Dihydropyrimidines Research Articles

Novel diaryl dihydropyrimidines as promising anticancer agents: In silico, in vitro investigation

Due to the structural resemblance with the nucleic acid bases, Dihydropyrimidines (DHPs) gained a special attention for exploring for chemotherapeutic agents. Diaryl dihydropyrimidines (DADPs) were reported to have anticancer properties and antiviral and antibacterial activities. In an attempt to design new DADP compounds, we have come up with some novel compounds (3a–3o, 4a–4o, 5a–5o) by incorporating the piperonal to check its significance on biological activity. Initially, computational screening has been performed to shortlist the top molecules which are showing better binding interactions with the selected targets of cancer treatment such as VEGFR2, JAK1 kinase, and JAK3 kinase. Later the selected compounds were synthesized (15 compounds) and characterized by spectral analysis. In the in vitro anti-proliferative activity in the three cell lines, it was observed that the compounds have exhibited potential biological activity (IC50 values 3d – 42.67 ± 2.28 μM against MCF-7; 3n – 59.68 ± 2.81 μM against Hep G-7; 3d – 70.64 ± 3.12 μM against A-549). It was observed that the piperonal, substituted phenyl ring, secondary amine in mannich base has resulted with improved biological activity, the same has been observed in molecular docking studies.

Structural optimization, synthesis and in vitro synergistic anticancer activities of combinations of new N3-substituted dihydropyrimidine calcium channel blockers with cisplatin and etoposide

T-type calcium channels are considered potential drug targets to combat cancer. Combining T-type calcium channel blockers with conventional chemotherapy drugs represents a promising strategy towards successful cancer treatment. From this perspective, we report in this study the design and synthesis of a novel series of N3-sustituted dihydropyrimidines (DHPMs) as anticancer adjuvants to cisplatin (Cis) and etoposide (Eto). Full spectral characterization of the new compounds was done using FT-IR, 1H NMR, 13C NMR, and HRMS. Structure elucidation was confirmed by 2D NMR 1H-H COSY, HSQC and NOESY experiments. Novel derivatives were tested for their Ca2+ channel blocking activity by employing the whole cell patch-clamp technique. Results demonstrated that most compounds were potential T-type calcium channel blockers with the triazole-based C12 and C13 being the most selective agents against CaV3.2 channel. Further electrophysiological studies demonstrated that C12 and C13 inhibited CaV3.2 currents with respective affinity of 2.26 and 1.27 µM, and induced 5 mV hyperpolarizing shifts in the half-inactivation potential. Subsequently, C12 and C13 were evaluated for their anticancer activities alone and in combination with Cis and Eto against A549 and MDA-MB 231 cancer cells. Interestingly, both compounds exhibited potential anticancer effects with IC50 values < 5 µM. Combination studies revealed that both compounds had synergistic effects (combination index CI < 1) on Cis and Eto through induction of apoptosis (p53 activation and up-regulation of BAX and p21 gene expression). Importantly, in silico physicochemical and ADMET assessment of both compounds revealed their potential drug-like properties with decreased risk of cardiac toxicity. Hence, C12 and C13 are promising anticancer adjuvants through inhibition of CaV3.2 T-type calcium channels, thereby serving as eminent leads for further modification.

Interplay of Halogen and Hydrogen Bonding through Co-Crystallization in Pharmacologically Active Dihydropyrimidines: Insights from Crystal Structure and Energy Framework.

A solvent-assisted grinding method has been used to prepare co-crystals in substituted dihydropyrimidines (DHPM) that constitutes pharmacologically active compounds. These were characterized using FT-IR, PXRD, and single-crystal X-ray diffraction. In order to explore the possibility of formation of halogen (XB) and hydrogen bonding (HB) synthons in the solid state, co-crystallization attempts of differently substituted DHPM molecules, containing nitro, hydoxy, and chloro substituents, with different co-formers, such as 1,4-diiodo tetrafluorobenzene (1,4 DITFB) and 3-nitrobenzoic acid (3 NBA) were performed. The XB co-crystals (C2aXB, C2bXB, and C2cXB) prefer the formation of C-I⋅⋅⋅O/C-I⋅⋅⋅S XB synthon, whereas the HB co-crystal (C2dHB) is stabilized by N-H⋅⋅⋅O H-bond formation. Hirshfeld surface analysis revealed that the percentage contribution of intermolecular interactions for XB co-crystals prefer equal contribution of XB synthon along with HB synthon. Furthermore, the interaction energy was analyzed using energy frameworks, which suggests that their stability, a combination of electrostatics and dispersion, is enhanced through XB/HB in comparison to the parent DHPMs.

