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.

New 4-imino-4H-Chromeno[2,3-d]Pyrimidin-3(5H)-Amine: Synthesis, Cytotoxic Effects on Tumoral Cell Lines and in Silico ADMET Properties

The synthesis of new 4-imino-4H-chromeno[2,3-d]pyrimidin-3(5H)-amine in four steps including one step under microwave dielectric heating is reported. The structural identity of the synthesized compounds was established according to their spectroscopic analysis, such as FT-IR, NMR and mass spectroscopy. These new compounds were tested for their antiproliferative activities on seven representative human tumoral cell lines (Huh7 D12, Caco2, MDA-MB231, MDA-MB468, HCT116, PC3 and MCF7) and also on fibroblasts. Among them, only the compounds 6c showed micromolar cytotoxic activity on tumor cell lines (1.8 50 50 > 25 μM). Finally, in silico ADMET studies ware performed to investigate the possibility of using of the identified compound 6c as potential anti-tumor compound.

(1-3)-β-D葡聚糖联合降钙素原、CD4^(+)T淋巴细胞多指标在艾滋病患者马尔尼菲篮状菌感染早期诊断临床研究

目的探讨(1-3)-β-D葡聚糖联合降钙素原(procalcitonin,PCT)、CD4^(+)T淋巴细胞多指标在艾滋病患者马尔尼菲篮状菌感染早期诊断临床研究。方法回顾性选取我院2020年1月—2022年6月住院的120例艾滋病患者为研究对象。依据实验室结果,将其分为马尔尼菲篮状菌感染确诊组(血或组织液培育养出马尔尼菲篮状菌),简称A组(62例),及马尔尼菲篮状菌感染临床诊断组[根据临床症状、体征、血常规及(1-3)-β-D葡聚糖、PCT、CD4^(+)T淋巴细胞多指标诊断],简称B组(58例)。检测患者(1-3)-β-D葡聚糖、PCT、CD4^(+)T淋巴细胞的表达水平,采用受试者工作特征(receiver-operating characteristic,ROC)曲线下面积(area under the curve,AUC)评估上述指标联合检测对艾滋病患者感染马尔尼菲篮状菌的诊断效能。结果A组的(1-3)-β-D葡聚糖和PCT水平均高于B组,CD4^(+)T淋巴细胞个数低于B组(P<0.05);(1-3)-β-D葡聚糖、PCT、CD4^(+)T淋巴细胞联合检测的AUC为0.933,(1-3)-β-D葡聚糖单独检测的AUC是0.812,PCT单独检测的AUC为0.883,CD4^(+)T淋巴细胞单独检测的AUC是0.810,(1-3)-β-D葡聚糖、PCT和CD4^(+)T淋巴细胞联合检测的AUC皆优于三项单独检测,表明(1-3)-β-D葡聚糖、PCT和CD4^(+)T淋巴细胞联合检测的诊断价值皆优于单一指标诊断,且联合检测的特异度、约登指数分别为92.43%和0.580,均高于三项单独检测。结论(1-3)-β-D葡聚糖联合PCT和CD4^(+)T淋巴细胞多指标对艾滋病马尔尼菲篮状菌感染具有非常高的临床诊断价值,能够帮助医生分析出高危风险患者,及时制定治疗方案,同时也承担预后效果的判断依据,对治疗艾滋病马尔尼菲篮状菌感染具有非常重要的研究价值。

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.

Synthesis, Crystal Structure and Biological Activities of 3-[2-(4-Fluoro-phenyl)-ethyl]-5-methyl-4-hydroxyl-4-methyl-7-methylsulfanyl-3,4-dihydro-pyrido[4,3-d]pyrimidine-8-carbonitrile

The title compound, 3-[2-（4-fluoro-phenyl）-ethyl]-5-methyl-4-hydroxyl-4-methyl- 7-methylsulfanyl-3,4-dihydro-pyrido[4,3-d]pyrimidine-8-carbonitrile, has been prepared and detemined by single-crystal X-ray diffraction. The crystal belongs to the triclinic system, space group P1 with a = 6.8754（8）, b = 10.2617（12）, c = 13.3491（16） A, α = 93.163（2）, β = 96.704（2）, γ = 102.421（2）°, V= 910.35（19）A^3, Z= 2, Mr= 370.44, Dc= 1.351 g/cm^3,μ = 0.203 mm^-1,F（000） = 388, the final R = 0.0573 and wR = 0.1497. X-ray analysis reveals that the pyridine and pyrimidine rings are almost coplanar.

