Dihydropyrimidine Derivatives Research Articles

Green Nanospheres Natural Camphor Coated Ferrite as a Highly Efficient Nanocatalyst for the Synthesis of Dihydropyrimidine Derivatives

AbstractDihydropyrimidines are synthesized by a one‐pot condensation of an aldehyde, β‐ketoester and urea or thiourea in the presence of Fe3O4@camphor as a new heterogeneous magnetic nanocatalyst. The nanospheres morphology of the green natural camphor/ferrite was characterized by Fourier transform infrared (FT‐IR) spectroscopy, field‐emission scanning electron microscopy (FE‐SEM) images, X‐ray diffraction (XRD) pattern, energy‐dispersive X‐ray (EDX), vibrating sample magnetometer (VSM), N2 adsorption‐desorption by Brunauer–Emmett‐Teller (BET) and inductively coupled plasma (ICP) analyses. The advantages of this new report are short reaction times, high yields, easy workup, low cost and eco‐friendly protocol. The recoverable nanocatalyst was simply prepared and effectively employed for the one‐pot multicomponent synthesis of dihydropyrimidine derivatives, for the first time, at room temperature.

Synthesis and biological evaluation of novel N3-substituted dihydropyrimidine derivatives as T-type calcium channel blockers and their efficacy as analgesics in mouse models of inflammatory pain

Low-voltage-activated calcium channels are important regulators of neurotransmission and membrane ion conductance. A plethora of intracellular events rely on their modulation. Accordingly, they are implicated in many disorders including epilepsy, Parkinson's disease, pain and other neurological diseases. Among different subfamilies, T-type calcium channels, and in particular the CaV3.2 isoform, were shown to be involved in nociceptive neurotransmission. The role of CaV3.2 in pain modulation was supported by demonstrating selective antisense oligonucleotide-mediated CaV3.2 knockdown, in vivo antinociceptive effects of T-type blockers, and pain attenuation in CaV3.2 knockout formalin-induced pain model. These Emerging investigations have provided new insights into targeting T-type calcium channels for pain management. Within this scope, various T-type calcium channel blockers have been developed such as mibefradil and ethosuximide. Although being active, most of these molecules interact with other receptors as well. This addresses the need for T-selectivity. Few selective T-type channel blockers of diverse chemical classes were developed such as ABT-639 and TTA-P2. Interestingly, R(-) efonidipine which is a dihydropyridine (DHP) showed T-channel selectivity. Systematic modification of 1,4-dihydropyridine scaffold introduced novel derivatives with 40-fold T-type selectivity over L-type calcium channels. Along these lines, substitution of the DHP core with various analogues favored T-selectivity and may serve as novel pharmacophores. Several dihydropyrimidine (DHPM) mimics were introduced by Squibb as potential candidates. As a continuation of this approach, the current study describes the synthesis of Novel N3 substituted DHPMs with structure similarities to the active DHPs. Different functional groups were introduced to the N3 position through a spacer to gain more information about activity and selectivity. Furthermore, the spacer aims at improving the metabolic stability of the molecules. Initial screening data by whole patch clamp technique showed a robust inhibition of Cav3.2 T-type channels by eleven compounds. Interestingly, four compounds of these were efficient selective T-type blockers. Based on selectivity and efficiency, two compounds were selected for in vivo evaluation in mouse models of inflammatory pain. Results showed effective attenuation of nociception and mechanical hypersensitivity.

P-gp and BCRP inhibition induced by some new 1,4-Dihydropyridine and Dihydropyrimidines

Overexpression of ABC transporters leads to MDR (Multiple Drug Resistance). MDR is considered to be the major contributor to failure of chemotherapy in metastatic cancers. ABC transporters have protective role in normal cells by extruding xenobiotics of cytotoxic compounds from the cell. The development of selective inhibitors of P-gp, MRP1, MRP2, and BCRP has been a major goal of many research groups in the last few years. Previous studies have shown that 1,4-dihydropyridines could inhibit these transporters. In this study, some new 1,4-dihydropyridine and pyrimidine have been developed and their inhibitory effect on the resistant cancer cell lines was examined. In order to elucidate the binding mode of these compounds, a molecular docking and molecular dynamic simulation was performed for the protein-ligand complex. Dihydropyridines were more potent than dihydropyrimidines. However, one of the dihydropyrimidine derivatives selectively inhibited BCRP. The binding mode of these compounds showed that methoxy groups and heterocyclic rings could create hydrogen bonds with polar residues at the active sites. These regions were more stable during MD simulation.

