Synthesis and Antiviral Properties of Spirocyclic [1,2,3]‐Triazolooxazine Nucleosides

An efficient synthesis of spirocyclic triazolooxazine nucleosides is described. This was achieved by the conversion of β‐D ‐psicofuranose to the corresponding azido‐derivative, followed by alkylation of the primary alcohol with a range of propargyl bromides, obtained by Sonogashira chemistry. The products of these reactions underwent 1,3‐dipolar addition smoothly to generate the protected spirocyclic adducts. These were easily deprotected to give the corresponding ribose nucleosides. The library of compounds obtained was investigated for its antiviral activity using MHV (mouse hepatitis virus) as a model wherein derivative 3 f showed the most promising activity and tolerability.     

Synthesis and Biological Evaluation of Halogenated E-Stilbenols as Promising Antiaging Agents

The increased risk of illness and disability is related to the age inevitable biological changes. Oxidative stress is a proposed mechanism for many age-related diseases. The crucial importance of polyphenol pharmacophore for aging process is largely described thanks to its effects on concentrations of reactive oxygen species. Resveratrol (3,5,4′-trihydroxy-trans-stilbene, RSV) plays a critical role in slowing the aging process but has a poor bioavailabity after oral intake. In this present work, a series of RSV derivatives was designed, synthesized, and evaluated as potential antioxidant agents. These derivatives contain substituents with different electronic and steric properties in different positions of aromatic rings. This kind of substituents affects the activity and the bioavailability of these compounds compared with RSV used as reference compound. Studies of Log P values demonstrated that the introduction of halogens gives the optimum lipophilicity to be considered promising active agents. Among them, compound 6 showed the higher antioxidant activity than RSV. The presence of trifluoromethyl group together with a chlorine atom increased the antioxidant activity compared to RSV.     

双环及三环核苷的合成

摘要综述了天然双环核苷、抗病毒构效研究中的双环核苷和反义寡核苷酸领域中双环及三环核苷的合成研究进展,介绍了常规官能团转化法及近年来出现的自由基环合、1,3-偶极环加成和烯烃复分解等新方法。     

Nucleosides: Synthesis of Some New Naphthimidazole Ribonucleosides as Potential Antibacterial Agents

Reaction of 2-trifluoromethyl- or 2-cyanonaphth[2,3-d] imidazole (1 or 2) with 1-O-acetyl-2,3,5-tri-O- benzoyl-β-D-ribofuranose (3), using the triflate or fusion method afforded 2-trifluoromethyl-1-(2,3,5-tri- O-benzoyl-α-D- or -β-D-ribofuranosyl)naphth[2,3-d]imidazole (4 or 6) and 2-cyano-1-(2,3,5-tri-O-benzoyl-α-D- or β-D-ribofuranosyl)naphth[2,3,-d] imidazole (5 or 7), respectively. The products 4 and 5 or 6 and 7 were separated by chromatography on silica gel. Treatment of the blocked nucleosides 4-7 with methanolic NH₃ at 0 °C furnished the deblocked nucleosides 8-11 respectively. Treatment of 10 with 5% NH₃ (aq) at 60 °C gave 11. Structural elucidation is based on elemental analysis, UV, FAB-MS and ¹H NMR spectra. Compounds 4-11 were subjected to antibacteial testing. Compounds 5, 7 and 10 have significant activity against Staphylococous aureus (gram positive) and Esherichia coli (gram negative) bacteria, whereas the other tested compounds showed no significant activity.     

Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics

The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation.     

Some Novel Thiopyrimidine Nucleoside Analogs: Synthesis and In Vitro Antimicrobial Evaluation

Some new S-alkyl derivatives of indeno[1′,2′:4,5]thieno[2,3-d]pyrimidine 2–8 were prepared starting with pyrimidine-2(1H)-thione derivative (1). Also, treatment of compound 1 with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide or 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose afforded nucleosides 9 and 12, respectively. Furthermore, deprotection of the latter blocked nucleosides was achieved in methanolic ammonia to afford the desired free S-nucleoside derivatives 10 and 13, respectively. Some prepared products were screened for antimicrobial activity, and some of them showed promising activity.     

Ultrasensitive Simultaneous Detection of Multiple Rare Modified Nucleosides as Promising Biomarkers in Low-Put Breast Cancer DNA Samples for Clinical Multi-Dimensional Diagnosis

