity of these compounds in the hydrolysis reaction.

Green Synthesis of Dihydropyrimidinone Derivatives and Study of Physicochemical Properties and Antimicrobial Activity

Versatile biological activity of dihydropyrimidinone (DHPM) derivatives makes it more interesting in medicinal chemistry.In present work green synthesis method was used to prepare a series of DHPM derivative by Biginelli reaction at room temperature in common fruit juice. Spectroscopic methods were used to characterize structures of all synthesized compounds.The viscometric and surface tension measurements have been carried out in different percentage solvent system. Viscosity increases with increases in concentration for all the tested derivatives may be attributed to the increases in solute – solvent interactions.Study was extended to find conductivity of synthesized derivative in different solvents. The data obtained was used to evaluate nature and magnitude of ion-solvent and ion-ion interactions. The primary purpose of this study to evaluate antibacterial activity against some Gram-positive and Gram-negative pathogens. It was observed that the compounds show poor or good activity which depend upon electronic factor of the phenyl ring of DHPM

Application of Design of Experiments (DoE) Approach for the Optimization of Phase-transfer Catalyzed Biginelli Dihydropyrimidinone (DHPM) Synthesis

The conventional Biginelli synthesis is more cumbersome and produces lower yields. Several improved methods are reported in the literature to replace the Biginelli catalyst. The design of biocompatible organic transformation is a major concern and a versatile greener procedure to construct Biginelli analogs is in great demand. Factorial design guided, energy-efficient, and versatile synthesis of 3,4-dihydropyrimidin-2-(1H)-ones (DHPM) was developed. One-factor-at-a time (OFAT) and factorial design (2<sup>3</sup>) studies were utilized for screening the independent variables. The optimum levels of potential variables (benzyl-n-triethylammonium chloride (BTEAC) and glacial acetic acid) were determined through studies. The factorial design (3<sup>2</sup>) analysis inferred the use of BTEAC (10.25 mol%) and glacial acetic acid (7.6 ml) as optimal for the 60 min condensation. Thirteen new 3,4- dihydropyrimidine-2-(1H)-one (DHPM) analogs were synthesized using optimized reaction conditions. The quaternary ammonium ion of BTEAC stabilizes the polarization of carbonyl group in aryl aldehydes and enolizable ketone (alkyl acetoacetate) to facilitate the cyclocondensation, in order to produce DHPMs through N-acyliminium ion and Michael adducts formation. The biocompatible strategy, simple product isolation (non-chromatographic method), and good to excellent yields are attractive features of this new protocol. Hence, the newly developed methodology is superior to the literature methods.

Synthesis and cytotoxicity evaluation of novel cyclic/non-cyclic N-aryl enamino amides against human cancer cell lines.

Background and purpose:Considering the undesirable consequences of prevalent cancer diseases, design and development of potent and selective anticancer chemotherapeutics is a major concern. Several studies have unraveled the potential of dihydropyrimidinone (DHPM) scaffold toward generating anticancer agents.Experimental approach:In the present work, a series of new dihydropyrimidinethiones (DHPMTs) along with a few acyclic enamino amides were synthesized and evaluated for their cytotoxic activity against human gastric (AGS), liver (Hep-G2), and breast (MCF-7) cancer cell lines.Findings/Results:Among the assessed compounds, one of the DHPMT derivatives (compounds, one of the DHPMT derivatives (compound 5: 4-(3- fluorophenyl)-6-methyl-N-phenyl-2-thioxo-1,2,3,4-ttrahydropyrimidine-5-carboxamide) exhibited superior cytotoxicity in all of the target cell lines (AGS, IC50 9.9 μM; MCF-7, IC50 15.2 μM; and Hep-G2, IC50 40.5 μM). Cytotoxicity assessments showed that non-cyclic enamino amides exhibited weaker activities when compared to cyclic analogues (DHPMs).Conclusion and implications:DHPMTs were better cytotoxic agents than non-cyclic enamino amides. Structure activity relationship studies guided us toward the design of DHPMT derivatives with OH and NH groups particularly on meta position of 4-phenyl ring and hydrophobic bulky substituents on carboxamide side chain within the structure. Possible interaction with the hydrophobic site(s) of the cellular target was supposed. The results of this study emphasized the potential role of DHPMTs and their optimized derivatives as privileged medicinal scaffolds to inhibit the growth of gastric, breast, and liver cancer cells.

