<i>β</i>-Oxoanilides in Heterocyclic Synthesis: Synthesis and Antimicrobial Activity of Pyridines, Pyrans, Pyrimidines and Azolo, Azinopyrimidines Incorporating Antipyrine Moiety

Condensation of β-Oxoanilide 1 with active methylene derivatives 2a,bafforded the pyridine derivative 5, and with crotononitrile afforded the pyridine 8. Compounds 9 and 11a-c were obtained by reaction of 1 with malononitrile dimer and arylidinemalononitrile 10a-10c. In contrast, when compound 1 reacted with ethoxymethylen malononitrile afforded the pyridine derivative 13. On the other hand, treatment of 1 with anthranilic acid gave the quinoline derivative 14. Also, reactions of 1 with isothiocyanate derivatives afforded compounds 16-18. The reaction of 1 with chalcone derivative afforded the pyridine derivative 22. Treatment of compound 1 with thiourea produced pyrimidine derivative 23. Furthermore, compound 1 converted into pyrimidinethione 24a and pyrimidinone 24b on treatment with a mixture of aromatic aldehydes and thiourea or urea respectively. Reaction of 24a with hydrazonyl halide, thiosemicarbazide and arylidinecyanothioacetamide afforded compounds 26, 28 and 29. Compound 29 was treated with chloroacetonitrile to afford compound 30. Six compounds from the newly synthesized were screened for antibacterial and antifungal activity against bacteria staphylococcus aureus, bacillus cereus and klebsiella pneumonia and fungi aspergillus flavus and aspergillus ochraceous, respectively. Some of the tested compounds showed significant antimicrobial activity. IR, 1H NMR, mass spectral data, and elemental analysis elucidated the structures of all the newly synthesized compounds.

Synthesis, Structure and Biological Activity of 2-[2-(4-Fluorobenzylidene)hydrazinyl]-4-(1-methyl-1H-indol-3-yl)thieno[3,2-d]pyrimidine

The title compound 2-[2-(4-fluorobenzylidene)hydrazinyl]-4-(1-methyl-1 H-indol-3-yl)thieno[3,2-d] pyrimidine(8) was synthesized by the condensation of 4-fluorobenzaldehyde(7) with 2-hydrazinyl-4-(1-methyl-1 H-indol-3-yl)thieno[3,2-d]pyrimidine(6). This intermediate was prepared from methyl 3-aminothiophene-2-carboxylate(1) by the condensation with urea, chlorination with phosphorus oxychloride and then condensation with hydrazine hydrate. The crystal of 8 belongs to monoclinic system, space group P21/c with a = 14.0453(18), b = 17.436(2), c = 18.0982(17) ? and β = 122.969(7)°. In addition, 8 possesses marked inhibition against the proliferation of human colon cancer cell line HT-29(IC50 = 6.09 μM) and human gastric cancer cell line MKN45(IC50 = 3.04 μM), displaying promising anticancer activity.

Crystal and Molecular Structure of 2-(2, 6-Dinitro-4-Trifluoromethyl) phenylthio-5, 7-Dimethyl-1,2,4-Triazolo [1, 5-a] Pyrimidine

The crystal structure of the title compound has been determined bysingle crystal X-ray diffraction analysis. C14H9F3N6O4S, Mr = 414. 32, monoclinic,space group P21/n, a=8. 287(3), b= 24. 972(4), c= 8. 617(3)A, β= 108. 36(3)°,V= 1693(2) A3, Z=4, Dx=1. 626 g. cm-3, μ=0. 2481 mm-1; F(000) =840, finalR = 0. 057 and Rw= 0. 057 for 1169 observed reflections [I≥3σ(I)]. The results showthat all ring atoms in the triazolopyrimidinyl moiety were coplanar with strong tensileforce, which might be an important active site.

Coupling Reaction of 4-Chloro-7-H-Pyrrolo[2,3-d]Pyrimidine with 2,3,5-Tri-O-Acetyl-b-D-Ribofuranosyl Chloride

Coupling reaction of 4-chloro-7-H-pyrrolo[2,3-d]pyrimidine with 2,3,5-tri-O-acetyl -β-D-ribofuranosyl chloride under the basic condition was investigated. An abnormal coupling reaction, in which the heterocyclic base attacked at the carbon of 1,2-O-methylidene moiety instead of anomeric carbon of ribose was observed and the structure of products 5a, 5b were identified by NMR and X-Ray diffraction.

