Pyrimidine Series Research Articles

ChemInform Abstract: Facile Synthesis of 6‐(Heptadec‐8‐enyl)thiopyrimidines Incorporating Glycosyl Moiety and Their Antitumor Activity.

AbstractA New series of pyrimidine S‐ and N‐glycosides, [cf.

Synthesis of thio-heterocyclic analogues from Baylis–Hillman bromides as potent cyclooxygenase-2 inhibitors

A series of thio-substituted pyrimidine, benzoxazole, benzothiazole and triazole analogues were synthesized from Baylis–Hillman bromides in a clean and efficient way. The synthesized twenty new compounds were subjected to in vitro COX-1 and COX-2 inhibitory activity. Majority of compounds found to be highly selective COX-2 inhibitor. Seven compounds (16e, 16f, 16k, 16l, 16m, 16r and 16s) displayed anti-inflammatory activity at micromolar concentrations with IC50 values for COX-2 inhibition ranging from 2.93 to 5.34μM compared to reference drug whose IC50 is 2.66μM. All these seven compounds had very little COX-1 inhibition property and thus are suitable candidates for anti-inflammatory drugs with less gastrointestinal side effect.

Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis.

Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFα induced lethal shock.

Synthesis and Evaluation of Chalcone Analogues Based Pyrimidines as Angiotensin Converting Enzyme Inhibitors

Hypertension is a widespread and frequently progressive ailment that imparts a foremost threat for cardiovascular and renal disorders. Mammoth efforts are needed for the synthesis of innovative antihypertensive agents to combat this lethal disease. Chalcones have shown antihypertensive activity through inhibition of Angiotensin Converting Enzyme (ACE). Hence, a series of chalcone analogues is synthesized and used as precursor for the synthesis of novel series of pyrimidines. Precursor chalcones were prepared by reacting aldehydes and ketones in presence of sodium hydroxide followed by synthesis of corresponding pyrimidines by reaction with urea in presence of potassium hydroxide. Both groups were then evaluated for their effects on ACE. The results depicted that pyrimidines were more active than chalcones with methoxy (C5 and P5) substitution showing best results to inhibit ACE. Given that chalcone analogues and pyrimidines show a potential as the angiotensin converting enzyme inhibitors.

DNA binding, docking studies, artificial nuclease activity and in vitro cytotoxicity of newly synthesized steroidal 1H–pyrimidines

Abstract A new series of steroidal pyrimidines (7–9) has been synthesized by reacting steroidal thiosemicarbazones (4–6) with ethyl cyanoacetate. The compounds were characterized by IR, 1H NMR, 13C NMR, MS and analytical data. The interaction studies of compounds 7–9 with DNA were carried out by UV–vis and luminescence spectroscopy. Compounds (7–9) bind to DNA preferentially through electrostatic and hydrophobic interactions, with Kb values found to be 6.56 × 103 M−1, 1.54 × 104 M−1 and 9.34 × 103 M−1, respectively, indicating the higher binding affinity of compound 8 towards DNA. Gel electrophoresis pattern demonstrated that compound 8 shows strong interaction with DNA and that, during its cleavage activity with pBR322 DNA, it seems to follow the mechanistic pathway involving the generation of singlet oxygen and a superoxide anion, which are responsible for initiating DNA strand scission. The docking study suggested that the intercalation of compounds in between the nucleotide base pairs is due to the presence of a pyrimidine moiety in the steroid molecule. MTT assay was carried out to check the toxicity of new compounds 7–9 against the different human cancer as well as non-cancer cell lines A545, MCF-7, HeLa, HL-60, SW480, HepG2, HT-29, A549, 184B5, MCF10A, NL-20, HPC, and HPLF. Apoptotic degradation of DNA in the presence of steroidal pyrimidines 7–9 was analysed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay).