Early cancer diagnosis is essential for successful treatment and prognosis, and modified nucleosides have attracted widespread attention as a promising group of cancer biomarkers. However, analyzing these modified nucleosides with an extremely low abundance is a great challenge, especially analyzing multiple modified nucleosides with a different abundance simultaneously. In this work, an ultrasensitive quantification method based on chemical labeling, coupled with LC-MS/MS analysis, was established for the simultaneous quantification of 5hmdC, 5fdC, 5hmdU and 5fdU. Additionally, the contents of 5mdC and canonical nucleosides could be obtained at the same time. Upon derivatization, the detection sensitivities of 5hmdC, 5fdC, 5hmdU and 5fdU were dramatically enhanced by several hundred times. The established method was further applied to the simultaneous detection of nine nucleosides with different abundances in about 2 μg genomic DNA of breast tissues from 20 breast cancer patients. The DNA consumption was less than other overall reported quantification methods, thereby providing an opportunity to monitor rare, modified nucleosides in precious samples and biology processes that could not be investigated before. The contents of 5hmdC, 5hmdU and 5fdU in tumor tissues and normal tissues adjacent to the tumor were significantly changed, indicating that these three modified nucleosides may play certain roles in the formation and development of tumors and be potential cancer biomarkers. While the detection rates of 5hmdC, 5hmdU and 5fdU alone as a biomarker for breast cancer samples were 95%, 75% and 85%, respectively, by detecting these three cancer biomarkers simultaneously, two of the three were 100% consistent with the overall trend. Therefore, simultaneous detection of multiple cancer biomarkers in clinical samples greatly improved the accuracy of cancer diagnosis, indicating that our method has great application potential in clinical multidimensional diagnosis.     

The Synthesis of Some New Sulfur Heterocyclic Compounds as Potential Radioprotective and Anticancer Agents

Some novel 5-subistituted amino-3-methylthiophene-2,4-dicarboxylic acid diethyl ester (3–6), 3,5-dimethyl-4-oxo-2-thioxo-1,2,3,4-tetra-hydro-thieno[2,3-d]pyrimi-dine (7), imidazothienopyrimidene (8), and 1,2,4-triazolo-thienopyrimidine (11) were synthesized via a reaction of the isothiocyanate 2 with different reagents. The identification of the new compounds was established by elemental analysis, and IR, ¹H NMR, and mass spectral data. Some prepared compounds were tested for their radioprotective and anticancer activities. Compounds 7 and 16 showed significant activities against EAC cells, while compound 5 exhibited radioprotective activity.     

The Synthesis and Antimicrobial Screening of Some Novel AZA-Imidoxy Compounds as Potential Chemotherapeutic Agents

Some novel azaimidoxy compounds viz. 2-{[(4-chlorophenyl)diazenyl]oxy}-1H-isoindole-1,3-(2H)-dione (Va), and 1-{[1-naphthyldiazenyl]oxy}pyrrolidine-2,5-dione (IVc), etc. have been synthesized by a simple diazotization reaction followed by a coupling with 2-hydroxy-1H-isoindole-1,3(2H)-dione (III)/1-hydroxypyrrolidine-2,5-dione (II) of corresponding aromatic primary amine derivatives at a suitable pH. A similar reaction with a [1,3]thiazolo[4,5-b]pyridin-2-amine (VIII) lead us to some interesting results variable with a pH. The structure of all synthesized compounds has been established by IR, ¹H NMR, and mass studies. These compounds have been screened for antimicrobial activities in order to evaluate the possibility of the derivatives to be used as potential chemotherapeutic agents.     

Synthesis and Applications of Nitrogen-Containing Heterocycles as Antiviral Agents

Viruses have been a long-term source of infectious diseases that can lead to large-scale infections and massive deaths. Especially with the recent highly contagious coronavirus (COVID-19), antiviral drugs were developed nonstop to deal with the emergence of new viruses and subject to drug resistance. Nitrogen-containing heterocycles have compatible structures and properties with exceptional biological activity for the drug design of antiviral agents. They provided a broad spectrum of interference against viral infection at various stages, from blocking early viral entry to disrupting the viral genome replication process by targeting different enzymes and proteins of viruses. This review focused on the synthesis and application of antiviral agents derived from various nitrogen-containing heterocycles, such as indole, pyrrole, pyrimidine, pyrazole, and quinoline, within the last ten years. The synthesized scaffolds target HIV, HCV/HBV, VZV/HSV, SARS-CoV, COVID-19, and influenza viruses.     

Synthesis of 1-[(3-Halo-1-Hydroxy-2-Propoxy)methyl]uracil and Thymine as Potential Antiviral Agents

3′-Halogen acyclonucleoside analogs have been prepared. The starting material, benzyl glycidyl ether (5) , prepared from eplchlorohydrin and sodium benzyloxidc, underwent ring opening by soft halogen ions to give l-benzyloxy-3-fluoro-2-propanol (6) , l-bcnzyloxy-3-chloro-2-propanol (7) , and l-benzyloxy-3- bromo-2-propanol (8) respectively. The treatment of 5 with lithium iodide in the presence of acetic acid provided 1-benzyloxy-3-iodo-2-propanol (9) . The treatment of 8 with sodium iodide in anhydrous acetone also produced l-benzyloxy-3-iodo-2-propanol (9) . Chloromethylation of these halohydrins 6-9 using paraformaldehyde and hydrogen chloride gas produced the chloromcthyl ethers 10-13 . These chloromethyl ethers without further purification were allowed to react with the silylated bases 16-17 , previously prepared by silylating the bases 14-15 with HMDS in the presence of ammonium sulfate to give 1- [(l-benzyloxy-3-halogen-2-propoxy)methyl]uracils and thymines 19-25 . The target compounds 26-33 were obtained respectively after the debcnzylation of 18-25 . Compounds 26, 27, 30 and 31 had no significant cell toxicity in the range of concentrations 0.001-20 mM. Compounds 26, 27, 28 and 29 have no significant activity against HSV II (for less than 2 mM there is a cytopathic effect). Compounds 30, 31, 32 and 33 show no activity against HSV II virus even at the level 20 mM.     