Bioinspired synergistic formulation from dihydropyrimdinones and iodide ions for corrosion inhibition of carbon steel in sulphuric acid

The adsorption and corrosion inhibition behavior of three dihydropyrimidinone (DHPM) derivatives on carbon steel in 0.5 M sulphuric acid solution is investigated in the present work. It was observed that among the three studied DHPMs; the inhibition efficiency trends were governed by substituent effects where the –OCH3 substituted DHPM provided the best performance (96.05% efficiency) at a concentration of 3.27 × 10−4 M. The influence of iodide ions is also studied using electrochemical methods, gravimetric studies, and surface analysis. It was observed that the addition of iodide ions further improved the inhibition efficiency to >99% at 3.01 × 10−4 M concentration of KI. This significant increase in corrosion protection was explained by the synergistic action of DHPM derivatives and iodide ions. The adsorption of the inhibitor obeyed the Langmuir isotherm and exhibited a mixed physical/chemical adsorption. Potentiodynamic polarization studies showed a decrease in both anodic and cathodic reactions at carbon steel/0.5 M H2SO4 interface. The adsorption was supported by scanning electron microscopy study, and the reactivity parameters of the inhibitors were computationally evaluated using DFT analysis and Monte Carlo simulations.

Biginelli Reaction: Polymer Supported Catalytic Approaches.

The Biginelli product, dihydropyrimidinone (DHPM) core, and its derivatives are of immense biological importance. There are several methods reported as modifications to the original Biginelli reaction. Among them, many involve the use of different catalysts. Also, among the advancements that have been made to the Biginelli reaction, improvements in product yields, less hazardous reaction conditions, and simplified isolation of products from the reaction predominate. Recently, solid-phase synthetic protocols have attracted the research community for improved yields, simplified product purification, recyclability of the solid support, which forms a special economic approach for Biginelli reaction. The present Review highlights the role of polymer-supported catalysts in Biginelli reaction, which may involve organic, inorganic, or hybrid polymers as support for catalysts. A few of the schemes involve magnetically recoverable catalysts where work up provides green approach relative to traditional methods. Some research groups used polymer-catalyst nanocomposites and polymer-supported ionic liquids as catalyst. Solvent-free, an ultrasound or microwave-assisted Biginelli reactions with polymer-supported catalysts are also reported.

Microwave Assisted Synthesis of Pyrimidine Carboxamide Catalyzed by Ruthenium Chloride and their Antioxidant Studies

A systematic and simple method for the preparation of pyrimidinone compound utilizing RuCl3.2H2O catalyst under traditional and microwave method. The preparation of dihydro pyrimidinone utilizing ruthenium chloride dihydrate had generated lots of interest which includes easy work up, less reaction period and better yields under the usage of CH3CN as a solvent. The structures of the new substances have been affirmed throgh FT-IR, 13C NMR, 1H NMR and mass spectra. All the new substances were screened for antioxidant nature.

Antibacterial Studies of Dihydropyrimidinones and Pyrimidinethiones

Some new dihydro pyrimidinone and pyrimidinethione compounds have been synthesized and their antibacterial activities have been studied in dimethyl formamide and dimethyl sulphoxide against some Gram positive and Gram negative bacteria For this Agar well diffusion method is used It is observed that inhibition depends on solvent bacterial strain nature and position of substitution in a compound When the same substitution is attached to different moieties its effect on bacterial strains changes in different solvents nbsp

An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors

Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP). Mechanism of action (MOA) studies using cellular and biochemical assays coupled with 3D fingerprinting and in silico modeling demonstrated that these drug-like probe compounds exert their effects by inhibiting the viral reverse transcriptase polymerase (RT). This led to the design and synthesis of the novel DHPM 1at that inhibits the replication of drug resistant strains of HIV. Our work demonstrates that combining flow chemistry-driven analogue refinement with phenotypic assays, in silico modeling and MOA studies is a highly effective strategy for hit-to-lead optimization applicable to the discovery of future therapeutic agents.

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.