Synthesis of Novel Heteropolycyclic Nitrogen Systems Bearing Fluorine Substituted Pyrazolo[3,4-d] Pyrimidine Derived from Polyfunctional π-Acceptor Compounds and Guanidine as Fungicidal Probes

Novel heteropolycyclic nitrogen systems bearing fluorine substituted pyrazolo[3,4-d] pyrimidine moiety have been synthesis by the interaction between N’-heteroaryl guanidine 4 with polyfunctional π-acceptors in different media and condition. The structures of the synthesis compounds were established by spectroscopic analysis and evaluated as antifungal probes in various concentration.

Insights into the pyrimidine biosynthetic pathway of human malaria parasite Plasmodium falciparum as chemotherapeutic target

Malaria is a major cause of morbidity and mortality in humans. Artemisinins remain as the first-line treatment for Plasmodium falciparum(P. falciparum) malaria although drug resistance has already emerged and spread in Southeast Asia. Thus, to fight this disease, there is an urgent need to develop new antimalarial drugs for malaria chemotherapy. Unlike human host cells, P. falciparum cannot salvage preformed pyrimidine bases or nucleosides from the extracellular environment and relies solely on nucleotides synthesized through the de novo biosynthetic pathway. This review presents significant progress on understanding the de novo pyrimidine pathway and the functional enzymes in the human parasite P. falciparum. Current knowledge in genomics and metabolomics are described, particularly focusing on the parasite purine and pyrimidine nucleotide metabolism. These include gene annotation, characterization and molecular mechanism of the enzymes that are different from the human host pathway. Recent elucidation of the three-dimensional crystal structures and the catalytic reactions of three enzymes: dihydroorotate dehydrogenase, orotate phosphoribosyltransferase, and orotidine 5'-monophosphate decarboxylase, as well as their inhibitors are reviewed in the context of their therapeutic potential against malaria.

SYNTHSIS OF 5-CYANO-2-(4-n-PENTYL-4-BIPHENYLYL)-PYRIMIDINE

Condensation of substituted diethyl-malonates withphenylamidine hydrochloride give liquid crystals with a pyrimidinering,which then subjeet graup transformation to give thetitle compound—5-cyano-2-(4-n-peatyl-4-biphenylyl)pyrimidine in high yield.

SYNTHESIS AND STRUCTURE OF A NOVEL INFINITE-LAYER COPPER(Ⅱ)COMPLEX BRIDGED BY OXAMIDE AND PYRIMIDINE

The complex polymer[Cu2（oxap）（pyr）2]n（ClO4）2n,where oxap2-stands for N,N’-bis（2—aminopropyl）oxamide,have been synthesized.It crystallizes in monoclinic system,space group P21/C,with a=8.721（2）,b=8.679（2）,c=16.741（2）,β=98.59（0）,Z=4.Theleast-square refinement coverged at R=0.054,Rw=0.055 with 1869 unique reflections.Thewhole structure of the complcx consists of layers of two-dimensional network arrayingalong a-axis with perchlorate ions interspersed in the gap between layers.Inside the layer.trans-oxamide-bridged copper（Ⅱ）dimers connected by pyrimidine in an asymmetric fashionspread out along be plane to form an infinite two-dimensional network.

Synthesis of 5,7-Dimethyl-2-(5-Substituted-1,3,4-Oxadiazole-2-yl)- Methylenethio-1,2,4-Triazolo[1,5-a]Pyrimidines as Potential Fungicides

A series of diheterocyclic compounds containing 1,2,4-triazolo [1,5-a]pyrimidine and 1, 3,4-oxadiazole were designed and synthesized starting from 2-mercapto-5,7-dimethyl-1,2,4- triazolo [1,5-a] pyrimidine. The structure of all compounds prepared were confirmed by 1H NMR spectroscopy and elemental analysis. The preliminary bioassay indicated that the title compounds displayed good fungicidal activity against Rhizoctonia solani.

