Pyrimidine Template Research Articles

Ultrasound assisted regioselective synthesis of novel adamantyl-pyrazolo[1,5-a]pyrimidines in aqueous media and molecular docking and drug likeness studies

Multi-step synthesis of adamantyl-pyrazolo[1,5-a]pyrimidine derivatives under ultrasound irradiation has been described adopting the technique of molecular hybridization, whereby two core bioactive units- adamantanamine and pyrazolo[1,5-a]pyrimidine templates have been brought together into a new chemical entity. Ultrasound irradiation of N-(adamantan-1-yl)-3-amino-1H-pyrazole-4-carboxamide with formylated active proton compounds yields the desired hybrids in good to excellent yields. The N-(adamantan-1-yl)-3-amino pyrazolo[1,5-a]pyrimidine carboxamide derivatives were successfully identified with the help of spectral and analytical data. X-ray crystallography of ethyl 3-(adamantan-1-ylcarbamoyl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (14c) unambiguously confirmed the formation of the desired hybrid. The results and the findings of the docking scores indicate that the active ligands 7a and 11b exhibited highest binding energies with a score of –7.33 Kcal/mol and – 8.73 Kcal/mol, respectively. The inhibition constant (KI) for ligands 7a and 11b were found to be 4.24 µM and 396.32 µM, respectively which are comparatively lower than the control favipiravir thereby conforming to the drug-likeness prediction. These compounds as such become favorable for screening as drug candidates compared to the control favipiravir with lower binding energy, lower lipophilicity range and very high KI constant. The active ligands have promising functions to inhibit and interfere with the replication and maturation of Chymotrypsin-like protease (3CLpro) of SARS-Coronavirus 2. The lower KI, high binding energy and drug-likeness efficiency of the compounds can be further developed into a potent drug molecule against the uncontrollable SARS-COV-2.

Palladium‐Catalyzed meta‐Selective C‐H Alkenylation and Acetoxylation of Arylacetic Acid Using a Pyrimidine Template

Palladium‐catalyzed remote meta‐selective C‐H functionalization of arylacetic acid has been developed using a pyrimidine template. This transformation is not only tolerated to a diverse range of arylacetic acid and alkene substrates but also applicable to the synthesis of pharmaceutically active ibuprofen derivatives. Moreover, the pyrimidine template was readily removable and recyclable under mild conditions.

Synthesis and in vitro biological evaluation of new pyrimidines as glucagon-like peptide-1 receptor agonists

The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small-molecule GLP-1 receptor agonists. In this study, two series of new pyrimidine derivatives were designed and synthesized using an efficient route, and were evaluated in terms of GLP-1 receptor agonist activity. In the first series, novel pyrimidines substituted at positions 2 and 4 with groups varying in size and electronic properties were synthesized in a good yield (78–90%). In the second series, the designed pyrimidine templates included both urea and Schiff base linkers, and these compounds were successfully produced with yields of 77–84%. In vitro experiments with cultured cells showed that compounds 3a and 10a (10−15–10−9M) significantly increased insulin secretion compared to that of the control cells in both the absence and presence of 2.8mM glucose; compound 8b only demonstrated significance in the absence of glucose. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1 receptor agonists that can be administered orally.

Design and synthesis of sulfonamide-substituted diphenylpyrimidines (SFA-DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors with improved activity toward B-cell lymphoblastic leukemia

A new series of diphenylpyrimidine derivatives (SFA-DPPYs) were synthesized by introducing a functional sulfonamide into the C-2 aniline moiety of pyrimidine template, and then were biologically evaluated as potent Bruton's tyrosine kinase (BTK) inhibitors. Among these molecules, inhibitors 10c, 10i, 10j and 10k displayed high potency against the BTK enzyme, with IC50 values of 1.18 nM, 0.92 nM, 0.42 nM and 1.05 nM, respectively. In particular, compound 10c could remarkably inhibit the proliferation of the B lymphoma cell lines at concentrations of 6.49 μM (Ramos cells) and 13.2 μM (Raji cells), and was stronger than the novel agent spebrutinib. In addition, the inhibitory potency toward the normal PBMC cells showed that inhibitor 10c possesses low cell cytotoxicity. All these explorations indicated that molecule 10c could serve as a valuable inhibitor for B-cell lymphoblastic leukemia treatment.