Elemental steps of the thermodynamics of dihydropyrimidine: a new class of organic hydride donors.

25 Dihydropyrimidine derivatives, a new class of organo-hydrides, were designed and synthesized by the Biginelli reaction. For the first time, the thermodynamic driving forces of the six elemental steps to obtain a hydride in acetonitrile were determined by isothermal titration and electrochemical methods, respectively. The effects of molecular structures and substituents on these thermodynamic parameters were examined, uncovering some interesting structure-reactivity relationships. Both the thermodynamic and kinetic studies show that the hydride transfer from dihydropyrimidines to 9-phenylxanthylium (PhXn+ClO4-) prefers a concerted mechanism.

P-gp and BCRP inhibition induced by some new 1,4-Dihydropyridine and Dihydropyrimidines

Overexpression of ABC transporters leads to MDR (Multiple Drug Resistance). MDR is considered to be the major contributor to failure of chemotherapy in metastatic cancers. ABC transporters have protective role in normal cells by extruding xenobiotics of cytotoxic compounds from the cell. The development of selective inhibitors of P-gp, MRP1, MRP2, and BCRP has been a major goal of many research groups in the last few years. Previous studies have shown that 1,4-dihydropyridines could inhibit these transporters. In this study, some new 1,4-dihydropyridine and pyrimidine have been developed and their inhibitory effect on the resistant cancer cell lines was examined. In order to elucidate the binding mode of these compounds, a molecular docking and molecular dynamic simulation was performed for the protein-ligand complex. Dihydropyridines were more potent than dihydropyrimidines. However, one of the dihydropyrimidine derivatives selectively inhibited BCRP. The binding mode of these compounds showed that methoxy groups and heterocyclic rings could create hydrogen bonds with polar residues at the active sites. These regions were more stable during MD simulation.

Solubility and thermodynamic parameters of a novel anti-cancer drug (DHP-5) in polyethylene glycol 400 + water mixtures

Abstract Solubility of dihydropyrimidine derivative 4-(4-ethoxyphenyl)-5-(3,4,5 trimethoxybenzoyl)-3,4-dihydropyrimidine-2(1H) one (DHP-5), a novel anticancer drug, was experimentally measured in PEG-400 + water binary solvent mixtures over a temperatures range from 298.15 to 318.15 K. Thermodynamic parameters including enthalpy, entropy and Gibbs free energy of the solubility data were calculated using van't Hoff equation. Experimental solubility data was employed to evaluate the relative performance of a number of models including van't Hoff, Apelblat, Yalkowsky and Jouyban–Acree models for their prediction efficacy. The Jouyban–Acree model covering both solvent composition and temperature effects on drug's solubility proved to be superior to the other three models for its prediction accuracy.

Solubility and thermodynamics of 4-(4-ethoxyphenyl)-5-(3,4,5-trimethoxybenzoyl)-3,4-dihydropyrimidin-2(1H)-one in various pure solvents at different temperatures

Dihydropyrimidine derivatives have great potential in the treatment of various kinds of cancers. The main problem associated with these medicines is the poor solubility of these drugs in an aqueous media. Hence, in the current research work, the solubility of dihydropyrimidine derivative i.e. 4-(4-ethoxyphenyl)-5-(3,4,5-trimethoxybenzoyl)-3,4-dihydropyrimidin-2(1H)-one [coded as DHP-5] was measured in twelve different pure solvents such as water, methanol, ethanol, 1-butanol, 2-butanol, isopropyl alcohol (IPA), ethylene glycol (EG), propylene glycol (PG), ethyl acetate (EA), dimethyl sulfoxide (DMSO), polyethylene glycol-400 (PEG-400) and Carbitol® at five different temperatures and atmospheric pressure. Experimental solubilities (expressed as mole fraction) of DHP-5 were fitted and correlated with Van't Hoff and Apelblat models. The solubilities (expressed as mole fraction) of DHP-5 at T=318.15K were observed highest in PEG-400 (1.21×10−2) followed by DMSO (9.96×10−3), Carbitol® (6.24×10−3), EA (3.45×10−3), 1-butanol (1.46×10−3), 2-butanol (1.45×10−3), PG (1.33×10−3), IPA (1.13×10−3), EG (1.07×10−3), ethanol (8.02×10−4), methanol (5.77×10−4) and water (2.54×10−5) and similar trend was observed at all five different temperatures investigated. Apparent thermodynamic analysis indicated that the dissolution behavior of DHP-5 was spontaneous, endothermic and entropy-driven in all pure solvents investigated.