Optimization, Spectroscopic(FT-IR, Excited States, UV/Vis) Studies, FMO, ELF, LOL, QTAIM and NBO Analyses and Electronic Properties of Two New Pyrimidine Derivatives

In the given research,the molecular structures of two new compounds,4-((E)-3-(dimethylamino)styryl)-6-((E)-4-(dimethylamino)styryl)pyrimidine-2-amine(PM-1)and N-(4-((E)-3-(dimethylamino)styryl)-6-((E)-4-(dimethylamino)styryl)pyrimidine-2-yl)-4,6-dichloro 1,3,5-1,3,5-triazin-2-amine(PM-2),have been studied with the use of density functional theory(DFT/B3LYP/MidiX)in dimethylformamide(DMF)for the first time.The electronic spectra of the new compounds in a DMF solvent were carried out by temporally dependent density functional theory(TD-DFT)method.The computed absorption spectral data of the title compounds are in good agreement with the experimental data,thus allowing an assignment of the UV/Vis spectra.The equilibrium geometry,the HOMO and LUMO molecular orbitals,excitation energies,oscillator strengths and Natural Bond Orbital(NBO)analysis for the molecules have also been calculated and presented.FT-IR spectra of the title molecules are recorded and discussed.The electron location function(ELF),localized orbital locator(LOL)and quantum theory of atoms in molecules(QTAIM)analyses were also carried out.On the basis of polyvinyl alcohol(PVA)and synthesized molecules,polarizer for UV/Vis region of the spectrum has been developed.

Synthesis, Crystal Structure and Antitumor Activity of 4-(5-(2,6-Difluorophenyl)-1,3,4-oxadiazol-2-ylthio)-2-(trifluoromethyl)thieno[2,3-d]pyrimidine

The title compound 4-(5-(2,6-difluorophenyl)-1,3,4-oxadiazol-2-ylthio)-2-(trifluoromethyl)thieno[2,3-d]pyrimidine(C15H5F5N4OS2, Mr = 416.35) was designed and synthesized as antitumor agent, and its structure was determined by 1H NMR, 13C NMR, MS, elemental analysis and single-crystal X-ray diffraction. The crystal belongs to monoclinic system, space group P21/c with a = 9.904(2), b = 10.057(2), c = 16.595(3) ?, β = 100.000(3)°, V = 1627.9(6) ?3, Z = 4, F(000) = 832, Dc = 1.699 g/cm3, μ = 0.395 mm-1, R = 0.0468 and wR = 0.1255 for 4726 independent reflections(Rint = 0.0336) and 2847 observed ones(I > 2σ(I)). The in vitro antitumor activity of the title compound was preliminarily evaluated by the standard MTT assay.

Novel Ethyl 2-(1-aminocyclobutyl)-5-(benzoyloxy)-6-hydroxy-pyrimidine-4-carboxylate Derivatives: Synthesis and Anticancer Activities

To explore the anticancer activity of 2, 4, 5, 6-substituted pyrimidines, several ethyl 2-(1-aminocyclobutyl)-5-(benzoyloxy)-6-hydroxy-pyrimidine-4-carboxylate?derivatives associated with the different substituted aromatic/aliphatic carboxamides?and sulfonamides were synthesized. Different groups and position on phenyl ring attached to the carboxamide?and sulfonamide of the pyrimidine led to two set of compounds. Their chemical structures were confirmed by IR,1H NMR and LC/MS analysis. Cytotoxicity of all the synthesized compounds were examined on human leukemia celllines (K562 and CEM). The preliminary results showed most of the derivatives exhibited good antitumor activity. Compound?with para chloro substitution among carboxamides and compound with meta dichloro substitution among sulphonamidesexhibited significant antitumor activity with IC50 value of 14.0 μM and 15.0 μM respectively against K562cell line. For comparison among electron donating groups between carboxamides and sulfonamides, compounds with?para tert-butyl substitution were chosen for further studies. Cell cycle analysis suggests that both tert-butyl substituted?compounds are able to induce apoptosis.