Development of Efficient Synthetic Method for Tautomeric Dihydropyrimidines and Analysis of Their Functionality

I here present the results of our studies on the synthesis and functional analysis of tautomeric dihydropyrimidines (DPs) and related compounds in two sections. In the first section, we describe our experimental and theoretical studies on the thermodynamics and properties of 2-substituted 1,4- and 1,6-dihydropyrimidine-5-carboxylates by 1H NMR measurements and density functional theory (DFT) calculations, respectively. The concentration ratios of tautomers a/b of DPs 1, 2, and 3 were determined under various conditions to determine the effects of temperature, solvent, and concentration on thermodynamics data. The obtained free energy differences (ΔG), enthalpy differences (ΔH), and entropy differences (ΔS) are discussed in terms of the molecular structures, dipole moments (DM), and electrostatic potential maps obtained by DFT calculations to clarify the nature of DPs 4-8. In the second section, an efficient synthetic method developed for 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-thiones 9 and 2-ones 10 is described. The novelties of the synthesis protocol are as follows: 1) the use of Lewis acid-mediated reaction, 2) good to high yields, and 3) its broad scope of applicability to aldehydes and ureas. Hitherto unavailable 6-unsubstituted 2-amino DP 11 and 2-aryl DP 12 were obtained from 9 by a substitution reaction with the amine and the Liebeskind-Srogl reaction, respectively. The compounds 9, 10, and related 6-methyl derivatives 19-21 were assessed for their antiproliferative effect on the human promyelocytic leukemia cell line HL-60. 4,4-Dipropyl derivative 20 showed relatively strong activity with an IC50 value of 341 nM.

Experimental and theoretical studies on thermodynamics and properties of tautomers of 2-substituted 6(4)-methyl-1,4(1,6)-dihydropyrimidine-5-carboxylates

Experimental and theoretical studies on the thermodynamics and properties of 2-substituted 6(4)-methyl-1,4(1,6)-dihydropyrimidine-5-carboxylates were undertaken by 1H NMR measurements and DFT (density functional theory) calculations. The ratios of tautomers a/b of dihydropyrimidines (DPs) 1, 2, and 3 were determined under various conditions to reveal the effects of temperature, solvent, and concentration on the thermodynamic data. The observed results, the free energy differences (ΔG), enthalpy differences (ΔH), and entropy differences (ΔS), are discussed in terms of the molecular structures, dipole moments (DM), and the electrostatic potential maps calculated by the DFT to clarify the nature of the DPs.

Membrane effects of dihydropyrimidine analogues with larvicidal activity

Two recently synthesized dihydropyrimidines (DHPMs) analogues have demonstrated larvicide and repellent activity against Anopheles arabiensis. DHPMs high lipophilicity suggests that these compounds may interact directly with the membrane and modify their biophysical properties. The purpose of the present study was to characterize the interaction of both compounds with artificial membranes. Changes on the properties of DPPC films were studied using Langmuir monolayers. The presence of DHPMs in the subphase modified the interfacial characteristics of DPPC compression isotherms, causing the expansion of the monolayer, inducing the disappearance of DPPC phase transition and increasing the molecular packing of the film. Moreover, both compounds showed ability to penetrate into the lipid monolayers at molecular pressures comparable to those in biological membranes. The effects of both DHPMs on the molecular organization of DPPC liposomes were measured by fluorescence anisotropy. The results indicate that their presence between lipid molecules would induce an increasing intermolecular interaction, diminishing the bilayer fluidity mainly at the polar region. Finally, we performed free diffusion MD simulations and obtained spatially resolved free energy profiles of DHPMs partition into a DPPC bilayer through Potential of Mean Force (PMF) calculations. In agreement with the experimental assays, PMF profiles and MD simulations showed that DHPMs are able to partition into DPPC bilayers, penetrating into the membrane and stablishing hydrogen bonds with the carbonyl moiety. Our results suggest that DHPMs bioactivity could involve their interaction with the lipid molecules that modulate the supramolecular organization of the biological membranes and consequently the membrane proteins functionality.

New Potential Antimalarial Agents: Design, Synthesis and Biological Evaluation of Some Novel Quinoline Derivatives as Antimalarial Agents.