Fe(III)-montmorillonite catalysed one pot synthesis of 5-substituted dihydropyrimidine derivatives as potent antimicrobial agents.

ObjectivesThis paper aims to describe the synthesis of a series of novel 5-substituted dihydropyrimidine derivatives using Fe-(III)-montmorillonite as an efficient and reusable catalyst.MethodsThe structures of the synthesized compounds were confirmed by Fourier transform-infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) and mass spectroscopy methods. The title compounds were screened for antimicrobial activity, and molecular docking studies were conducted.ResultsThe results revealed that the catalyst significantly enhanced the reaction time and product yield. The antimicrobial activity results indicated that compounds 4c, 4e and 4k exhibited promising antimicrobial activity against the tested microorganisms.ConclusionThe catalyst can be recycled at least two to three times without a noticeable decrease in its catalytic activity. The synthesized compounds displayed promising antimicrobial activity.

COPPER-NICKEL TARTARATES COMPOSITES: A REUSABLE AND GREEN CATALYSTS FOR THE SYNTHESIS OF QUINOLINES AND DIHYDROPYRIMIDINES DERIVATIVES

A series of Cu-Ni tartarate composites at various compositions is prepared and used as green catalyst for the synthesis of quinoline and dihydropyrimidine derivatives. Time required for the completion of reaction using such new catalyst is comparatively less and affording high percentage yield of products.

Preparation, biological evaluation and molecular docking study of imidazolyl dihydropyrimidines as potential Mycobacterium tuberculosis dihydrofolate reductase inhibitors

A series of novel dihydropyrimidine derivatives bearing an imidazole nucleus at C-4 position were synthesized in excellent yields via Biginelli multi-component reaction. The newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR and Mass spectroscopy. In vitro antitubercular evaluation of all the newly synthesized compounds 4a–p against Mycobacterium tuberculosis (Mtb) H37Rv showed, 4j (MIC: 0.39μg/mL; SI: >25.64), 4m (MIC: 0.78μg/mL; SI: >12.82) and 4p (MIC: 0.39μg/mL; SI: 24.10) as the most promising lead analogues. Compounds 4j, 4m and 4p displayed effective reduction in residual Mtb growth within the tuberculosis-infected macrophage model. Further, molecular docking study of active molecules 4j, 4m and 4p against Mycobacterium tuberculosis dihydrofolate reductase (Mtb DHFR) proved their potency as Mtb DHFR inhibitors acting as potential leads for further development. Pharmacokinetic properties leading to drug-likeness were also predicted for most active molecules 4j, 4m and 4p.

Multicomponent Biginelli's Synthesis, Antimycobacterial Activity and Molecular Docking Studies of Dihydropyrimidine Derivatives as Thymidylate Kinase Protein Targets

Multicomponent Biginelli's Synthesis, Antimycobacterial Activity and Molecular Docking Studies of Dihydropyrimidine Derivatives as Thymidylate Kinase Protein Targets

Poly(vinylpyrrolidonium) perchlorate catalyzed one-pot synthesis of tricyclic dihydropyrimidine derivatives

A simple and efficient procedure for the synthesis of benzo[4,5]imidazo[1,2-α]pyrimidine and 2-amino-4-substituted-1,4-dihydrobenzo[4,5]imidazolo[1,2-α]pyrimidine-3-carbonitrile derivatives using poly(vinylpyrrolidonium) perchlorate {[PVPH]ClO4} as a newly reported, modified polymeric catalyst is reported. Some of the advantages of this novel synthetic method are: easy preparation of the catalyst, simple and easy work-up procedure, short reaction times, high to excellent yields of the products and reusability of the catalyst.