Facile synthesis of 6-(heptadec-8-enyl)thiopyrimidines incorporating glycosyl moiety and their antitumor activity

A facile, convenient, and high yielding synthesis of a new series of pyrimidine N- and S-glycosides incorporating an oleyl residue from readily available starting materials was developed. The key step of this protocol is the formation of a 2-thioxopyrimidine as aglycon which is coupled with an activated cyclic and acyclic halo sugar in the presence of sodium hydride. In addition, 5-fluorouracil analogues containing an oleyl moiety were prepared. The in vitro anticancer activity of the newly synthesized compounds was evaluated against two human cancer cell lines, namely MCF-7 (breast) and HEPG2 (liver) carcinoma. The compounds exhibited moderate to high activities with IC 50 values of 13.2–34.2 μM for MCF-7 and 16.2–63.8 μM for HEPG-2 cell lines. 5-Fluorouracil derivatives incorporating a fatty residue are therefore potent against both cell lines.

An Alternative Pathway to Ribonucleoside β-Hydroxyphosphonate Analogues and Related Prodrugs

Nucleoside β-(S)-hydroxyphosphonate analogues have recently proven to be interesting bioactive compounds as 5'-nucleotidase inhibitors. These derivatives were obtained in a pyrimidine series through an ex-chiral pool pathway or the stereoselective reduction of a β-ketophosphonate intermediate. Herein, an original synthesis of these compounds using nucleoside epoxide intermediates, containing either a pyrimidine or a purine as nucleobase, was explored and allowed the direct synthesis of the corresponding bis S-acyl-2-thioethyl (SATE) prodrugs.

Steroidal pyrimidines: Synthesis, characterization, molecular docking studies with DNA and in vitro cytotoxicity

A series of new steroid pyrimidines (7–9) were synthesized by reacting steroidal thiosemicarbazones (4–6) with diethyl malonate. The new compounds were characterized by IR, 1H NMR, 13C NMR, MS and analytical data. The interaction studies of compounds (7–9) with DNA were carried out by employing gel electrophoresis, UV–vis and fluorescence spectroscopy. The acting force between the compounds (7–9) and DNA was mainly hydrophobic while the other interactions like van der Waals, hydrogen bonding cannot be ruled out. The gel electrophoresis pattern also demonstrated that the compound 7 alone or in presence of Cu (II) causes the nicking of supercoiled pBR322 and it seems to follow the mechanistic pathway involving generation of hydroxyl radicals that are responsible for initiating DNA strand scission. The docking study of compounds (7–9) suggested that the intercalation of compounds in between the nucleotide base pairs might be due to the presence of pyrimidine moiety in steroid molecule. MTT assay was carried out to check the toxicity of new compounds (7–9) against the different human cancer as well as non-cancer cell lines A545, MCF-7, HeLa, HL-60, SW480, HepG2, HT-29, A549, 184B5, MCF10A, NL-20, HPC and HPLF. Apoptotic degradation of DNA in presence of steroidal pyrimidines (7–9) was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay).

Synthesis of three 18F-labelled cyclooxygenase-2 (COX-2) inhibitors based on a pyrimidine scaffold

Cyclooxygenase (COX) is the key enzyme within the complex conversion of arachidonic acid into prostaglandins (PGs). Inhibitors of this enzyme represent a particularly promising class of compounds for chemoprevention and cancer therapy. The experimental data on the involvement of COX isoform COX-2 in tumour development and progression, as well as the observed overexpression of COX-2 in a variety of human cancers provide the rationale for targeting COX-2 for molecular imaging and therapy of cancer. A series of trifluoromethyl-substituted pyrimidines was prepared as a novel class of selective COX-2 inhibitors, based on the lead structure 1a. All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Molecular docking studies using the catalytic site of COX-1 and COX-2, respectively, provided complementary theoretical support for the obtained experimental biological structure–activity relationship data of three highly potent and selective fluorobenzyl-containing COX-2 inhibitors. Selected fluorobenzyl-substituted pyrimidine derivatives were further developed as (18)F-labelled radiotracers ([(18)F]1a, [(18)F]2a, [(18)F]3a). Radiotracers [(18)F]1a and [(18)F]2a were radiolabelled using 4-[(18)F]fluorobenzylamine ([(18)F]FBA) as a building block. Radiotracer [(18)F]3a was radiofluorinated directly using a nucleophilic aromatic substitution reaction with no-carrier-added (n.c.a.) [(18)F]fluoride on an iodylaryl compound as a labelling precursor.

