Synthesis of 9-(hexane-1,6-diol-3-yl)purines,a novel series of acyclic nucleoside analogs and antiviral evaluation

New acyclic purine nucleoside analogs lacking the C(3′)? C(4′) bond, have been prepared from 4-aminocyclohexene and evaluated for antiviral activity. A new synthesis of 4-aminocyclohexene from cyclohex-3-ene-1-carbonyl chloride is also reported via a Curtius reaction. None of the two compounds exhibited any antiviral activity in vitro against HSV-1, HCMV and HIV-1.     

Inhibitory effects of lupene-derived pentacyclic triterpenoids from Bursera simaruba on HSV-1 and HSV-2 in vitro replication

The cytotoxicity and antiviral properties of Bursera simaruba against herpes simplex viruses (HSV-1 and HSV-2) were investigated through a bioactivity-guided isolation protocol. The plant material was fractionated using solvent-solvent partitioning, size-exclusion and thin-layer chromatography. The antiviral compounds present in the most active fractions were identified by means of LC-MS and NMR. Three different methods were compared during the evaluation of antiviral activity of samples. Four lupene-related pentacyclic triterpenes were found to be responsible for the anti-herpesvirus effects of B. simaruba and were isolated from this species for the first time. The selective indexes (SI) of B. simaruba-derived samples ranged from 7.7 to 201.9.     

Antiviral properties from plants of the Mediterranean flora

Natural products are a successful source in drug discovery, playing a significant role in maintaining human health. We investigated the in vitro cytotoxicity and antiviral activity of extracts from 18 traditionally used Mediterranean plants. Noteworthy antiviral activity was found in the extract obtained from the branches of Daphne gnidium L. against human immunodeficiency virus type-1 (EC₅₀ = 0.08 μg/mL) and coxsackievirus B5 (EC₅₀ = 0.10 μg/mL). Other relevant activities were found against BVDV, YFV, Sb-1, RSV and HSV-1. Interestingly, extracts from Artemisia arborescens L. and Rubus ulmifolius Schott, as well as those from D. gnidium L., showed activities against two different viruses. This extensive antiviral screening allowed us to identify attractive activities, offering opportunities to develop lead compounds with a great pharmaceutical potential.     

Synthesis, Characterization, and Biological Activity of Amino Acid Derivatives of the Heteropolytungstophosphoric Acid

Summary. Compounds of phosphotungstic acid (WPA) containing the amino acids alanine (WPA–Ala) or glycine (WPA–Gly) as counter cations were synthesized and characterized by elemental analysis, thermal analysis, and IR spectroscopy. Cellular toxicity was assessed by the trypan blue exclusion method, and the antiviral activity of WPA and the modified WPA compounds was tested against herpes simplex viruses (HSV) type 1 and type 2. Biological assays indicate that the newly synthesized compounds exhibit no evident cytotoxic effects on Vero cells and negligible antiviral activity against HSV-1 and HSV-2.     

Synthesis, Characterization, and Biological Activity of Amino Acid Derivatives of the Heteropolytungstophosphoric Acid

Compounds of phosphotungstic acid (WPA) containing the amino acids alanine (WPA–Ala) or glycine (WPA–Gly) as counter cations were synthesized and characterized by elemental analysis, thermal analysis, and IR spectroscopy. Cellular toxicity was assessed by the trypan blue exclusion method, and the antiviral activity of WPA and the modified WPA compounds was tested against herpes simplex viruses (HSV) type 1 and type 2. Biological assays indicate that the newly synthesized compounds exhibit no evident cytotoxic effects on Vero cells and negligible antiviral activity against HSV-1 and HSV-2.     

Chemical analysis and antiviral activity evaluation of Baccharis anomala

The chemical composition and antiviral activity of aqueous extract from Baccharis anomala was studied by bioactivity-guided fractionation. Ethanol precipitation and fractionation by molecular permeation allowed the separation of the anti-herpes simplex virus 1 (HSV-1) active fraction from aqueous extract (Fraction B). Natural Product Reagent A, FeCl₃ and thin-layer chromatography indicated the presence of phenolic compounds in the aqueous extract. Fraction B showed pronounced antiviral activity when tested with HSV-1 strains VR733/ATCC and Acyclovir-resistant 29-R, displaying virucidal but not virustatic activity.     

