Synthesis and antiviral effect against herpes simplex type 1 of 12-substituted benzo[c]phenanthridinium salts

The synthesis of benzo[c]phenanthridine alkaloid derivatives is described. In vitro antiviral activity against herpes simplex type 1 (HSV1) has been investigated. Contrary to the natural product fagaronine, which did not have any activity in the HSV1 antiviral tests, four 12-alkoxy derivatives showed good activity demonstrating the importance of the 12-substitution in the structure-activity relationships.     

Breaking Down the Barriers to a Natural Antiviral Agent: Antiviral Activity and Molecular Docking of Erythrina speciosa Extract,Fractions, and the Major Compound

The in vitro cytotoxic activity in Vero cells and the antiviral activity of Erythrina speciosa methanol extract, fractions, and isolated vitexin were studied. The results revealed that E. speciosa leaves ethyl acetate soluble fraction of the methanol extract (ESLE) was the most active against herpes simplex virus type 1 (HSV‐1). Bioactivity‐guided fractionation was performed on ESLE to isolate the bioactive compounds responsible for this activity. One sub‐fraction from ESLE (ESLE IV) showed the highest activity against HSV‐1 and Hepatitis A HAV‐H10 viruses. Vitexin isolated from ESLE VI exhibited a significant antiviral activity (EC₅₀=35±2.7 and 18±3.3 μg/mL against HAV‐H10 and HSV‐1 virus, respectively), which was notably greater than the activity of the extract and the fractions. Molecular docking studies were carried out to explore the molecular interactions of vitexin with different macromolecular targets. Analysis of the in silico data together with the in vitro studies validated the antiviral activity associated with vitexin. These outcomes indicated that vitexin is a potential candidate to be utilized commendably in lead optimization for the development of antiviral agents.     

Antiviral activity of Distictella elongata (Vahl) Urb. (Bignoniaceae), a potentially useful source of anti-dengue drugs from the state of Minas Gerais, Brazil

Aims: To investigate the in vitro antiviral activity of Distictella elongata (Vahl) Urb. ethanol extracts from leaves (LEE), fruits (FEE), stems and their main components. Methods and Results: The antiviral activity was evaluated against human herpesvirus type 1 (HSV‐1), murine encephalomyocarditis virus (EMCV), vaccinia virus Western Reserve (VACV‐WR) and dengue virus 2 (DENV‐2) by the 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) colorimetric assay. LEE presented anti‐HSV‐1 [EC₅₀ 142·8 ± 5·3 μg ml^?1; selectivity index (SI) 2·0] and anti‐DENV‐2 activity (EC₅₀ 9·8 ± 1·3 μg ml^?1; SI 1·5). The pectolinarin ( 1 ) isolated from LEE was less active against HSV‐1 and DENV‐2. A mixture of the triterpenoids ursolic, pomolic and oleanolic acids was also obtained. Ursolic and oleanolic acids have shown antiviral activity against HSV‐1. A mixture of pectolinarin ( 1 ) and acacetin‐7‐O‐rutinoside ( 2 ) was isolated from FEE and has presented anti‐DENV‐2 activity (EC₅₀ 11·1 ± 1·6 μg ml^?1; SI > 45). Besides the antiviral activity, D. elongata has disclosed antioxidant effect. Conclusions: These data shows that D. elongata has antiviral activity mainly against HSV‐1 and DENV‐2, besides antioxidant activity. These effects might be principally attributed to flavonoids isolated. Significance and Impact of the Study: Distictella elongata might be considered a promising source of anti‐dengue fever phytochemicals.     

Synthesis and Antiviral Activities of New Pyrazolo[4,3‐c]quinolin‐3‐ones and Their Ribonucleoside Derivatives

Several new pyrazolo[4,3‐c]quinolin‐3‐one ribonucleosides (5a–g) and their corresponding heterocycle moieties (3a–g) were synthesized and evaluated against vaccinia virus (VV) and herpes simplex virus type 1 (HSV‐1). The derivatives 3c and 3d showed modest inhibitory activity against vaccinia virus reaching 70% at a concentration of 100 µM. All heterocyclic compounds (3a–f) showed a modest inhibition against HSV‐1, reaching the maximal inhibitory effect around 20–30%. The antiviral effects of most of the pyrazolo[4,3‐c]quinolin‐3‐one ribonucleosides (5a–f) on VV and HSV were not impressive.     