Synthesis, characterization, antimicrobial, anticancer, and antituberculosis activity of some new pyrazole, isoxazole, pyrimidine and benzodiazepine derivatives containing thiochromeno and benzothiepino moieties

In an attempt to find a new class of antimicrobial, anticancer, and antituberculosis agents, a series of pyrazole, isoxazole, pyrimidine and benzodiazepine derivatives containing thiochromeno and benzothiepino moieties were prepared via the reaction of diketoester 2 and 11 with appropriate chemical reagents. Single crystal XRD studies have been done on compounds 3 and 12. All compounds were evaluated for antimicrobial, anticancer, and antituberculosis activity. The benzodiazepine compounds (9 and 18) displayed the highest activity among the tested compounds with an IC50 equal to 15 and 16 μM for HeLa cells, and 13 and 12 μM for HCT116 cells. They were also found to be more active against H37Rv with an MIC of 7.0 and 6.5 μM compared to other analogues. Similarly these compounds (9 and 18) showed higher activity than chloroamphenicol against Klebsiella pneumoniae and Escherichia coli.

Inhibition Studies of Pyrimidine Class of Compounds on Enoyl-Acp Reductase Enzyme

Present work is aimed to identify and understand the inhibiting nature of Pyrimidine class of compounds to Enoyl acyl carrier proteinreductase (Enoyl-ACP reductase), which is one of the main receptor proteins used in drug discovery for screening anti-leprosy agents. Series of Pyrimidine based compounds virtually designed using the Molecular mechanic technique. The designed molecules were docked using with crystal structure of Enoyl-ACP reductase (PDB ID : 2NTV) using Autodock molecular docking software. The method uses rigid-protein and flexible ligand-techniques to acquire maximum conformations of ligand molecules. The docking results were evaluated using the acquired binding energy values for each ligand-protein complex. Those molecules having higher negative binding energy values with higher hydrogen bonds are selected for further analysis. The selected molecules show better hydrophobic, electrostatic and steric interactions with receptor protein. It is reported that the presence of –CH2OH at R1 and –C6H5 at R2 and R3 positions enhance the negative binding energy (∆G kcal mol-1) values. Particularly –OC6H5 at R1and –OH at R2 help in increasing the interactions between ligand and protein. The results show the molecular level interactions and inhibit the receptor protein.

Synthesis and structure–activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases

The design, synthesis and structure–activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.

Multisubstituted quinoxalines and pyrido[2,3-d]pyrimidines: Synthesis and SAR study as tyrosine kinase c-Met inhibitors

Two series of new analogues were designed by replacing the quinoline scaffold of our earlier lead 2 (zgwatinib) with quinoxaline and pyrido[2,3-d]pyrimidine frameworks. Moderate c-Met inhibitory activity was observed in the quinoxaline series. Among the pyrido[2,3-d]pyrimidine series, compounds 13a–c possessing an O-linkage were inactive, whilst the N-linked analogues 15a–c retained c-Met inhibitory potency. Highest activity was observed in the 3-nitrobenzyl analog 15b that showed an IC50 value of 6.5nM. Further structural modifications based on this compound were undergoing.