Design,Synthesis and Biological Evaluation of Novel N‐(4‐([2,2′:5′,2′′‐Terthiophen]‐5‐yl)‐2‐methylbut‐3‐yn‐2‐yl) Benzamide Derivatives

On the basis of the principle of combination of active groups, a series of novel N‐(4‐([2,2′:5′,2′′‐terthiophen]‐5‐yl)‐2‐methylbut‐3‐yn‐2‐yl) benzamide derivatives were designed, synthesized and systematically evaluated for their antiviral activity against tobacco mosaic virus (TMV). The bioassay results showed that most of these compounds displayed good anti‐TMV activity, and some of them exhibited higher antiviral activity than commercial Ningnanmycin. Especially, compound 8e with excellent anti‐TMV activity (inactivation activity, 92.3%/500 µg·mL^?1; curative activity, 85.7%/500 µg·mL^?1 and protection activity, 64.7%/500 µg·mL^?1) emerged as a potential inhibitor of plant virus TMV. Quantitative structure‐activity relationship studies proved that the van der Waals volume (V) and electronic parameter (∑(∑σ_o+σ_p) and ∑σ_m) for the substituent R¹ were very important for antiviral activities in this class of compounds.     

Sodium and potassium benzeneazophosphonate complexes with crown ethers: Solid-state microwave synthesis, characterization and biological activity

The eco-friendly synthesis, spectroscopic (IR, MS, ¹H and ¹³C NMR) study and biological (cytostatic, antiviral) activity of sodium and potassium benzeneazophosphonate complexes, obtained by reaction in the solid state under microwave irradiation of the alkali salts of ethyl [α-(4-benzeneazoanilino)-N-benzyl]phosphonic acid and [α-(4-benzeneazoanilino)-N-4-methoxybenzyl]phosphonic acid with crown ethers containing 18-membered (dibenzo-18-crown-6 and bis(4′-di-tert-butylbenzo)-18-crown-6), 24-membered (dibenzo-24-crown-8) and 30-membered (dibenzo-30-crown-10) macrocyclic rings, have been described. The simple work-up solvent free reaction is an efficient green procedure for the formation of mononuclear crown ether complexes in which the sodium/potassium ion is bound to oxygen atoms of the macrocycle and the phosphonic acid oxygen. The free crown ethers, alkali benzeneazophosphonate salts and their complexes were evaluated for their cytostatic activity in vitro against murine leukemia L1210, murine mammary carcinoma FM3A and human T-lymphocyte CEM and MT-4 cell lines, as well as for their antiviral activity against a wide variety of DNA and RNA viruses. The investigated compounds showed no specific antiviral activity, whereas all the free crown ethers and their complexes demonstrated cytostatic activity, which was especially pronounced in the case of bis(4′-di-tert-butylbenzo)-18-crown-6 and its complexes.     

Synthesis and antiviral evaluation of some carbonucleoside analogues

1,2‐O‐Isopropylidene‐α‐L‐threofuranosyl heterocyclic derivatives were synthesized from 1,2‐O‐iso‐propylidene‐α‐D‐xilopentadialdo‐1,4‐furanose and tested for antiviral activity against herpes simplex virus type 1, dengue virus type 2 and Junin virus. For comparative propose, the antiviral activity of some of their pyranosyl analogues were also tested. The furanosyl derivatives showed to be moderate inhibitors of Junin virus and, in general, proved to be more effective than the pyranosyl analogues.     

A new antiviral pregnane from a gorgonian-derived Cladosporium sp. fungus

A new pregnane, 3α-hydroxy-7-ene-6,20-dione (1), and five known steroids (2–6), along with one known steroidal glycoside (7) were obtained from the fungus Cladosporium sp. WZ-2008-0042 cultured from a gorgonian Dichotella gemmacea collected from the South China Sea. The structure and absolute configuration of the new compound (1) were elucidated by comprehensive spectroscopic data and X-ray diffraction data. The compound has a rare configuration of 3α-OH that is different from most of pregnanes. All of the isolated compounds were evaluated for their antiviral activities against respiratory syncytial virus (RSV). Among them, 1 exhibited potential antiviral activity with the IC₅₀ value of 0.12 mM.     