Synthesis of Some Pyrazolo[3, 4]pyrimidine Derivatives for Biological Evaluation

Abstract

A novel β -enaminonitrile of 1-(6-p-tolyl-pyridazin-3-yl)-pyrazole derivative 2 was formed using (6-p-tolyl-pyridazin-3-yl)-hydrazine ( 1 ) and 2-ethoxymethylenemalononitrile. The β-enaminonitrile derivative 2 was in turn used as a precursor for the preparation of pyrazoles ( 4 , 6 ), pyrazolo[3, 4-d]-pyrimidines ( 3 , 7–12 ) and pyrazolo[4, 3-e][1,2,4]triazolo[4,3-c]pyrimidine ( 13 ). Also, N- and S-acyclic nucleosides 14 and 15 were prepared. Some of the prepared products showed potent antimicrobial activity.     

三甲基溴代硅烷促进的非环状与环状缩醛(酮)的合成

以三甲基溴代硅烷作为反应促进剂, 在室温和原甲酸酯或原乙酸酯存在的条件下, 利用醇、二醇处理羰基化合物, 高收率地实现了一系列非环状与环状缩醛(酮)的合成. 产物结构经1H NMR、元素分析等进行了表征.     

Synthesis and evaluation of hexitol nucleoside congeners as ambiguous nucleosides

A series of anhydrohexitol nucleoside congeners was synthesized as ambiguous or so-called universal nucleosides and was evaluated for their hybridization potential and discrimination properties. The 1,5-anhydro-2,3-dideoxy-2-(5-nitroindazol-1-yl)-d-arabino-hexitol 4e showed the lower spread in T_m values upon hybridization to the natural bases, with minimal destabilization, and therefore behaved as a true ambiguous nucleoside.     

Synthesis and Anti‐Avian Influenza Virus (H5N1) Evaluation of Some Novel Nicotinonitriles and Their N‐Acylic Nucleosides

Pyridine and fused pyridines derivatives are interesting compounds with diverse chemical properties and pharmacological activities. Herein, the synthesis and antiviral evaluation of some new pyridines are described.     

Synthesis of Carbocyclic Pyrimidine Nucleosides Using the Mitsunobu Reaction: O2‐ vs. N1‐Alkylation

The Mitsunobu reaction is an important tool in carbocyclic nucleoside chemistry for the direct coupling of alcohols with heterocyclic bases under mild conditions. Chemical evidences for an unusual competitive O²‐ vs. N¹‐alkylation of 3‐substituted pyrimidines is presented.     

4,7-Disubstituted 7H-Pyrrolo[2,3-d]pyrimidines and Their Analogs as Antiviral Agents against Zika Virus

Discovery of compound 1 as a Zika virus (ZIKV) inhibitor has prompted us to investigate its 7H-pyrrolo[2,3-d]pyrimidine scaffold, revealing structural features that elicit antiviral activity. Furthermore, we have demonstrated that 9H-purine or 1H-pyrazolo[3,4-d]pyrimidine can serve as an alternative core structure. Overall, we have identified 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs including compounds 1, 8 and 11 as promising antiviral agents against flaviviruses ZIKV and dengue virus (DENV). While the molecular target of these compounds is yet to be elucidated, 4,7-disubstituted 7H-pyrrolo[2,3-d]pyrimidines and their analogs are new chemotypes in the design of small molecules against flaviviruses, an important group of human pathogens.     

Synthesis,Characterization, and Biological Evaluation of Some Novel Thiosemicarbazones as Possible Antibacterial and Antioxidant Agents

Abstract

The synthesis and characterization of 18 novel thiosemicarbazones have been investigated as part of a research program on development of compounds with antibacterial and antioxidant activities. Among the tested compounds, 2-(4-hydroxybenzylidene)-N-[4-(trifluoromethoxy)phenyl]hydrazine carbothioamide (3g) and 2-(thiophen-2-ylmethylidene)-N-[4-(morpholin-4-yl)phenyl]hydrazine carbothioamide (4b) showed excellent inhibition potency at low concentration (0.5 μg/mL) against Gram-positive pathogens (Enterococcus faecalis and Staphylococcus aureus). All tested compounds were also found to possess antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and 2,2’-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical cation.

[Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental files: Additional text, tables, and figures.]     

Synthesis of N-Substituted Iminosugar C-Glycosides and Evaluation as Promising α-Glucosidase Inhibitors

A series of N-substituted iminosugar C-glycosides were synthesized and tested for α-glucosidase inhibition. The results suggested that 6e is a promising and potent α-glucosidase inhibitor. Enzymatic kinetic assays indicated that compound 6e may be classified as an uncompetitive inhibitor. The study of structure-activity relationships of those iminosugars provided a starting point for the discovery of new α-glucosidase inhibitors.