Synthesis of 5-substituted benzyl-2,4-diamino pyrimidine derivatives as c-Fms kinase inhibitors

A serials of novel 5-substituted benzyl-2,4-diamino pyrimidine derivatives have been synthesized and evaluated as inhibitors of c-Fms kinase by the standard MTT method.The results showed that compound 15,5-[3-methoxy-4-（pyridine-3-yl）benzyl]-2,4-diamino pyrimidine,had an IC50 of 1.45μmol/L in inhibiting the proliferation of M-CSF-dependent myeloid leukemia cells in mice （NFS-60）,which was similar with GW2580,a selective inhibitor of c-Fms kinase.

Synthesis,Crystal Structure and Antitumor Activities of Ethyl 5-methyl-4-morpholino-2-(3-Methyl-phenylamino)-furo[2,3-d] pyrimidine-6-carboxylate

The title compound （C21H24N4O4, Mr = 396.44） has been synthesized by the func- tionalized ethyl 4-chloro-6-methyl-2-arylamino-furo[2,3-d]pyrimidine-5-carboxylates and mor- pholine. Its structure was confirmed by means of 1H NMR IR, MS and elemental analysis. The crystal structure of the title compound was determined by X-ray single-crystal diffraction. The compound crystallizes in triclinic system, space group P1, a = 7.9919（8）, b = 9.9312（1）, c = 12.9380（13） A, aα = 86.987（2）, β = 83.604（2）, γ = 89.641（2）°, V = 1019.08（18） A3, Z = 2, F（000） = 420, Dc = 1.292 g/cm3,μ = 0.091 mm-1, R = 0.0602 and wR = 0.1548 for 3943 independent （Rint = 0.0639） and 3414 observed （I 〉 2σ（I）） reflections, lntermolecular N-H…O and π-π stacking interactions contributed to the stability of the structure. The preliminary biological test indicated the title compound exhibited cytotoxicity against human lung cancer cell lines.

Synthesis and Crystal Structure of Ethyl 3-(4-Chlorophenyl)-3,4-dihydro-6-methyl-4-oxo-2-(pyrrolidin-1-yl)furo[2,3-d]pyrimidine-5-carboxylate

The crystal structure of the title compound ethyl 3-（4-chlorophenyl）-3,4-dihydro-6- methyl-4-oxo-2-（pyrrolidin-1-yl）furo[2,3-d]pyrimidine-5-carboxylate （C20H20ClN3O4, Mr= 401.84） has been prepared and determined by single-crystal X-ray diffraction. The crystal is of monoclinic, space group P21/n with a = 20.6215（9）, b = 8.5311（4）, c = 21.6886（9） A^°, β = 91.607（1）°, V = 3814.0（3）A^°^3, Z = 8, Dc = 1.400 g/cm^3, F（000） = 1680, μ = 0.233 mm^-1, R = 0.0718 and wR = 0.1545 for 6717 observed reflections with I 〉 2σ（I）. X-ray diffraction analysis reveals two crystallographically independent molecules in the asymmetric unit.

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 thiopyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidines

Reactions of the 6-hydroxy-thiopyrano[3,4-c]pyridine-5-carbonitrile derivative 1 withα-halo-carbonyl compounds gave the ortho-substituted intermediates 2a-c which were converted into furo[2,3-b]thiopyrano[4,3-d]pyridines 3a-c by fusion of a furan moiety under basic conditions.Further cyclization of 3a-c led to a fusion of a pyrimidine ring,yielding the tetracyclic products 6,7 and 8.In addition,condensation of 6 with various aromatic aldehydes afforded the corresponding imines 9a,b.Mannich reaction of 7 gave products 10a,b.

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.

Facile and efficient synthesis of 5,7-disubstituted thiazolo[5,4-d] pyrimidine-4,6(5H,7H)-diones

A facile and efficient approach was developed to access 5, 7-disubstitued thiazolo[5,4-d]pyrimidine-4, 6（5H, 7H）-diones through condensation of N-substituted 5-amino-4-carbethoxythiazole with structurally diverse isocyanates in the presence of sodium hydride. The easy availability of substrates and tolerance of structural diversity in this reaction make it attractive to be used for construction of libraries in drug discovery process.

Synthesis and Crystal Structure of 3-(4-Chlorophenyl)-8-cyano-2-(di-isopropylamino)-5-methyl-7-(methylthio)-pyrido[4,3-d]pyrimidine-4(3H)-one

The crystal structure of the new title compound 3-（4-chlorophenyl）-8-cyano-2-（di-iso-propylamino）-5-methyl-7-（methylthio）-pyrido[4,3-d]pyrimidine-4（3H）-one（C22H24ClN5OS,Mr = 441.97）has been determined by single-crystal X-ray diffraction. The crystal is of orthorhombic,space group Pna21 with a = 7.6721（5）,b = 18.9370（11）,c = 15.6260（9）A,V = 2270.2（2）A^3,Z = 4,Dc = 1.293 g/cm^3,F（000）= 928,μ = 0.283 mm^-1,MoKa radiation（λ = 0.71073 A）,R = 0.0494 and wR = 0.1062 for 3278 observed reflections with I 〉 2σ（I）. X-ray diffraction analysis reveals that all ring atoms in the py-ridopyrimidinone moiety are almost coplanar. Intramolecular C（20）-H（20）···N（4）,C（19）-H（19A）···N（3）,C（18）-H（18C）···N（3）and C（16）-H（16B）···O（5）hydrogen bonds together with weak C···π interactions are found in the structure.