Synthesis, 18F‐Radiolabelling and Biological Evaluations of C‐6 Alkylated Pyrimidine Nucleoside Analogues

Synthesis of pyrimidine derivatives with a side‐chain attached to the C‐6 of pyrimidine ring (6–14) is reported. Target compounds 8 and 12 were subjected to in vitro phosphorylation tests, determination of their binding affinities to herpes simplex virus (HSV‐1) thymidine kinase (TK) and catalytic turnover constants. Fluorinated pyrimidine derivative 12 (40 µM) exhibited better binding affinity for HSV‐1 TK than acyclovir (ACV, 170 µM) and ganciclovir (GCV, 48 µM). Catalytic turnover constant (k _cat) of 12 (0.08 s^? 1) was close to the k _cat values of ACV (0.10 s^? 1) and GCV (0.10 s^? 1). Furthermore, compounds 8 and 12 showed no cytotoxic effects in HSV‐1 TK‐transduced and non‐transduced cell lines. Besides, compounds 8 and 12 did not exhibit antiviral or cytostatic activities against several viruses and malignant tumor cell lines that were evaluated. The new fluorinated pyrimidine derivative 16 that is phosphorylated by HSV‐1 TK could be developed as non‐toxic PET‐tracer molecule. Thus, ¹⁸F labelling of the precursor 14 was performed by nucleophilic substitution using [¹⁸F] tetrabutylammonium fluoride as the fluorinating reagent.     

Synthesis of (Z)-(1-Fluoro-2-hydroxymethyl-cyclopropylmethyl)purines

Abstract

(Z)-(1-fluoro-2-hydroxymethylcyclopropylmethyl)purines were designed, synthesized and evaluated their antiviral activity against poliovirus, HSV, and HIV.     

Synthesis of [1′-Fluoro-2′,2′-bis-(hydroxymethyl)-cyclopropylmethyl]purines as Antiviral Agents

Abstract

[1′-fluoro-2′,2′-bis-(hydroxymethyl)cyclopropylmethyl]purines were designed, synthesized and their antiviral activity against poliovirus, HSV and HIV was evaluated.     

In vitro multitarget activity of sulfadiazine substituted triazenes as antimicrobial,cytotoxic, and larvicidal agents

Multidrug resistance (MDR) causes difficulties in the treatment of infections and cancer. Research and development studies have become increasingly important for the strategy of preventing MDR. There is a need for new multitarget drug research and advancement to reduce the development of drug resistance in drug-drug interactions and reduce cost and toxic effects. This study aimed to determine the effects of multi-target triazene compounds on antibacterial, antifungal, antiviral, cytotoxic, and larvicidal activities were investigated in vitro. A series of 12 novel of 1,3-diaryltriazene-substituted sulfadiazine (SDZ) derivatives were synthesized, and the obtained pure products characterized in detail by spectroscopic and analytic methods (FT-IR, ¹H-NMR, ¹³C-NMR, and melting points). The antibacterial and antifungal activities of these derivatives (AH1-12) were determined by broth microdilution method. All derivatives have been evaluated in cell-based assays for cytotoxic and antiviral activities against Modified Vaccinia Virus Ankara. The larvicidal efficacy of these chemical compounds was also investigated by using Lucilia sericata (L. sericata) larvae. Twelve 1,3-diaryltriazene-substituted SDZ derivatives (AH1-12) were designed and developed as potent multitargeted compounds. Among them, the AH1 derivative showed the most antibacterial and antifungal activity. Besides, synthesized derivatives AH2, AH3, AH5, and AH7 showed higher antiviral activity than SDZ. All synthesized derivatives showed higher cytotoxic activity than SDZ. Also, they showed larvicidal activity at 72 h of the experiment. As a result, these compounds might be great leads for the development of next-generation multitargeted agents.     

Isolation and Identification of Three New Sterigmatocystin Derivatives from the Fungus Aspergillus versicolor Guided by Molecular Networking Approach

Molecular networking approach was applied for the targeted isolation of new sterigmatocystin derivatives, sterigmatocystins A–C, from the marine sponge‐derived fungus Aspergillus versicolor. Sterigmatocystin A features a rare 6/6/6/6/5 polycyclic system. The structures of sterigmatocystins A–C, including absolute configurations, were determined on the basis of spectroscopic data and ECD calculations. Sterigmatocystin A showed more stronger promoting angiogenesis activity than the positive control at 1.25 μM level in transgenic fluorescent zebrafish. Sterigmatocystins A–C also exhibited moderate antiviral activity by the inhibition of HSV‐2.     

Synthesis and Antiviral Activity of Hydrazides and Substituted Benzalhydrazides of Betulinic Acid and Its Derivatives

New nitrogen-containing derivatives of betulinic and betulonic acids, hydrazides and N"-benzalhydrazides, were synthesized. Their antiviral activities toward viruses of influenza A virus, herpes simplex type I virus, enterovirus ECHO6, and HIV-1 were studied in vitro. Betulinic acid 3-oxime was found to have the highest activity against the influenza virus. Betulonic acid, betulinic acid 4-chlorobenzalhydrazide, betulonic acid 3-oxime benzalhydrazide, and betulinic acid hydrazide inhibited the replication of herpes simplex type I virus. Betulinic acid hydrazide also showed antiviral activity toward HIV-1. All the derivatives of betulinic acid under study displayed a low antiviral activity toward enterovirus ECHO6.     