Application of quinazoline and pyrido[3,2-d]pyrimidine templates to design multi-targeting agents in Alzheimer's disease

A quinazoline and pyrido[3,2-d]pyrimidine based compound library was designed, synthesized and evaluated as multi-targeting agents aimed at Alzheimer's disease (AD).

Identification of a New Series of Potent Adenosine A2A Receptor Antagonists Based on 4-Amino-5-carbonitrile Pyrimidine Template for the Treatment of Parkinson's Disease.

Adenosine receptor A2A antagonists have emerged as potential treatment for Parkinson's disease in the past decade. We have recently reported a series of adenosine receptor antagonists using heterocycles as bioisosteres for a potentially unstable acetamide. These compounds, while showing excellent potency and ligand efficiency, suffered from moderate cytochrome P450 inhibition and high clearance. Here we report a new series of adenosine receptor A2A antagonists based on a 4-amino-5-carbonitrile pyrimidine template. Compounds from this new template exhibit excellent potency and ligand efficiency with low cytochrome P450 inhibition. Although the clearance remains moderate to high, the leading compound, when dosed orally as low as 3 mg/kg, demonstrated excellent efficacy in the haloperidol induced catalepsy rat model for Parkinson's disease.

Sequence Context Effect on Strand Slippage in Natural DNA Primer–Templates

Strand slippage has been found to occur in primer-templates containing a templating thymine, cytosine, and guanine, leading to the formation of misaligned structures with a single-nucleotide bulge. If remained in the active site of low-fidelity polymerases during DNA replication, these misaligned structures can ultimately bring about deletion mutations. In this study, we performed NMR investigations on primer-template models containing a templating adenine. Similar to our previous results on guanine, adenine templates are also less prone to strand slippage than pyrimidine templates. Misalignment occurs only in primer-templates that form a terminal C·G or G·C base pair. Together with our previous findings on thymine, cytosine, and guanine templates, the present study reveals strand slippage can occur in any kind of natural templating bases during DNA replication, providing insights into the origin of mutation hotspots in natural DNA sequences. In addition to the type of incoming base upon misincorporation, the propensity of strand slippage in primer-templates depends also on the type of templating base, its upstream and downstream bases.

Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach—Part 1

The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described leading to a series of potent, selective CHK1 inhibitors such as compound 17r. In the Letter, the further utility of the pyrazolo[1,5-a]pyrimidine template for the development of potent, selective kinase inhibitors is detailed.

NMR Investigation of DNA Primer-Template Models: Guanine Templates Are Less Prone to Strand Slippage upon Misincorporation

Misaligned structures can result from strand slippage during DNA replication and, if not repaired, would lead to mutations. Previously, we showed that strand slippage can occur upon misincorporation of a dNTP opposite thymine and cytosine templates, resulting in a misaligned structure with a T- or C-bulge. The formation propensity for misaligned structures was found to depend on the type of terminal base pair. In this study, we performed NMR investigations on primer-template models containing a guanine template. Our results reveal guanine templates are less prone to strand slippage than pyrimidine templates. Misalignment was found to occur only in 5'-CG templates with a downstream purine. In addition to the significance of terminal base pair and upstream nucleotide, the present study reveals the importance of the templating base and its downstream nucleotide, which also determine the propensity of strand slippage in primer-templates.

Optimization of a series of 4,6-bis-anilino-1 H-pyrrolo[2,3- d]pyrimidine inhibitors of IGF-1R: Elimination of an acid-mediated decomposition pathway

Initial evaluation of a series 4,6-bis-anilino-1 H-pyrrolo[2,3- d]pyrimidines revealed a C(1′) carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1′) carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1 H-pyrrolo[2,3- d]pyrimidine template.