A novel series of dihydropyrimidines (DHPMs) 4a–j; 2-oxopyran-3-carboxylate 7a,b; 1-amino-1,2-dihydropyridine-3-carboxylate 8; and 1,3,4-oxadiazole derivatives 12 with quinolinyl residues have been synthesized in fairly good yields. The structure of the newly synthesized compounds was elucidated on the basis of analytical and spectral analyses. In vitro antimalarial evaluation of the synthesized quinoline derivatives against Plasmodium falciparum revealed them to possess moderate to high antimalarial activities, with IC50 values ranging from 0.014–5.87 μg/mL. Compounds 4b,g,i and 12 showed excellent antimalarial activity against to Plasmodium falciparum compared with the antimalarial agent chloroquine (CQ).

One-pot synthesis of ferrocenyl-pyrimidones using a recyclable molibdosilicic H4SiMo12O40 heteropolyacid

A series of ferrocene-containing dihydropyrimidines (DHPs) were prepared by the one-pot Biginelli reaction of formylferrocene, 1,3-dicarbonyl component and urea/thiourea. The reaction was catalyzed by a commercial Keggin heteropolyacid (H4SiMo12O40) as a safe, clean and recyclable catalyst. Three different synthetic protocols were examined in order to improve the yields of the reaction and to elucidate its mechanism. Intermediates of the competitive Knoevenagel reaction were also isolated. The methodology is operationally simple and provides access to highly substituted dihydropyrimidines containing ferrocene in very good yields. The catalyst can be used and recycled without appreciable loss of the catalytic activity.

ChemInform Abstract: Preparation of Dihydrotetrazolo[1,5‐a]pyrimidine Derivatives from Biginelli 3,4‐Dihydropyrimidine‐2‐thiones.

Abstract Dihydropyrimidines (DHPM) with a fused tetrazole ring have been synthesized via a smooth and efficient three-step protocol involving N,S-dimethylated and 2-hydrazinyl-dihydropyrimidine intermediates, respectively. The described protocol is applicable to electron rich and electron poor DHPM precursors as well. The insertion of tetrazole ring in monastrol type dihydropyrimidines makes it interesting for pharmacological investigations.

ZSM-5 Catalyzed Solvent Free Ecofriendly Synthesis of Substituted Pyrimidine Derivatives

Azeolite ZSM-5 catalyzed simple, one-pot solvent-free, cost-effective and environmental benign protocol for the synthesis of dihydropyrimidines (DHPMs) have been developed. Aseries of substituted 1,4-DHPM derivatives have been synthesized by one-pot Biginelli type cyclocondensation of ethylacetoacetate, aromatic/heteroaromatic aldehydes, and urea/thiourea with a catalytic amount of zeolite under solvent-free protocol in a sufficiently high yield. The catalyst is recyclable and can be used repeatedly.

Preparation of dihydrotetrazolo[1,5-a]pyrimidine derivatives from Biginelli 3,4-dihydropyrimidine-2-thiones

Dihydropyrimidines (DHPM) with a fused tetrazole ring have been synthesized via a smooth and efficient three-step protocol involving N,S-dimethylated and 2-hydrazinyl-dihydropyrimidine intermediates, respectively. The described protocol is applicable to electron rich and electron poor DHPM precursors as well. The insertion of tetrazole ring in monastrol type dihydropyrimidines makes it interesting for pharmacological investigations.

Ferrocene as a functional group enhances the inhibitive effect of dihydropyrimidine on radical-induced oxidation of DNA

Phenyl and ferrocenyl groups are involved in 3,4-dihydropyrimidin-2(1H)-one (-thione) to form eleven dihydropyrimidines (DHPMs) in this work, aiming to explore the effects of the ferrocene moiety, the CS bond, and the phenolic hydroxyl group on the abilities of DHPMs to protect DNA against 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation. It is found that the antioxidant abilities of DHPMs containing CS are higher than those of DHPMs containing CO. In addition, the phenolic hydroxyl group and the CS bond show similar effects on the antioxidant capacities of DHPMs. On the other hand, the ferrocenyl group remarkably increases the antioxidant capacities of DHPMs, while the antioxidant effects of ferrocenyl-appended DHPMs are further improved by the CS bond. Therefore, the influence of the functional group on the antioxidant abilities of DHPMs follows the order: ferrocenyl group > CS bond > phenolic hydroxyl group.