Synthesis and Biological Activity of a Series of Methylene-Expanded Oxetanocin Nucleoside Analogues

Summary.  A series of methylene-expanded oxetanocin nucleoside analogues, e.g. analogues of 2 and the known antiviral nucleosides AZT, FLT, and ddC (3) were prepared by a very direct route beginning with the readily available (S )-glycidol 4 and proceeding via the dihydrofuran-3-methanols 9a,b. Biological testing of these modified nucleosides indicates that they are non-cytotoxic compounds with generally weak antiviral activity. However, the guanosine analogue 2G showed pronounced activity vs. herpes simplex virus type 1 (HSV-1) in cell culture and was HSV-1-encoded thymidine kinase dependent. This compound is therefore an interesting new lead structure for the development of new anti-HSV agents. Received September 3, 2001. Accepted September 17, 2001     

Anti-herpes activity of polysaccharide fractions from Stevia rebaudiana leaves

Abstract

The antiviral potential of natural polysaccharide compounds has been demonstrated, especially against enveloped viruses and members of the Herpesviridae family. Two polysaccharide fractions obtained from Stevia rebaudiana (Bertoni) leaves, that were active against Herpes simplex virus type 1 (HSV-1) were studied to investigate their mode of action. Both polysaccharides - SFW (crude faction) and SSFK (homogeneous alkaline fraction) - exerted antiviral effects on the initial stages of HSV-1 infection by inhibiting viral adsorption and penetration. When added after virus internalization, both fractions decreased plaque size. The effect of the fractions was confirmed by investigating viral glycoprotein expression. Based on the mode of action of the polysaccharides demonstrated in the present work and on their selectivity index, the polysaccharides obtained from S. rebaudiana could be an alternative treatment of infections caused by HSV-1.     

Constituents and biological activity of the chloroform extract and essential oil of <Emphasis Type="Italic">Cupressus sempervirens</Emphasis>

The essential oil of the leaves of Cupressus sempervirens L. was isolated by hydrodistillation and tested against gram positive and gram negative bacteria, showing remarkable antimicrobial activity against Bacillus subtilis with minimum inhibitory concentration (MIC) 75%. The antiviral activity of the essential oil was tested against Herpes simplex virus type 1 (HSV-1), showing antiviral activity with virucidal percentages of 68.0% and 53.2% at concentrations of 1:32 and 1:64, respectively. We firstly reported the isolation of two epi-betulin esters of fatty acids from the CHCl₃ fraction of Cupressus sempervirens L. leaves, which were isolated and purified using HPLC, and identified using PMR and MS. The CHCl₃ fraction showed significant cytotoxicity against HeLa cells. Published in Khimiya Prirodnykh Soedinenii, No. 3, pp. 265–268, May–June, 2009.     

Bis coumarinyl bis triazolothiadiazinyl ethane derivatives: Synthesis,antiviral activity evaluation,and molecular docking studies

A series of novel 3,3′-(3,3′-(dihydroxy/hydroxyethane-1,2-diyl)bis(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6,3-diyl))bis(2H-chromen-2-ones) were prepared by the condensation of thiocarbohydrazide with tartaric acid or malic acid followed by various 3-(2-bromoacetyl)-2H-chromen-2-ones in two steps with good yields. All the synthesized compounds were characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR, and mass) data. These synthesized bis(triazolothiadiazinyl coumarin) compounds were evaluated for broad spectrum of antiviral activity. Among all the tested compounds, compound 5f exhibited antiviral activity against H1N1 virus. The molecular docking studies of these compounds against H1N1 neuraminidase enzyme were performed. The binding affinity and binding values were compared with standard drugs.     