Nuclear Magnetic Resonance Investigation of Primer−Template Models: Formation of a Pyrimidine Bulge upon Misincorporation

Our previous studies have shown that misaligned structures can occur upon misincorporation of a dNTP opposite thymine templates. The formation of misaligned structures during DNA replication, if not repaired properly, can be bypassed and extended by low-fidelity polymerases and ultimately lead to mutations. In this study, the base pair structures at the replicating sites of a set of primer-template models which mimic the situation upon misincorporation of a dNTP opposite cytosine templates have been determined. High-resolution NMR structural results show that misaligned structures with a C-bulge can be formed upon incorporation of dCTP, dTTP, and dATP opposite 5'-GC, 5'-AC, and 5'-TC templates, respectively. The stabilities of misaligned structures depend on the types of terminal base pairs at the replicating sites. Together with the structural findings in thymine templates, we conclude that terminal G.C and C.G base pairs always contribute a larger stabilizing effect to the misaligned structures containing a pyrimidine bulge than terminal A.T and T.A base pairs. Misalignment and thus deletion mutation are more likely to occur if misincorporation of a nucleotide opposite a pyrimidine template can cause template slippage to form a terminal G.C or C.G base pair. Although misalignment also occurs when the newly formed terminal base pair is an A.T base pair or a T.A base pair, both misaligned and mismatched conformers coexist, which can lead to deletion and substitution mutations, respectively.

Efficient Conversion of Biginelli 3,4‐Dihydropyrimidin‐2(1H)‐one to Pyrimidines via PyBroP‐Mediated Coupling.

An efficient two-step procedure is described to convert the Biginelli 3,4-dihydropyrimidin-2(1H)-one to various multifunctionalized pyrimidines via the Kappe dehydrogenation and a new mild PyBroP-mediated coupling with C, N, O, and S nucleophiles, which provides a readily accessible multifunctionalized pyrimidine template for diversity-oriented synthesis.

Efficient Conversion of Biginelli 3,4-Dihydropyrimidin-2(1H)-one to Pyrimidines via PyBroP-Mediated Coupling

An efficient two-step procedure is described to convert the Biginelli 3,4-dihydropyrimidin-2(1H)-one to various multifunctionalized pyrimidines via the Kappe dehydrogenation and a new mild PyBroP-mediated coupling with C, N, O, and S nucleophiles, which provides a readily accessible multifunctionalized pyrimidine template for diversity-oriented synthesis.

Microwave‐Assisted Synthesis of Pyrimidine Libraries

AbstractDi‐ or trisubstituted pyrimidine libraries are prepared in good yield by the microwave irradiation of an alkynone and either an amidine or guanidine at 120–150 °C in acetonitrile in the presence of sodium carbonate or at 100 °C after treatment with methanolic sodium methoxide in a sealed tube using a monomodal microwave synthesiser. These rapid and efficient methods often require no chromatographic purification and so are appropriate for automated combinatorial methodology and have been applied in the synthesis of a small library of potentially useful novel ligands for the estrogen receptor based on the pyrimidine template.

4‐Acylamino‐6‐arylfuro[2,3‐d]pyrimidines: Potent and Selective Glycogen Synthase Kinase‐3 Inhibitors

AbstractFor Abstract see ChemInform Abstract in Full Text.

4-Acylamino-6-arylfuro[2,3- d]pyrimidines: potent and selective glycogen synthase kinase-3 inhibitors

Modeling studies of a furo[2,3- d]pyrimidine GSK-3 hit compound 1 superimposed onto the X-ray crystal structure of a legacy pyrazolo[3,4- c]pyridazine GSK-3 inhibitor 2 led to the identification of 4-acylamino-6-arylfuro[2,3- d]pyrimidine template 3. Synthesis of analogues based on template 3 has resulted in a number of potent and selective GSK-3β inhibitors. The most potent and selective compound was the m-pyridyl analogue 24.

5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK(1)receptor antagonists: structure-activity relationship studies on the substituent at N2-position.