Synthesis and Antiviral Activity of Dihydropyrimidines - Ciprofloxacin Mannich bases Against Various Viral Strains

Background: Dihydropyrimidinone is considered as a pharmacophoric skeleton in many drug discovery programmes. To explore the activity of dihydropyrimidines, we regioselectively synthesized some of the substituted mannich bases of dihydropyrimidinone (DHPM) analogues regioselectively with fluoroquinolones (Ciprofloxacin). Methods: Regioselectivity in these structures is achieved by the influence of weak base like potassium carbonate and synthesized some novel dihydropyrimidine N- and O-Mannich bases of ciprofloxacin (3a-j, 4a-g) using microwave technology. All the synthesized molecules have been evaluated for their antiviral activity against hepatitis C, hepatitis B, vaccinia, cowpox, severe acute respiratory syndrome, West Nile, dengue, Venezuelan equine encephalitis viruses, Flu A (H1N1, H3N2 and H5N1) and Flu B viral strains as well as for their cytotoxicity using standard protocols. Results: An attempt was made to interpret the structure activity relation of compounds with their antiviral activity data. Compounds 3a, 3e, 3f, 4e, 4g were found to be active against Flu A (H1N1), TCRV, hepatitis B, yellow fever, vaccinia virus respectively. Conclusion: Some of the synthesized compounds exhibited potent activity against some viral strains. Out of O- and N-mannich bases, O-mannich bases were found to be more potent with high selectivity index. Keywords: Antiviral activity, dihydropyrimidinones, hepatitis B, influenza virus A (H1N1), microwave technology, regioselectivity, TCRV, vaccinia virus, yellow fever.

Design, synthesis, and evaluation of dihydropyrimidinone (DHPM) based muscarinic receptor antagonist

Organophosphorus compounds (OPCs) are highly toxic being used in pest control. Some of the OPCs are lethal chemical warfare agents and their toxicity is due to inhibition of acetylcholine esterase (AChE), the enzyme that hydrolyses neurotransmitter acetylcholine (ACh). Due to over accumulation of ACh at muscarinic acetylcholine receptors (mAChRs) several cholinergic functions increase uncontrollably like salivation, lacrimation, urination, defecation, gastrointestinal upset, and emesis. Atropine is used to treat OPC poisoning because it is a mAChR antagonist. But atropine has several unwanted side effects including dryness of mucous membrane, hot and dry skin, tachycardia, and restlessness. Our goal was to find out molecules having antimuscarinic activity which may be developed as potential alternatives for atropine in future. In this work pharmacophore-based screening, structure identification, synthesis and ex vivo evaluation of a new class of muscarinic receptor antagonist are described. The antagonists are based on dihydropyrimidinone scaffold with a tertiary or quaternary amine side group. A series of molecules were evaluated for preliminary pharmacological activity on rat ileum out of which three molecules found active.

Novel racemic tetrahydrocurcuminoid dihydropyrimidinone analogues as potent acetylcholinesterase inhibitors

The synthesis of racemic tetrahydrocurcumin- (THC-), tetrahydrodemethoxycurcumin- (THDC-) and tetrahydrobisdemethoxycurcumin- (THBDC-) dihydropyrimidinone (DHPM) analogues was achieved by utilizing the multi-component Biginelli reaction in the presence of copper sulphate as a catalyst. The evaluation of acetylcholinesterase inhibitors for Alzheimer’s disease of these compounds showed that they exhibited higher inhibitory activity than their parent analogues. THBDC–DHPM demonstrated the most potent inhibitory activity with an IC50 value of 1.34±0.03μM which was more active than the approved drug galanthamine (IC50=1.45±0.04μM).

A novel 3,4-dihydropyrimidin-2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability

Following the previous SAR of a novel dihydropyrimidinone scaffold as HIV-1 replication inhibitors a detailed study directed towards optimizing the metabolic stability of the ester functional group in the dihydropyrimidinone (DHPM) scaffold is described. Replacement of the ester moiety by thiazole ring significantly improved the metabolic stability while retaining antiviral activity against HIV-1 replication. These novel and potent DHPMs with bioisosteres could serve as advanced leads for further optimization.

Pineapple Juice as a Natural Catalyst: An Excellent Catalyst for Biginelli Reaction

An efficient and greener synthesis of a series of dihydropyrimidinone (DHPMs) derivatives were accomplished via three-component one-pot cyclocondensation between substituted aryl aldehydes, diketone/ke- toester and urea. This solvent free approach is totally nonpolluting having several advantages such as shorter reaction time, mild reaction conditions, simple workup and reduced environmental impact.