Synthesis and Antiviral Activity of Novel Fluorinated 2′,3′‐Dideoxynucleosides

A series of 5‐(trifluoroethoxymethyl)‐2′,3′‐dideoxyuridines and 5‐[bis(trifluoroethoxy)‐methyl]‐2′,3′‐dideoxyuridines have been prepared and screened for antiviral activity. The conformations of these compounds are discussed on the bases of NOE studies and the MO calculations. Modelling and NOE studies suggest both syn‐ and anti conformations for these 5‐(2,2,2‐trifluoroethoxymethyl)‐ and 5‐[bis(2,2,2‐trifluoroethoxy)‐methyl]‐ derivatives. The NOE parameters are also suggested to be more attributable to the nature of the fluorine atom than to structural or conformational changes. Compounds 17, 26 and 30 showed some activity in anti‐HIV‐1 and anti‐HIV‐2 assays, but the compounds were devoid of activity against HSV and human rhinovirus. The compounds tested exhibited low cytotoxicity and were inactive against a bank of cancer cells in vitro.     

Antiviral effect of red microalgal polysaccharides on Herpes simplex and Varicella zoster viruses

The cell-wall sulphated polysaccharide of the red microalga Porphyridium sp. has impressive antiviral activity against Herpessimplex viruses types 1 and 2 (HSV 1, 2) and Varicella zoster virus(VZV). Treatment of cells with 1 g mL^-1 polysaccharideresulted in 50% inhibition of HSV-infection as measured by the plaqueassay. Inhibition of the production of new virus particles was also shownwhen pre-infected cell cultures were treated with the polysaccharide. Inaddition, there was indirect evidence for a strong interaction between thepolysaccharide and HSV and a weak interaction with the cell surface.Depending on the concentration, the polysaccharide completely inhibitedor slowed down the development of the cytopathic effect in HSV or VZVpreinfected cells, but did not show any cytotoxic effects on Vero cells evenwhen a concentration as high as 250 g mL^-1 was used. Itseems therefore that the polysaccharide is able to inhibit viral infection bypreventing adsorption of virus into the host cells and/or by inhibiting theproduction of new viral particles inside the host cells. Thus, this alga seems tobe a good candidate for the development of an antiviral drug.     

A Convenient Synthesis of Acyclic Adenosines with an Unsaturated Side Chain by Modification of 9-(2,3-O-Isopropylidene-D-Ribityl)Adenine

Abstract

In expectation of discovering their antiviral activity, acyclic adenosine derivatives 7, 11, 12, and 16 were designed as analogs of neplanocin A (NPA) and L-eritadenine which are strong inhibitors of S-adenosyl-L-homocysteine hydrolase. The 1′,5′-seco-analog of 4′-deoxymethyl-NPA (DHCA) 7 was synthesized by dideoxygenation of 9-(2,3-O-isopropylidene-D-ribityl)adenine (2). Acyclic DHCA analogs 11 and 16 were obtained by Wittig reaction of the aldehyde 3 with Ph₃P=CHCO₂Et and Ph₃P=CHCN, respectively. Hydrolysis of the ester 11 afforded a vinylog of L-eritadenine 12. The synthesized acyclic nucleosides 7, 10, and 11 were evaluated for antiviral activity, however, none of them showed any significant antiviral activity.     

Synthesis and in vitro evaluation of antiviral and cytostatic properties of novel 8-triazolyl acyclovir derivatives

Abstract

As a part of the research aimed on identification of new nucleobase derivatives with improved biological properties, a series of novel 8-substituted acyclovir derivatives were synthesized. The 8-azidoguanosine 4 and novel 8-azidoacyclovir 9 were synthesized from commercially available guanosine 1 and acyclovir 6 which were transformed into 8-bromopurine derivatives 2 and 7 and hydrazine derivatives 3 and 8, respectively. 8-Triazolylguanosine 5 and 8-triazolylacyclovir analogs 10–12 were successfully synthesized via the Cu(I) catalyzed 1,3-dipolar cycloaddition reaction of azides 4 and 9 with propargyl alcohol, 4-pentyn-1-ol and 5-hexyn-1-ol. The novel 1,4-disubstituted 1,2,3-triazolyl compounds 5, 10–12 were evaluated for antiviral activity against selected DNA and RNA viruses and cytostatic activity against normal Madine Darby canine kidney (MDCK I) cells, and seven tumor cell lines (HeLa, CaCo-2, NCI-H358, Jurkat, K562, Raji and HuT78). While tested compounds exerted no antiviral activity at nontoxic concentrations, the 8-triazolyl acyclovir derivative 10, with the shortest alkyl substituent at the C-4 of triazole ring, was found to be the most active against the CaCo-2 cell line.     