Synthesis of C(5)-(p-Toluoyl substituted)-3,4-dihydropyrimi- dinones (or -thiones) via Biginelli Reaction Promoted with Microwave Irradiation under Solvent-Free Conditions

The Biginelli reaction, which involves the one-pot acid catalyzed cyclocondensation of ethyl acetoacetate, urea, and arylaldehyde, was first discovered by Italian chemist Pietro Biginelli about 120 years ago. A large number researchers have shown persistent attention to the study of Biginelli reaction on account of its significant biological and pharmaceutical activities and diversity of structural changes of dihydropyrimidines (DHPMs) and its derivatives. Herein, the synthesis of C(5)-(p-toluoyl)-3,4-dihydropyrimidin-2(1H)-ones (or -thiones) via Biginelli reaction has been accomplished from aldehydes, p-toluoylacetone, and urea or thiourea in the presence of TsOH promoted with microwave irradiation under solvent-free condi- tions in good yields and high purity without chromatographic separation. Keywords Biginelli reaction; 3,4-dihydropyrimidin-2(1H)-ones (or -thiones); β-diketone; microwave irradittion

English

ObjectiveTo investigate the myocardial depressant activity of a newly synthesised dihydropyrimidine derivative 5-acyl-6-methyl-4-phenyl-2 -S-ethyl-1,4-dihydropyrimidine (BK vi) and comparing with nifedipine on Isolated perfused rabbit heart. Material and MethodsEffects of the test compound BK-vi on the amplitude,heart rate and coronary flow on isolated perfused rabbit heart was compared with nifedipine.Observations were made with increasing concentrations of BK-vi and Nifedipine with dimethylsulfoxide (DMSO) as the solvent.Six preparations were used for each dose of BK-vi and nifedipine.Heart rate ,amplitude and coronary flow were noted down every minute for five minutes after injection of each drug and control. ResultsOn comparing the effects of BK-vi and nifedipine, it was found that both had a negative inotropic and negative chronotropic effect. Compound BK -vi did not produce significant effect on heart rate at all the four doses. In comparison, nifedipine produced a significant to highly significant decrease in heart rate.Significant decrease in amplitude with BK-vi was seen at dose of 7.29 X 10-4M and 14.5 X 10-4M by 42% and 56.98% respectively and in coronary flow by 39.95% at dose of 14.5 X 10-4M .Nifedipine significantly decreased heart rate and amplitude at all doses with cardiac arrest at 4.6 X 10-5M.A significant increase in coronary flow was seen with nifedipine by 9.4% and 13% at doses of 0.5 X 10-5M and 1.15 X 10-5M respectively though this property was lost at higher doses.On comparison, BK-vi produced significant myocardial depression at much higher dose than nifedipine. ConclusionBK-vi has calcium channel blocking activity like nifedipine and produced less potent myocardial depression in comparison with nifedipine. Key wordsDihydropyrimidines, Voltage dependent calcium channels, Nifedipine, Dihydropyridines International Journal of Medical and Clinical Research ISSN:0976-5530 & E-ISSN:0976-5549, Volume 3, Issue 3, 2012 Introduction Modern drug discovery involves screening small molecules for their ability to bind to a preselected protein target as well as to modulate a biological pathway in cells [1].The demand for diverse compound libraries for screening in drug discovery is the driving force behind the development of new technologies for rapid parallel and combinatorial synthesis [2].Bignelli in 1893 first described the synthesis of 6-methyl-4-substituted phenyl 2-oxo-1,2,3,4tetrahydropyrimidine-5-carboxylic acid ethyl esters by condensation of an aldehyde, urea and ethyl acetoacetate [3] .DHP (Dihydropyridines) and DHPMs(Dihydropyrimidines) represent important and extensively studied compounds belonging to the class of calcium channel blockers.Many researchers have determined the synthetic routes and biological activities of these compounds.These developments led to the pharmacological evaluation of these compounds [4]. Much interest has been shown in the design of Bignelli-like compounds which are valuable substitutes for the nifedipine and other 1,4-dihydropyridine drugs [5], regarded as aza-analogues of nifedipine related dihydropyridines [6].Out of the diverse range of biological activities shown by dihydropyrimidines, most notable is the cardiovascular activity that compares favourably with activity shown by structurally related drugs amlodipine, nicardipine. A reasonable pharmacophore model for DHP/DHPM calcium channel modulators has been proposed Citation: Shalini Salwan, et al (2012) Myocardial Depressant Activity of a Newly Synthesised Dihydropyrimidine Derivative 5-acyl-6-methyl4-phenyl-2-S-ethyl-1, 4-dihydropyrimidine (bk-vi) in comparison with nifedipine. International Journal of Medical and Clinical Research, ISSN:0976-5530 & E-ISSN:0976-5549, Volume 3, Issue 3, pp.-132-135. Copyright: Copyright©2012 Shalini Salwan, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Synthesis of 4-unsubstituted dihydropyrimidines. Nucleophilic substitution at position-2 of dihydropyrimidines