Nucleosides 10: Synthesis of New Derivatives of Pyrimidine and Fused Pyrimidine Nucleosides of Expected Biological Activity

Pyrimidines, such as 6-amino-2-thio and 2-methylthiouracils and fused pyrimidines, such as thienopyrimidines reacted with 1-O-acetyl-2,3,5-tri-O- benzoyl-β-D-ribofuranose to get new derivatives of the corresponding nucleosides. The obtained protected nucleosides were deprotected by methanolic sodium methoxide to get the corresponding free uracil and thienopyrimidine nucleosides. The new nucleosides formed were tested for biological activity against some of microorganism (some fungi and bacteria species). Some of the tested products showed moderate activity and the results were reported.

Efficient Synthesis of a New Class of <i>N</i>-Nucleosides of 4<i>H</i>-Thiochromeno[2,3-<i>d</i>]pyrimidine-10-Sulfone as Potential Anticancer and Antibacterial Agents

A highly practical and efficient preparation of 6-methy-4H-thiochromene and 7-methyl-thiochromene[2,3-d]pyrimidine derivatives was developed via a multi-component reaction of 3-methyl-thiophenol (1), aldehydes (2), and malononitrile (3). A series of pyrimidine nucleoside, thiochromene[2,3-d]pyrimidine and thiochromene[2,3-d]pyrimidine-10-sulfone was efficiently obtained. These hybrid compounds were evaluated as potential antibacterial and anticancer agents and showed encouraging biological activities. Some of these derivatives showed broad-spectrum antitumour activity against the nine tumour subpanels tested, and demonstrated significant activity in the in vitro antitumour screening expressed by MG-MID log10GI50 value of -4.55, -4.67 and -4.73 of compounds 9a, 9b and 9c, respectively.

An Efficient Synthesis of Pyrido[2,3-<i>d</i>]pyrimidine Derivatives via One-Pot Three-Component Reaction in Aqueous Media

A series of pyrido[2,3-d]pyrimidines derivatives have been prepared by one-pot three-component reaction of 4(6)-aminouracil, malononitrile and aromatic aldehydes. This efficient synthesis was done under microwave irradiation conditions (method A) and also using catalytic amount of diammonium hydrogen phosphate [(NH4)2HPO4] (DAHP) in aqueous media (method B). This procedure has the advantages of good yields, easy work-up, and benign environmentally friendly character. Reaction could proceed via domino Knoevenagel-Michael-cyclization reactions.

Synthesis, Characterization and <i>In Vitro</i>Antitumor Evaluation of New Pyrazolo[3,4-d]Pyrimidine Derivatives

A new series of 3-(methylthio)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives was synthesized. The structures of the new derivatives were confirmed by the spectral data and elemental analyses. The antitumor activity of this series against human breast adenocarcinoma cell line MCF7 was evaluated. Out of twenty new derivatives, ten were revealed mild to moderate activity compared with doxorubicin as a reference antitumor. Among this new series N-(2-chlorophenyl)-2-(3-(methylthio)-4-oxo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-5(4H)-yl)acetamide (13a) was found the most active one with IC50 equal to 23 μM.

Purine and Pyrimidine-Linked Enzymes and Genes are Strongly Responsible for the Development of Tumors, Particularly Glioblastoma Multiforme

We were aiming to delineate, by the utility of the biological data results, in our investigations the link between the purine and pyrimidine metabolism and development of the glioblastoma. We analyzed the sets of the genes, belonging to the purine and pyrimidine metabolism by the utility of GSEA software as well as MSIgnDB application of the GSEA. The GEO database, GEOR2 tools were serving for the visualization of the genes expression profiles of the disease. The Cancer Proteome Atlas as well as the tools of the data sets were also used to collect and analyze the results. We concluded and came to the following consequential results. 1) Neurogenesis and Glioblastoma are sharing some common genes. 2) Purine and pyrimidine metabolism-linked enzymes and genes are responsible for the upregulation of DNA and mRNA synthesis in the settings of the tumor development. 3) EGFR expression responsible genes, mRNA as well as protein is upregulated during the development of the glioblastoma. 4) GMPS genes are more strongly upregulated in the settings of the glioblastoma than ADSL. 5) PRPS1 is strongly synthetized in neurospheres in contrast to the mature tissue during glioblastoma development.