Activated macrophages mediate interferon-independent inhibition of herpes simplex virus

Activated macrophages exhibit extrinsic antiviral activity (inhibition of virus replication in other cells) which may involve mechanisms similar to macrophage antitumor activity or macrophage-mediated immunosuppression. Peritoneal macrophages elicited in mice by Corynebacterium parvum vaccine suppressed the growth of herpes simplex virus (HSV) in infected cells by an interferon-independent mechanism. This was demonstrated by expression of activity against HSV-infected xenogeneic (Vero) cells. Culture supernatant fluids also did not mediate antiviral activity, and did not contain detectable levels of interferon (< 3 IU/ml). Moreover, antiviral activity was not affected by the presence of anti-mouse interferon IgG. Antiviral activity was expressed at 12–16 hr after infection, at the end of the first cycle of virus replication. Cell contact was required for optimal activity. No enhanced adsorption or phagocytosis of HSV by C. parvum macrophages could be detected nor was macrophage cytotoxicity responsible for the activity. Cytotoxicity (⁵¹Cr release) by macrophages for virus infected cells was low (< 6% specific cytotoxicity), and was not significantly higher with C. parvum macrophages than with resident macrophage controls. Although C. parvum macrophages were not cytotoxic at the macrophage-host cell ratio employed, they did significantly inhibit uptake of [³H]leucine by the host Vero cells. This suggests that inhibition of host cell metabolism by the macrophage, similar to macrophage immunosuppression, may be responsible for the antiviral activity in this system.     

SYNTHESIS AND IN VITRO ANTIVIRAL ACTIVITY EVALUATION OF 9-(2-AZIDO-2,3-DIDEOXY-β-D-THREO-PENTOFURANOSYL)ADENINE DERIVATIVES

9-(2-Azido-2,3-dideoxy-β-D-threo-pentofuranosyl)adenine derivatives (1a–e) containing a lipophilic function at the N-6 position in the purine ring were prepared and evaluated for their antiviral activity. The compounds 1a–e turned out to be inactive as antiviral agents.     

Phosphoramidate derivatives of acyclovir: Synthesis and antiviral activity in HIV-1 and HSV-1 models in vitro

The antiviral activity against HIV and HSV and the chemical stability of ACV phosphoramidate derivatives were studied. The phosphoramidates of ACV demonstrated moderate activity. The best compound appeared to be 9-(2-hydroxymethyl)guanine phosphoromonomorpholidate (7), which inhibited virus replication in pseudo-HIV-1 particles by 50% at 50 μM. It also inhibited replication of wild-type HSV-1 (9.7 μM) as well as an acyclovir-resistant strain (25 μM). None of the synthesised compounds showed any cytotoxicity.     

Synthesis and Antiviral Evaluation of 2-Mercapto-5,6-dichlorobenzimidazole-β-D-ribofuranonucleoside Derivatives

Abstract

2-Mercapto-5,6-dichlorobenzimidazole β-D-ribofuranonucleoside derivatives 8–10 have been synthesized and their antiviral properties examined. According to the glycosylation procedure used, the β-D-N-1 isomer (and the N, N-bis-riboside) or the β-D-S²-isomer have been obtained. All the prepared compounds were tested for their activity against a variety of RNA and DNA viruses, but they did not show significant antiviral activity.     

Synthesis and Antiviral Activities of Enantiomeric 1-[2-(Hydroxymethyl) Cyclopropyl] Methyl Nucleosides

Abstract

Cyclopropyl carbocyclic nucleosides have been synthesized from the key intermediate 2 which was converted to the mesylated cyclopropyl methyl alcohol 3. Condensation of compound 3 with various purine and pyrimidine bases gave the desired nucleosides. All synthesized nucleosides were evaluated for antiviral activity and cellular toxicity. Among them adenine 22 and guanine 23 derivatives showed moderate antiviral activity against HIV-1 and HBV. None of the other compounds showed any significant antiviral activities against HIV-1, HBV, HSV-1 and HSV-2 in vitro up to 100μM.     

Preparation and Antiviral Activity of Several Deoxygenated Ribavirin and Tiazofurin Derivatives

Abstract

Ribavirin and tiazofurin, two nucleosides of known antiviral activity, have been transformed by previously reported methods to yield several deoxy,epoxy, or dideoxy analogues. The deoxygenated derivatives were evaluated for antiviral activity against a host of DNA and RNA viruses; however, no significant in vitro activity was detected.