An efficient three-component, one-pot synthesis of 2-alkylthio-4-amino-5-cyano-6-aryl(alkyl)pyrimidines in water

A convenient and practical method for the synthesis of 2-alkylthio-4-amino-5-cyano-6-aryl(alkyl)pyrimidines has been developed via a three-component, one-pot reaction from aldehydes, malononitrile and S-alkylisothiouronium salts in water at room temperature. A series of polysubstituted pyrimidines were prepared by this method in moderate to excellent yields. In addition, two kinds of pyrimidine-fused heterocyclic derivatives with potential pharmacological activity were constructed from our 2-alkylthio-4-amino-5-cyano-6-arylpyrimidines.Electronic supplementary materialThe online version of this article (doi:10.1007/s11030-012-9376-z) contains supplementary material, which is available to authorized users.

Synthesis of New Pyrimidine, Quinazoline and Diazatricyclo Derivatives by Multicomponent Reaction and Evaluation of Their Biological Activity

A series of new pyrimidine and quinazoline derivatives was synthesized by a Biginelli-like reaction of urea/thiourea, aldehyde, and ketone in the presence of hydrochloric acid as a catalyst. In a similar way, some novel diazatricyclo derivatives were obtained via a Biginelli-like reaction followed by an intramolecular Michael-type addition. The yields of products were reasonable after recrystallization from ethanol. All newly synthesized compounds were characterized using IR and NMR (1H and 13C) spectroscopy and elemental analysis. The antibacterial activity of these compounds was investigated against Staphylococcus aureus (RTCC, 1885), and Escherichia Coli (ATCC, 35922). Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Pyrazole diaminopyrimidines as dual inhibitors of KDR and Aurora B kinases

In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.

Functionalization of pyrrolo[2,3-d]pyrimidine by palladium-catalyzed cross-coupling reactions (review)

Palladium-catalyzed cross-coupling reactions (Heck, Sonogashira, Stille, Suzuki) in the pyrrolo-[2,3-d]pyrimidine series with emphasis on synthesis of biologically active and functional materials are reviewed.

Synthesis and evaluation of chalcone analogues and pyrimidines as cyclooxygenase (COX) inhibitors

A series of chalcone analogues was synthesized and used as precursor for the synthesis of novel series of pyrimidines. Both groups have been evaluated for their effects on the cyclooxygenases (COXs) that are imperative enzymes in the genesis of prostaglandin H2, which is an antecedent for the biosynthesis of prostaglandins, thromboxanes and prostacyclins. The results depicted that chalcones and pyrimidines are very active inhibitors according to the pattern of substitution. Compounds C4, C5, P4 and P5 with methoxylation and nitro substitutions showed best results to inhibit COX-2. Key words: COX inhibitors, chalcones, pyrimidines, anti-inflammatory agents.

Platinum complexes with pyrimidine-functionalized N-heterocyclic carbene ligands – Synthesis and solid state structures

The ligands of the two most successful systems described in the literature for the activation and functionalization of methane have been merged and a series of novel pyrimidine functionalized platinum(II)(NHC) complexes with aryl and alkyl substituents [1-(2-Pyrimidyl)-3-( aryl or alkyl)imidazoline-2-ylidene platinum(II) chlorides] was synthesized by transmetalation via the corresponding silver complexes. All compounds have been fully characterized by 1H and 13C-NMR spectroscopy, elemental analysis, and with five X-ray single crystal structures. As for the related palladium(II)complexes in most cases we observed structures of the type [Pt(L)Cl 2], while for the sterically less demanding methyl substituent a complex is formed, where two ligands are coordinated to one metal center [Pt(L) 2Cl] +.

Synthesis and antimicrobial activity of novel derivatives of Biginelli pyrimidines

A series of novel Biginelli pyrimidines was prepared and evaluated for antimicrobial activity. Weak inhibitory activity (MIC = 128 μg/ml) was observed from 3b and 8b, against S. aureus and P. aeruginosa, respectively. Moderate antifungal agents: 4c, 4d, 4e with MIC = 32 μg/ml, 3d, 7b, and 8b with MIC = 64 μg/ml against C.albicans were determined. 4c, 4d, 4e, and 7b proved to be moderate antifungals against A. niger with MIC = 64 μg/ml.