Synthesis of novel 4-unsubstituted dihydropyrimidines (DPs) was performed. Subsequently, a variety of 4-unsubstituted 1,4(3,4)-DPs with amino moieties at position-2 were obtained in excellent yields by activation of position-2 owing to regioselective alkoxycarbonylation at position-3 of the DP skeleton. 3-Oxo-2-phenyl-2,3,5,8-tetrahydro[1,2,4]triazolo[4,3- a]pyrimidine was obtained using phenylhydrazine instead of amines. Individual tautomers of 1,4(3,4)-DP were observed in the 1H NMR spectra of one derivative depending on temperature and concentration. On the other hand, only 1,4-DP was found in the solid state by single-crystal X-ray crystallography.

ChemInform Abstract: Recent Developments in the Synthesis of Dihydropyridines (DHPs) and Dihydropyrimidines (DHPMs)

AbstractReview: 164 refs.

Adiabatic compressibilities of some synthesized derivatives of dihydropyrimidines in N,N-dimethylformamide and dimethyl sulfoxide at 298.15 K

Sound velocities of solutions of some derivatives of dihydropyrimidines (DHPMs) in N,N-dimethylforamide (DMF) and dimethyl sulfoxide (DMSO) were measured at 298.15 K over a wide range of concentration. Adiabatic compressibilities, apparent adiabatic molar compressibilities and apparent adiabatic molar volumes were also evaluated. Results of sound velocity measurements provide useful information about ion-ion and ion-solvent interactions and are of significant help in understanding the behavior of electrolytes in solutions.

Highly Enantioselective Biginelli Reaction Promoted by Chiral Bifunctional Primary Amine‐Thiourea Catalysts: Asymmetric Synthesis of Dihydropyrimidines

AbstractThe diastereospecific formation of dihydropyrimidines (DHPMs) has been achieved in moderate to high yields with up to 99% ee by a Biginelli reaction. The reaction was performed by using a combined catalyst consisting of a chiral bifunctional primary amine‐thiourea 9f and a Brønsted acid with tert‐butylammonium trifluoroacetate (t‐BuNH2⋅TFA) as additive in dichloromethane at room temperature. The possible mechanism for the reaction has been proposed to explain the origin of the activation and the asymmetric induction.

Multi‐Component Synthesis of Dihydropyrimidines by Iodine Catalyst at Ambient Temperature and in‐vitro Antimycobacterial Activity

An efficient and simple three-component domino synthesis of some new dihydropyrimidines (DHPMs) from aromatic aldehydes, 1,3-dicarbonyl compounds and N-(3-chloro-4-fluorophenyl)urea using molecular iodine as catalyst is described. The 1-substituted dihydropyrimidines were isolated in good to excellent yields (78-90%) within a short reaction time (4-6 h) at ambient temperature. The biological evaluation revealed that the newly synthesized compounds (4a-i and 5a-i) exhibited moderate antimycobacterial activity against Mycobacterium tuberculosis H(37) RV.

Structure of Human Eg5 in Complex with a New Monastrol-based Inhibitor Bound in the R Configuration

Drugs that target mitotic spindle proteins have been proven useful for tackling tumor growth. Eg5, a kinesin-5 family member, represents a potential target, since its inhibition leads to prolonged mitotic arrest through the activation of the mitotic checkpoint and apoptotic cell death. Monastrol, a specific dihydropyrimidine inhibitor of Eg5, shows stereo-specificity, since predominantly the (S)-, but not the (R)-, enantiomer has been shown to be the biologically active compound in vitro and in cell-based assays. Here, we solved the crystal structure (2.7A) of the complex between human Eg5 and a new keto derivative of monastrol (named mon-97), a potent antimitotic inhibitor. Surprisingly, we identified the (R)-enantiomer bound in the active site, and not, as for monastrol, the (S)-enantiomer. The absolute configuration of this more active (R)-enantiomer has been unambiguously determined via chemical correlation and x-ray analysis. Unexpectedly, both the R- and the S-forms inhibit Eg5 ATPase activity with IC(50) values of 110 and 520 nM (basal assays) and 150 nm and 650 nm (microtubule-stimulated assays), respectively. However, the difference was large enough for the protein to select the (R)- over the (S)-enantiomer. Taken together, these results show that in this new monastrol family, both (R)- and (S)-enantiomers can be active as Eg5 inhibitors. This considerably broadens the alternatives for rational drug design.