New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections

Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other hemorrhagic fever virus (HFV) infections. They can be considered as either (i) adenine analogues (3‐deazaneplanocin A, galidesivir, GS‐6620 and remdesivir) or (ii) guanine analogues containing the carboxamide entity (ribavirin, EICAR, pyrazofurin and favipiravir). All eight owe their mechanism of action to hydrogen bonded base pairing with either (i) uracil or (ii) cytosine. Four out of the eight compounds (galidesivir, GS‐6620, remdesivir and pyrazofurin) are C‐nucleosides, and two of them (GS‐6620, remdesivir) also contain a phosphoramidate part. The C‐nucleoside and phosphoramidate (and for the adenine analogues the 1′‐cyano group as well) may be considered as essential attributes for their antiviral activity.     

Synthesis and Antitumor Activity Evaluation of Pyrimidine Analogues Bearing Urea Moiety

A series of 4‐anilino‐6‐phenylpyrimidines containing urea moiety were synthesized and the structures of all products were confirmed by ¹H NMR, ¹³C NMR and HRMS. The antiproliferative activities of these compounds were evaluated against three human tumor cell lines (MGC‐803, MCF‐7 and EC‐109) by applying the MTT assay method. compounds 4a , 4b and 6a showed the most effective activity, among which, 6a was more cytotoxic than 5‐fluorouracil against all tested human cancer cell lines with IC₅₀ values ranging from 1.80 to 2.72 µmol·L^?1.     

Synthesis of Methylenecyclopropane Analogues of Antiviral Nucleoside Phosphonates

Synthesis of methylenecyclopropane analogues of nucleoside phosphonates 6a, 6b, 7a and 7b is described. Cyclopropyl phosphonate 8 was transformed in four steps to methylenecyclopropane phosphonate 16. The latter intermediate was converted in seven steps to the key Z- and E-methylenecyclopropane alcohols 23 and 24 separated by chromatography. Selenoxide eliminations (15→16 and 22→23+24) were instrumental in the synthesis. The Z- and E-isomers 23 and 24 were transformed to bromides 25a and 25b, which were used for alkylation of adenine and 2-amino-6-chloropurine to give intermediates 26a, 26b, 26c and 26d. Acid hydrolysis provided the adenine and guanine analogues 6a, 6b, 7a and 7b. Phosphonates 6b and 7b are potent inhibitors of replication of Epstein-Barr virus (EBV).     

Synthesis of Novel 1,3-Dioxolane Nucleoside Analogues

Novel 1,3-dioxolane C-nucleoside analogues of tiazofurin 2-(2-hydroxymethyl-1,3-dioxolan-4-yl)-1,3-thiazole4-carboxamide as well as N-nucleoside analogues of substituted imidazoles 1-(2-hydroxymethyl-1,3-dioxolan4-yl)-4-nitroimidazole and 1-(2-hydroxymethyl-1,3-dioxolan-4-yl)-4,5-dicyanoimidazole were synthesized from methyl acrylate through a multistep procedure. Their structures were confirmed by IR,^1H NMR,^13C NMR spectraand elemental analysis.     

A New Alkylation-Elimination Method for Synthesis of Antiviral Fluoromethylenecyclopropane Analogues of Nucleosides

A new method for the synthesis of fluoromethylenecyclopropane nucleosides by alkylation-elimination procedure is described. Fluorination of methylenecyclopropane carboxylate 6 gave fluoroester 7. Treatment of 7 with phenylselenenyl bromide afforded the desired ethyl (E)-2-bromomethyl-1-fluoro-2-phenylselenenylcyclopropane-1-carboxylate 11 in 85% yield. DIBALH reduction of 11 gave 13, which after acetylation to 14 was reacted with 2-amino-6-chloropurine to give the 9-alkylated product 15 in 87% yield. Se-oxidation of 15 with hydrogen peroxide afforded 16, which underwent smooth elimination in a mixture of THF-DMF at 60 °C giving rise to a Z,E mixture of protected nucleosides 17. Deacetylation gave Z-1a and E-1a which were separated on a silica gel column. Both Z-1a and E-1a were converted into the respective guanine analogues Z-1b and E-1b.     