To establish structure-activity relationships a new series of analogues of the highly potent and selective CCK(1) receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]-pyrimidine (1a) modified at N2-position of the central scaffold has been prepared and evaluated as CCK receptor ligands. With this aim the N2-benzyl group has been replaced by methyl, cyclohexyl, aromatic groups, 1-phenylethyl, and 1-carboxy-2-phenylethyl group. Then, substituents with different electronic and steric properties were introduced into different positions of the phenyl group of analogues 19a and 19b. The results of the CCK receptor binding and in vitro functional activity evaluation suggest the importance of the lipophilic character and an appropriate spatial orientation of the moiety linked at the N2-position of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine template for potent and selective binding and antagonist activity at CCK(1) receptor subtype. The 2-cyclohexyl and (2S)-1-naphthyl derivatives 18a and (2S)-20a have emerged as more potent and selective CCK(1) receptor antagonists than the lead compound 1a. Additionally, the results confirm the (4aS,5R)-stereochemistry at the central bicyclic skeleton as an essential structural requirement for potent binding to this receptor subtype.

SOLID-PHASE SYNTHESIS OF 2,4,6-TRIAMINOPYRIMIDINES

A novel method for polymer-supported synthesis of 2,4,6-triaminopyrimidines 1a–h on the basis of sequential nucleophilic substitution of appropriate amines to pyrimidine template is described.

Development of a binding model to protein tyrosine kinases for substituted pyrido[2,3-d]pyrimidine inhibitors.

Previously, our laboratories have reported on a new class of highly potent tyrosine kinase inhibitors based on the pyrido[2, 3-d]pyrimidine core template. To understand the structural basis for the potency and specificity, a model for the binding mode of this class of inhibitors to the tyrosine kinase domains of c-Src, PDGFr, FGFr, and EGFr tyrosine kinases was developed from structural information (principally utilizing the catalytic domain of c-AMP-dependent protein kinase as template) and structure-activity relationship (SAR) information. In the resulting docking mode, the pyrido[2,3-d]pyrimidine template shows a hydrogen-bonding pattern identical to that of olomoucine. The 6-aryl substituent of the heterocycle is located deep in the binding cleft in a pocket not used by ATP, which helps to confer high-affinity binding as well as specificity. The 2-anilino and 2-(dialkylamino)alkylamino substituents as well as the 7-urea substituent of inhibitors within this class are located at the entrance of the binding cleft and make contact with residues in the hinge region between the two kinase lobes. This allows considerable variability and bulk tolerance for C-2 and N-7 substituents. The models presented here are consistent with the SAR seen for the inhibition of a number of isolated enzymes and provide a structural basis to explain their specificity. They have been used successfully to design new highly potent protein kinase inhibitors.

Kinetic analysis of Escherichia coli deoxyribonucleic acid polymerase I.

The kinetic properties of Escherichia coli DNA polymerase I were simplified to those of a 1 deoxynucleotide substrate reaction by the use of polynucleotide templates. With poly(dA)-oligo(dT) as the template-primer complex, Mg2+ decreases the Km of the substrate dTTP but has little or no effect on the Km of the substrate Mg-dTTP, suggesting that multiple pathways involving the binding of Mg2+, dTTP, and Mg-dTTP are operative in forming the active complex. The Km of free Mg2+, extrapolated to zero concentration of substrate (830 = 62 muM), agrees within a factor of 2 with the dissociation constant of magnesium from 4 +/- 1 sites on the enzyme determined previously by binding studies (Slater, J.P., Tamir, I., Loeb, L.A., and Mildvan, A.S. (1972) J. Biol. Chem. 247, 6784-6794). The maximal turnover number with poly(dA) as template is 5.7 +/- 0.7 s-1. Changing the nature of the base in the polydeoxynucleotide template alters the maximal rate of polydeoxynucleotide synthesis by an overall factor of 31 with poly(dC) is greater than poly(dT) is greater than poly(dA) is greater than poly(dG), indicating that pyrimidine templates are copied faster than purine templates. Changing the sugar structure from poly(dA) to poly(rA) causes a 3-fold increase in the rate of template copying. A study of the kinetic effects of all noncomplementary deoxynucleotides with all deoxynucleotide templates, as well as with poly(rA)-oligo(dT), yields complex patterns of activation and inhibition requiring from 1 to 2 additional binding sites for the noncomplementary nucleotides. The kinetically determined affinities of the active site of the enzyme-template-primer complex for the complementary free nucleotide (as measured by Km) generally exceed those for the noncomplementary neuclotides (as measured by KI slope) by 1 or more than 3 orders of magnitude.