One-Pot Synthesis of Pyrido[2,3-d]pyrimidines Catalyzed by Bismuth(III)Triflate

Synthesis of uracil derivatives, such as pyrido[2,3-d]pyrimidine, is very important for the pharmaceutical industry due to their many biological activities. In our continuing efforts into the development of new synthetic strategies for the preparation of heterocyclic compounds in this study, we performed reflux reactions with the catalyst Bi(OTf)3 by using a one-pot, threecomponent method. The one-pot, three-component condensation of 6-amino-1,3-dimethyluracil, with arylaldehydes and malononitrile to generate a series of 7-aminopyrido[2,3-d]pyrimidine-6-carbonitrile derivatives has been carried out in the presence of bismuth triflate as a green and reusable catalyst.

Reaction of Nitrilimines with 2-Aminopicoline, 3-Amino-1,2,4-Triazole, 5-Aminotetrazole and 2-Aminopyrimidine

The reaction of picoline derivatives 3-6 with hydrazonoylhalide 1a produced imidazo[1,2-a]pyridines 7-10, while the reaction of the same picoline derivatives with hydrazonoylhalide 1b afforded imidazo[1,2-a]pyridine-2-ones 11-13. The reaction of 1b, c with 3-amino-1,2,4-triazole 14 produced the acyclic adducts 18 and 19, respectively. Reaction of 1b, 1c with 5-aminotetrazole 20 produced the acyclic products 23 and 24, respectively. Finally, the reaction of 1b with 4, 6-dimethyl-2-aminopyrimidine 27 afforded compound 29 rather than its isomeric structure 28. The structure of the products was confirmed by the different spectroscopic analytical methods including IR, MS, 1HNMR and 13CNMR.

d-limonene prevents ultraviolet irradiation:Induced cyclobutane pyrimidine dimers in Skh1 mouse skin

AIM: To establish whether d-limonene can protect against induction of cyclobutane pyrimidine dimers(CPDs) and sunburn in ultraviolet irradiation(UVR) irradiated mouse skin. METHODS: The d-limonene was given in 4 daily oral 20 μL aliquots at different concentrations as follows: 100%, 10% or 1% in liponate and 100% liponate as control. One day after the final d-limonene treatment, the mice were anesthetized with i.p. sodium pentobarbital and placed in boxes to allow a rectangular(2 cm × 4 cm) region of dorsal skin to be irradiated with a single, ultraviolet radiation dose of 1.5 kJ /m2. Skin samples from UVR irradiated area were obtained at 5 min after UVR exposure for CPD detection, at 6 d after UVR exposure, skin samples were obtained for in situ analysis for N-myc downstream regulating gene 1(NDRG1)(a stress response gene), proliferating cell nuclear antigen(PCNA)(an S-phase marker) and filaggrin(a barrier integrity gene). Based on immunohistochemistry staining, the number of CPD, NDRG1 and PCNA positive cells, as well as unstained cells was counted in 3 different individually selected areas and percentage of positive cells was established. RESULTS: CPD reduction occurred as follows: liponate only-none; 1% d-limonene-54.3% reduction of CPDs; 10% d-limonene-73.4% reduction of CPDs; 100% d-limonene-86.1% reduction of CPDs, the latter equivalent to a UV dose of only 0.21 k J/m2. Sunburn was also dose-dependently reduced by d-limonene. The NDRG1 protein was strongly induced by UVR(70.0% ± 10.4% positive cells), but 1% d-limonene reduced the response to 64.6% ± 9.2%, 10% d-limonene reduced the response to 16.2% ± 3.4% and 100% d-limonene reduced the response to 6.3% ± 1.7%. Similarly, PCNA was 52.4% ± 9.9% positive in UVR exposed skin, and 1% d-limonene reduced it to 42.9% ± 8.1%, 10% d-limonene reduced it to 36.2% ± 6.7% and 100% d-limonene reduce it to 13.8% ± 3.4%. NDRG1 and PCNA were increased by d-limonene or UVR separately, but combined they produced less than either agent separately owing to the protective effect of pre-exposure to d-limonene. CONCLUSION: Overall d-limonene acted to protect against ultraviolet B-induced DNA photodamage and sunburn in UVR exposed skin.