Efficient Synthesis of New Nucleoside Analogues with a Methylenecyclobutane Unit

Synthesis of eight nucleoside analogues 4–11 with a methylenecyclobutane unit is described. Wittig reaction with 2‐hydroxymethylcyclobutanone 12 gave a mixture of Z (13) and E (14) derivatives, which was separated before functional modifications. The heterocyclic moieties were introduced via a Mitsunobu reaction either on the saturated chain or on the unsaturated chain. When adenine was used in this reaction, only the N‐9 substitution products were obtained. Removal of the protecting groups provided the target products.     

含有二糖结构的核苷类似物的合成

利用Ferrier重排反应合成了两个系列的连有核音的2,3-不饱和糖苷(其中核耷包括尿苷、腺苷、肌苷等).这些新化合物的结构通过NMR和MS(HRFAB)得到证实.     

微分脉冲伏安法用于血液中两种核苷类抗病毒药物的同时测定

采用微分脉冲伏安法考察了两种核苷类抗病毒药物阿昔洛韦(aciclovir)和喷昔洛韦(penciclovir)在乙二胺修饰的玻碳电极上的电化学行为及其在代谢血样中的同时测定方法,并探讨了电极修饰和电极反应的机理。在pH2.56的Britton-Robinson缓冲溶液中,阿昔洛韦和喷昔洛韦在乙二胺修饰的玻碳电极上均有一灵敏的不可逆氧化峰,峰电位分别为1.20和1.17 V。在优化的实验条件下,阿昔洛韦和喷昔洛韦分别在0.20~4.0 mg/L和0.02~0.40 mg/L浓度范围内与峰电流呈线性关系,其检出限分别为77和12μg/L。引入化学计量学方法对其混合组分的伏安谱进行解析,实现了两组分的同时测定,并对小鼠血液中代谢的两种核苷类抗病毒药物进行了同时测定。     

右旋肌醇甲醚腺嘌呤核苷类似物的合成

以右旋肌醇甲醚为原料,经保护的甲烷磺酸酯与腺嘌呤缩合,合成了腺嘌呤核苷类似物5.此外,化合物3经酸水解,再经环氧化高产率地合成了重要的中间体7,腺嘌呤在强有机碱存在下,对环氧化合物7进行区域性的开环反应,合成了另外两种腺嘌呤核苷类似物8和9.     

Chemoselective and Diastereoselective Synthesis of C-Aryl Nucleoside Analogues by Nickel-Catalyzed Cross-Coupling of Furanosyl Acetates with Aryl Iodides

Canonical nucleosides are vulnerable to enzymatic and chemical degradation, yet their stable mimics—C-aryl nucleosides—have demonstrated potential utility in medicinal chemistry, chemical biology, and synthetic biology, although current synthetic methods remain limited in terms of scope and selectivity. Herein, we report a cross-electrophile coupling to prepare C-aryl nucleoside analogues from readily available furanosyl acetates and aryl iodides. This nickel-catalyzed modular approach is characterized by mild reaction conditions, broad substrate scope, excellent β-selectivity, and high functional-group compatibility. The exclusive chemoselectivity with respect to the aryl iodide enables efficient preparation of a variety of C-aryl halide furanosides suitable for various downstream transformations. The practicality of this transformation is demonstrated through the synthesis of a potent analogue of a naturally occurring NF-κB activator.     