Synthesis and antiviral activity of 4H-[1,2,5]oxadiazolo-[3,4-d]pyrimidine-5,7-dione 1-oxide nucleosides

A series of 4H-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7-dione 1-oxide nucleosides was designed, synthesized and evaluated against vesicular stomatitis virus （VSV） in Wish cell. The antiviral activities of all compounds were stronger than those of acyclovir, while their toxicities were similar to those of acyclovir.

Synthesis and Crystal Structure of 7-Amino-2,3,4,5-tetrahydro-1,3-dimethyl-5-(2-nitrophenyl)-2,4-dioxo-1H-pyrano[2,3-d]pyrimidine-6-carbonitrile DMF Solvate

The title compound 7-amino-2,3,4,5-tetrahydro-1,3-dimethyl-5-（2-nitrophenyl）- 2,4- dioxo-1H-pyrano[2,3-d] pyrirnidine-6-carbonitrile DMF solvate 1 （C19H20N6O6, Mr = 428.41） was synthesized and crystallized. The crystal belongs to the monoclinic system, space group P2 1/c with a = 11.383（2）, b = 13.372（2）, c = 13.673（2）A, β = 97.380（4）°, Z = 4, V = 2063.8（6）A^3, Dc = 1.379 g/cm^3,μ（MoKα） = 0.105 mm^-1, F（000） = 896, the final R = 0.0738 and wR = 0.1647 for 2964 observed reflections （I〉 2σ（I））. X-ray analysis reveals that the new pyran ring is coplanar, which is obviously different from those of other similar compounds. In addition, the unclassical hydrogen bonds of C-H…O and C-H…N are presented in the crystals except for the normal hydrogen bonds of N-H…O.

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.

Synthesis and Crystal Structure of 2-Benzylamino-6-methyl-3-cyano-8- phenyl-5H-bispyrazolo[3,4-d,3',2'-b]pyrimidine

The title compound 2-benzylamino-6-methyl-3-cyano-8-phenyl-5H-bispyrazolo[3,4-d,3＇,2＇-b]pyrimidine crystallizes in orthorhombic, space group Pbca with a = 17.945（7）, b =10.862（4）, c = 19.481（7） A°, β = 90°, Z = 8, V = 1151.8（4） A°^3, Mr = 379.43, Dx = 1.327 g/cm^3,μ（MoKa） = 0.084 mm^-1, F（000） = 1584, the final R = 0.0513 and wR = 0.1128 for 2608 observed reflections （I 〉 2σ（I））. X-ray analysis reveals that the tricyclic portion of the molecule is effectively planar. In addition, there exist three intermolecular hydrogen bonds.

New Convenient Synthesis and Biological Evaluation of a Series of Benzo [4,5] Thieno [2,3-d] Pyrimidine N-nucleosides

Novel conditions have been developed for the preparation of substituted 2-aminothiophenes employing the Knoevenagel condensation followed by the Gewald reaction. The benefits of these conditions are their mildness, and the ease of product isolation. Thus, the Knoevenagel condensation is run in the presence of sodium hydroxide and least amount of ethanol, （in domestic microwave） which combine to perform the roles of desiccant, and catalyst. The Gewald reaction is performed with inorganic base in Ethanol, which suppresses by product formation. This process has been employed in the synthesis of N-nucleosides as a tumor inhibitor.

新型吡唑并[3,4-d]嘧啶-4-酮类PDE5抑制剂的合成及其活性研究

设计并合成了一系列以吡唑并[3,4-d]嘧啶-4-酮为母核的PDE5抑制剂。通过放射性同位素法测定了其对PDE5的抑制活性,并计算半数有效抑制浓度(IC_(50)),随后对目标化合物进行了PDEs亚型选择性评价。化合物结构经核磁共振及质谱表征确认。活性评价结果显示,所合成的化合物对PDE5均具有一定的抑制活性,其中6-苄基-1-(4-苯基丁基)-1,5-二氢-4 H-吡唑并[3,4-d]嘧啶-4-酮表现出最强的PDE5抑制活性,其IC_(50)达到90 nmol/L,具有发展成为PDE5抑制剂的潜力。