Design, synthesis, and anti-TMV bioactivities of nucleobase phosphonate analogs

GRAPHICAL ABSTRACT ABSTRACT A series of novel nucleobase derivatives and their analogues possessing diethoxyphosphoryl scaffolds were synthesized through four-step reactions and screened for their antiviral activity toward tobacco mosaic virus (TMV). Preliminary bioassays suggested that some of these simple structures displayed appreciable anti-TMV activity in vivo. Among them, compound (diethoxyphosphoryl)methyl 4-[2-(1H-benzo[d][1,2,3]triazol-1-yl)acetamido]-benzoate (a-3) exerted the strongest chemotherapeutic and protective effects against TMV with the rates of 52.8 and 72.2% at the dosage of 500 µg/mL, respectively, which were comparable with those of the commercial agricultural antiviral agent ningnanmycin (54.2 and 70.2%). Molecular docking with TMV helicases revealed that compound a-3 had strong interactions with receptor amino acid residues. Given the facile synthetic route and significant chemotherapeutic and protective potentials, compound a-3 could be further studied and exploited as a promising antiviral candidate.

[1]  Guoqiang Zhang,et al.  Antiviral activity of glycoprotein GP-1 isolated from Streptomyces kanasensis ZX01. , 2016, International journal of biological macromolecules.

[2]  Qingmin Wang,et al.  Spatial Configuration and Three-Dimensional Conformation Directed Design, Synthesis, Antiviral Activity, and Structure-Activity Relationships of Phenanthroindolizidine Analogues. , 2016, Journal of agricultural and food chemistry.

[3]  B. Song,et al.  Design, synthesis, antiviral activity and three-dimensional quantitative structure-activity relationship study of novel 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety. , 2016, Pest management science.

[4]  Yao-Wei Gao,et al.  Synthesis of Azacyclic Nucleoside Analogues via Asymmetric [3 + 2] Cycloaddition of 9-(2-Tosylvinyl)-9H-purines. , 2016, Organic letters.

[5]  R. Schinazi,et al.  Synthesis and Evaluation of 2,6-Modified Purine 2'-C-Methyl Ribonucleosides as Inhibitors of HCV Replication. , 2016, ACS medicinal chemistry letters.

[6]  Cristina Tintori,et al.  Homology Model-Based Virtual Screening for the Identification of Human Helicase DDX3 Inhibitors , 2015, J. Chem. Inf. Model..

[7]  D. Holt,et al.  Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K). , 2015, Journal of medicinal chemistry.

[8]  G. Rastelli,et al.  Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn Kinases. , 2015, Journal of medicinal chemistry.

[9]  Alicia M. Hanson,et al.  Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase. , 2015, ACS infectious diseases.

[10]  B. Song,et al.  Design, synthesis, and antiviral activity of novel rutin derivatives containing 1, 4-pentadien-3-one moiety. , 2015, European journal of medicinal chemistry.

[11]  H. Niu,et al.  The Development for the Synthesis of Chiral Acyclic Nucleosides and Their Phosphonates , 2014 .

[12]  R. Schinazi,et al.  Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs , 2014, Chemical reviews.

[13]  Song Yang,et al.  Synthesis and bioactivities of novel thioether/sulfone derivatives containing 1,2,3-thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety. , 2013, Bioorganic & medicinal chemistry letters.

[14]  Alicia M. Hanson,et al.  Discovering New Medicines Targeting Helicases: Challenges and Recent Progress , 2013, SLAS Discovery.

[15]  Li-xia Xiong,et al.  Synthesis and characteristics of (Hydrogenated) ferulic acid derivatives as potential antiviral agents with insecticidal activity , 2013, Chemistry Central Journal.

[16]  Yuxiu Liu,et al.  Synthesis and antiviral activities of antofine analogues with different C-6 substituent groups. , 2013, Journal of agricultural and food chemistry.

[17]  Lizhong Wang,et al.  Design, synthesis, and anti-tobacco mosaic virus (TMV) activity of phenanthroindolizidines and their analogues. , 2012, Journal of agricultural and food chemistry.

[18]  Jing Qiao,et al.  Natural supramolecular building blocks: from virus coat proteins to viral nanoparticles. , 2012, Chemical Society reviews.

[19]  H. Niu,et al.  Synthesis of C6-azolyl purine nucleosides via C–N coupling reaction of unprotected 6-chloropurine nucleosides and N-heterocycles under catalyst- and solvent-free conditions , 2012 .

[20]  M. Ishikawa,et al.  Crystal Structure of the Superfamily 1 Helicase from Tomato Mosaic Virus , 2012, Journal of Virology.

[21]  H. Niu,et al.  Microwave-promoted "one-pot" synthesis of 4-nitrobenzylthioinosine analogues using thiourea as a sulfur precursor. , 2012, Chemistry, an Asian journal.

[22]  M. Ishikawa,et al.  Expression, purification, and functional characterization of a stable helicase domain from a tomato mosaic virus replication protein. , 2012, Protein expression and purification.

[23]  Z. Kelman,et al.  Helicase ATPase activity of the Tobacco mosaic virus 126-kDa protein modulates replicase complex assembly. , 2010, Virology.

[24]  Jian‐guo Wang,et al.  Synthesis and antiviral activity against tobacco mosaic virus and 3D-QSAR of alpha-substituted-1,2,3-thiadiazoleacetamides. , 2006, Bioorganic & medicinal chemistry letters.