Synthesis and Anti-HIV Activity of Triazolo-fused 3',4'-Cyclic and 4'-Spiro Nucleoside Analogues

Triazolo-fused 3',4'-cyclic nucleoside 4'-spiro nucleoside analogues were synthesized by an intramolecular 1,3-dipolar cycloaddition of 4'-azido nucleoside derived azido-alkynes in a regio- and stereo-specific manner. The thymine nucleoside base in these target compounds was transformed into the corresponding 5-methyl cytosine component. The synthesized com­pounds were examined in an MAGI(multinuclear-activation galactosidase indicator) assay for exploring the anti-HIV activity and in a H9 T(human T lymphocytes H9) assay for measuring the cell toxicity.     

1-取代-1H-1,2,3-三唑-4-甲酰胺类化合物的设计合成与生物活性

以吡唑酰胺类杀菌剂为模板,应用"生物等排原理"设计了1,2,3-三唑甲酰胺类具有等排结构的化合物,从丙炔酸出发合成内炔酰胺后,利用Cu(I)催化的1,3-偶极环加成反应,使其与叠氮化合物反应,快速合成了17个结构新颖的1-取代-1H-1,2,3-三唑-4-甲酰胺类化合物.当使用Cu/C催化时,中间体N-(3,4-二甲氧基苯基乙基)丙炔酰胺(4a)与2,2,2-三氟乙基叠氮(14)在三乙胺作添加剂的条件下,可以获得中等收率的偶联的1,2,3-三唑化合物17.所有目标化合物都通过核磁共振氢谱,元素分析或高分辨质谱的确认,并测试了其生物活性.结果表明,该类化合物虽无明显的杀菌活性,但在100μg/mL测试浓度下,化合物6a,6e,6k和61均表现出较好的除草活性.     

Synthesis of Pyrimidine Conjugates with 4-(6-Amino-hexanoyl)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and Evaluation of Their Antiviral Activity

A series of pyrimidine conjugates containing a fragment of racemic 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and its (S)-enantiomer attached via a 6-aminohexanoyl fragment were synthesized by the reaction of nucleophilic substitution of chlorine in various chloropyrimidines. The structures of the synthesized compounds were confirmed by ¹H, ¹⁹F, and ¹³C NMR spectral data. Enantiomeric purity of optically active derivatives was confirmed by chiral HPLC. Antiviral evaluation of the synthesized compounds has shown that the replacement of purine with a pyrimidine fragment leads to a decrease in the anti-herpesvirus activity compared to the lead compound, purine conjugate. The studied compounds did not exhibit significant activity against influenza A (H1N1) virus.     

新型含1,2,3-三氮唑的染料木素糖缀合物的合成

以染料木素为起始原料,经两步反应制得中间体7-O-炔丙基染料木素(3);以CuI为催化剂,3与叠氮乙酰基糖经Click反应合成了7-O-［1-(2,3,4,6-四-O-乙酰基-β-D-糖苷)1H-1,2,3-三氮唑-4-甲基］-染料木素(5a~5c); 5a~5c经去乙酰基制得三种含1,2,3-三氮唑的氮苷染料木素糖缀合物(6a~6c)。3, 5和6均为新化合物,其结构经¹H NMR, ¹³C NMR和HR-MS表征。     

Synthesis and Antimicrobial Activity Screening of Piperazines Bearing N,N′-Bis(1,3,4-thiadiazole) Moiety as Probable Enoyl-ACP Reductase Inhibitors

A new N,N′-disubstituted piperazine conjugated with 1,3,4-thiadiazole and 1,2,4-triazole was prepared and the chemical structures were identified by IR, NMR and elemental analysis. All the prepared compounds were tested for their antimicrobial activity. The antimicrobial results indicated that the tested compounds showed significant antibacterial activity against gram-negative strains, especially E. coli, relative to gram-positive bacteria. Docking analysis was performed to support the biological results; binding modes with the active site of enoyl reductase amino acids from E. coli showed very good scores, ranging from −6.1090 to −9.6184 kcal/mol. Correlation analysis was performed for the inhibition zone (nm) and the docking score.     