Nano-Fe3O4@silica sulfuric acid as a reusable and magnetically separable potent solid acid catalyst in Biginelli-type reaction for the one-pot multicomponent synthesis of fused dihydropyrimidine derivatives: A greener NOSE and SFRC approach

ABSTRACTAn efficient, highly product selective, eco-friendly, one-pot multicomponent synthesis of dihydropyrimidine derivatives via Biginelli reaction has been described. The reaction was developed by greener nanoparticle-catalyzed organic synthesis enhancement (NOSE) chemistry and solvent free reaction condition (SFRC) approaches, which helped us in making the procedure greener. The reaction went smoothly with a diverse range of aromatic, aliphatic, hetero-aromatic aldehydes, different amine sources, as well as various β-dicarbonyl compounds, showing the flexibility of this methodology. Magnetically separable nano-Fe3O4@SiO2@SO3H, which acts as a potent solid acid catalyst, was characterized by FT-IR, SEM, EDX and TEM, VSM, and TGA analyses. The catalyst was recycled from the reaction mixture easily by an external magnet and reused in five more consecutive runs without much decrease in catalytic activity. Its catalytic efficiency was compared to other nano and bulk solid acid catalyst in order to ascertain the best combination for the conversion.

Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors

Four series of heterocyclic compounds 4-dihydropyrimidine-2-thiones 7–12 (series A), N,S-dimethyl-dihydropyrimidines 13–18 (series B), hydrazine derivatives of dihydropyrimidine 19–24 (series C), and tetrazolo dihydropyrimidine derivatives 25–30 (series D), were synthesized and evaluated for in vitro urease inhibitory activity. The series B–D were first time examined for urease inhibition. Series A and C were found to be significantly active with IC50 values between 34.7–42.9 and 15.0–26.0μM, respectively. The structure–activity relationship showed that the free S atom and hydrazine moiety are the key pharmacophores against urease enzyme. The kinetic studies of the active series A (7–12) and C (19–24) were carried out to determine their modes of inhibition and dissociation constants Ki. Compounds of series A (7–12) and series C (19–24) showed a mixed-type of inhibition with Ki values ranging between 15.76–25.66 and 14.63–29.42μM, respectively. The molecular docking results showed that all the active compounds of both series have significant binding interactions with the active sites specially Ni-ion of the urease enzyme. Cytotoxicity of all series A–D was also evaluated against mammalian mouse fibroblast 3T3 cell lines, and no toxicity was observed in cellular model.

Synthesis of dihydropyrimidine derivatives of calix[4]arene via adaptation of Biginelli-3-Component reaction

Methods are described for the selective and rapid diametrical functionalization of calix[4]arene at the upper-rim as well as at the lower-rim with dihydropyrimidine derivatives via Biginelli-3-Component reaction. Studies on self-aggregating properties of these novel derivatives were also illustrated.

ChemInform Abstract: Synthesis of 3,4‐Dihydropyrimidin‐2(1H)‐ones (DHPMs) by Natural L‐Ascorbic Acid.

AbstractLemon juice contains ascorbic acid, which catalyzes the Biginelli synthesis of dihydropyrimidine derivatives.

ChemInform Abstract: One‐Pot Synthesis of Tricyclic Dihydropyrimidine Derivatives and Their Biological Evaluation.

AbstractThe title compounds are synthesized using one‐pot, three‐component Traube—Schwarz reaction with various aldehydes in presence of a zinc catalyst.

ChemInform Abstract: Synthesis, Biological Evaluation and in silico and in vitro Mode‐of‐Action Analysis of Novel Dihydropyrimidones Targeting PPAR‐γ.

AbstractA variety of novel dihydropyrimidine derivatives (IV), (VI) (17 examples in all) are synthesized via multicomponent Biginelli‐type reactions.

One-pot synthesis of tricyclic dihydropyrimidine derivatives and their biological evaluation

A series of tricyclic dihydropyrimidine derivatives were synthesized using a one-pot, three-component Traube–Schwarz reaction in the presence of catalyst Zn(ClO4)2·6H2O. All the purified compounds were evaluated for their in vitro anticancer activity against three different cancer cell lines such as prostate cancer cells (PC3), lung cancer cells (NCI-H1299) and colon cancer cells (HCT116). In vitro DNA-intercalation ability of the compounds was investigated by UV–vis absorption spectroscopy, showing the insertion of compound into the DNA base pairs and a strong interaction with the DNA double helix.

Synthesis and Evaluation of Dihydropyrimidine Derivatives as Antiulcer Agents.

Synthesis and Evaluation of Dihydropyrimidine Derivatives as Antiulcer Agents.