Enantioselective Michael Addition of the 2‐(1‐Ethylpropoxy)acetaldehyde to N‐[(1Z)‐2‐Nitroethenyl]acetamide – Optimization of the Key Step in the Organocatalytic Oseltamivir Synthesis

Organocatalytic Michael addition of alkoxyacetaldehyde 1 to N‐protected 2‐nitroethene‐1‐amine 2 (Scheme 2) is a key step in the synthesis of an important antiviral agent, oseltamivir. Screening of a large array of structurally diverse acids as potential promoters led to the identification of several useful acidic additives for this reaction (Tables 1–4). Also other reaction parameters were investigated with the aim of improving the diastereoselectivity of the Michael addition, while maintaining high enantiomer purity and yield (Tables 5 and 6).     

A new naphthoquinone analogue and antiviral constituents from the root of Rhinacanthus nasutus

Rhinacanthus nasutus (L.) Kurz (Acanthaceae) is known as traditional medicine for the treatment of fungal and herpes virus infections. A new naphthoquinone racemate, rhinacasutone (1) together with seven known compounds, rhinacanthone (2), rhinacanthins C, D, N, Q, and E (3–7), and heliobuphthalmin (8) were isolated from root of R. nasutus. Their structures were determined on the basis of extensive spectroscopic methods, including 1D-, 2D-NMR and MS data. All the isolated compounds were tested for their antiviral activities against PR8, HRV1B, and CVB3-infected vero cells. Compounds 3–6 exhibited significant antiviral activities with the IC₅₀ value ranging from 0.03 to 23.7 μM in all three infections.     

Synthesis of Phospholipid?Ribavirin Conjugates

New conjugates of antiviral nucleoside Ribavirin (=1‐(β‐D ‐ribofuranosyl)‐1H‐1,2,4‐triazole‐3‐carboxamide; 1 ) with 1,2‐ and 1,3‐diacyl glycerophosphates have been synthesized by the phosphoramidite method. A combination of 2′,3′‐phenylboronate protecting group for the sugar moiety of the ribonucleoside 1 and 2‐cyanoethyl protection for the phosphate fragment ensured the preparation of the desired compounds with reasonable yields via a small number of synthetic steps.     

A New Iridoid Alkaloid from the Flowers of Plumeria rubra L. cv. acutifolia

A new iridoid alkaloid containing a spirolactone unit, plumericidine ( 1 ), was isolated from the flowers of Plumeria rubra L. cv. Acutifolia. Its structure was elucidated by spectroscopic evidence and confirmed by X‐ray diffraction crystallography. Its anticancer and antiviral activities were evaluated, but found to be insignificant.     

Synthesis of adamantyl-containing cidofovir analogs as potential antiviral prodrugs with high bioavailability parameters

We report on preparation of potential nucleoside phosphonate prodrugs: 1-{3-hydroxy-2-[O-(adamantylalkyl)phosphorylmethoxy]propyl}cytosines containing two structural fragments providing antiviral activity, nucleoside phosphonate and adamantyl sites.

     

The S1′–S3′ Pocket of the SARS-CoV-2 Main Protease Is Critical for Substrate Selectivity and Can Be Targeted with Covalent Inhibitors

The main protease (M^pro) of SARS-CoV-2 is a well-characterized target for antiviral drug discovery. To date, most antiviral drug discovery efforts have focused on the S4–S1′ pocket of M^pro; however, it is still unclear whether the S1′–S3′ pocket per se can serve as a new site for drug discovery. In this study, the S1′–S3′ pocket of M^pro was found to differentially recognize viral peptidyl substrates. For instance, S3′ in M^pro strongly favors Phe or Trp, and S1′ favors Ala. The peptidyl inhibitor D-4–77, which possesses an α-bromoacetamide warhead, was discovered to be a promising inhibitor of M^pro, with an IC₅₀ of 0.95 μM and an antiviral EC₅₀ of 0.49 μM. The M^pro/inhibitor co-crystal structure confirmed the binding mode of the inhibitor to the S1′–S3′ pocket and revealed a covalent mechanism. In addition, D-4–77 functions as an immune protectant and suppresses SARS-CoV-2 M^pro-induced antagonism of the host NF-κB innate immune response. These findings indicate that the S1′–S3′ pocket of SARS-CoV-2 M^pro is druggable, and that inhibiting SARS-CoV-2 M^pro can simultaneously protect human innate immunity and inhibit virion assembly.