Design and Synthesis of Some Novel Oxiconazole‐Like Carboacyclic Nucleoside Analogues,as Potential Chemotherapeutic Agents

The syntheses of some novel carboacyclic nucleosides, 17a – 17o , containing oxiconazole‐like scaffolds, are described (Schemes 1–3). In this series of carboacyclic nucleosides, pyrimidine as well as purine and other imidazole derivatives were employed as an imidazole successor in oxiconazole. These compounds could be prepared in good yields by using two different strategies (Schemes 1 and 2). Due to Scheme 1, the N‐coupling of nucleobases with 2‐bromoacetophenones was attained for 18a – 18e , and their subsequent oximation affording 19a – 19e and finally O‐alkylation with diverse alkylating sources resulted in the products 17a – 17g, 17n , and 17o . In Scheme 2, use of 2‐bromoacetophenone oximes 20 , followed by N‐coupling of nucleobases, provided 19f – 19j whose final O‐alkylation produced 17h – 17m (Scheme 2). For the rational interpretation of the dominant formation of (E)‐oxime ethers rather than (Z)‐oxime isomers, PM3 semiempirical quantum‐mechanic calculations were discussed and the calculations indicated a lower heat of formation for (E)‐isomers.     

Synthesis of Novel Isoxazole-contained Analogues of Losartan

Losartan 1 (Dup-753) is a nonpeptide angiotensin II receptor (type AT1) antagonist discovered by Duncia, J.V. et al. 1 in 1990 and its potassium salt (cozaar) has been marketed as an antihypertensive since 1995 2. 1 2 Starting from Dup-753, a great number of structural related compounds have been prepared by several laboratories and several antihypertensive drugs have been developed3. In order to find new and more active compounds, a novel type of Losartan analogues 2 was designed and syn…     

抗流感病毒抑制剂Nucleozin衍生物的设计合成及抗病毒活性评价

小分子化合物Nucleozin作为靶向流感病毒核蛋白的抑制剂具有良好的抑制活性。本文围绕Nucleozin分子中与哌嗪环直接相连的芳环部分进行研究。通过钯催化偶联反应合成了一系列Nucleozin衍生物,通过检测所合成化合物对流感病毒H1N1的抑制活性,明确了Nucleozin分子中该部分的构效关系。利用甲基在药物分子设计中的作用,设计将分子中的氯原子替换为甲基,发现与原型分子Nucleozin相比其抑制活性有了明显的提高。本文的结果对该类分子成药性的提高具有积极意义。     

Microwave-assisted Green and Efficient Synthesis of N^6-（2-Hydroxyethyl）adenosine and its Analogues

Nucleoside analogues generally possess outstanding biological activity, mainly as antitumor and antiviral agents. Many works have been done for the synthesis of natural nucleosides and their analogues1-5. N6-(2-Hydroxyethyl)adenosine (HEA), which behaves …     

Synthesis and Biological Evaluation of Dipeptide-Based Stilbene Derivatives Bearing a Biheterocyclic Moiety as Potential Fungicides

The escalating demand for crop production, environmental protection, and food safety warrants the development of new fungicides with greater efficiency, environmental friendliness, and innocuous metabolites to fight against destructive phytopathogens. Herein, we report on the synthesis and antifungal activity of dipeptide-based stilbene derivatives bearing a thiophene-substituted 1,3,4-oxadiazole fragment for the first time. In vitro bioassay indicated that the target compounds had remarkable antifungal potency superior to previously reported counterparts without a dipeptidyl group, of which compound 3c exhibited the highest activity against Botrytis cinerea with EC₅₀ values of 106.1 μg/mL. Moreover, the in vivo protective effect of compound 3c (59.1%) against tomato gray mold was more potent than that of carboxin (42.0%). Preliminary investigations on the mode of action showed that compound 3c induced marked hyphal malformations and increased the membrane permeability of B. cinerea as well as inhibiting mycelial respiration. These promising results suggest that this novel type of molecular framework has great potential to be further developed as alternative fungicides.