Chloroquinolone Carboxamide Derivatives as New Anti-HSV-1 Promising Drugs.

BACKGROUND: Since the emergence of HSV resistant strains, new antiviral agents have emerged and still are urgently needed, especially those with alternative targets. OBJECTIVE: In this work, we evaluated new quinolone derivatives as anti-HSV. METHODS: For this study, cells were infected and treated with different components to evaluate the profile of HSV replication in vitro. In addition, studies were performed to determine the pharmacokinetic toxicity and profile of the compound. RESULTS: Indeed the EC50 values of these promising molecules ranged between 8 µM and 32 µM. We have also showed that all compounds inhibited the expression of ICP27 viral proteins, which gives new insights in the search for new target for antiherpetic therapy. Chlorine in positions C6 and phosphonate in position C1 have shown to be important for viral inhibition. The chloroquinolone carboxamide derivatives fulfilled "Lipinsky Rule of Five" for good oral bioavailability and showed higher intestinal absorption and blood brain barrier penetration, as well as lower toxicity profile. CONCLUSION: Although the inhibition activities of chloroquinolone carboxamide derivatives were lower than acyclovir, they showed different modes of action in comparison to the drugs currently available. These findings encourage us to continue pre-clinical studies for the development of new anti-HSV-1 agents.

Antiviral Potential of Naphthoquinones Derivatives Encapsulated within Liposomes.

HSV infections, both type 1 and type 2, are among the most widespread viral diseases affecting people of all ages. Their symptoms could be mild, with cold sores up to 10 days of infection, blindness and encephalitis caused by HSV-1 affecting immunocompetent and immunosuppressed individuals. The severe effects derive from co-evolution with the host, resulting in immune evasion mechanisms, including latency and growing resistance to acyclovir and derivatives. An efficient alternative to controlling the spreading of HSV mutations is the exploitation of new drugs, and the possibility of enhancing their delivery through the encapsulation of drugs into nanoparticles, such as liposomes. In this work, liposomes were loaded with a series of 2-aminomethyl- 3-hydroxy-1,4-naphthoquinones derivatives with n-butyl (compound 1), benzyl (compound 2) and nitrobenzene (compound 3) substituents in the primary amine of naphthoquinone. They were previously identified to have significant inhibitory activity against HSV-1. All of the aminomethylnaphthoquinones derivatives encapsulated in the phosphatidylcholine liposomes were able to control the early and late phases of HSV-1 replication, especially those substituted with the benzyl (compound 2) and nitrobenzene (compound 3), which yields selective index values that are almost nine times more efficient than acyclovir. The growing interest of the industry in topical administration against HSV supports our choice of liposome as a drug carrier of aminomethylnaphthoquinones derivatives for formulations of in vivo pre-clinical assays.

Subchronic toxicity and anti-HSV-1 activity in experimental animal of dolabelladienetriol from the seaweed, Dictyota pfaffii.

This study examined in rats the subchronic toxicity and anti- HSV-1activity after oral administration of dolabelladienetriol (D1), a diterpene isolated from the seaweed Dictyota pfaffii. In subchronic toxicity (SCT) tests, female rats received D1 by gavage 15 mg/kg/day (n = 5) for 50 days, and general behavior, death, hematological, biochemical and histological changes in the liver, kidney, stomach, and duodenum were determined. For the anti-HSV-1 activity, female mice were infected and treated orally with a dose of 20 mg/kg (n = 5) twice a day with D1 and any lesions in the skin were then recorded for 18 days. Dolabelladienetriol in SCT did not significantly change behavior, body weight, hematological or biochemical profiles. The liver and kidneys, however, showed some alterations in rats treated with D1, similar to those in rats treated with ACV, while the other tissues had no significant changes. The anti-HSV-1 activity of D1 had a similar efficacy to the ACV drug control in mice. Our results showed that D1 has potential commercial development as a new HSV-1drug.

Aminomethylnaphthoquinones and HSV-1: in vitro and in silico evaluations of potential antivirals.

BACKGROUND: Herpes simplex viruses (HSV) are leading causes of human infections which result in severe manifestations, especially in neonates, immunocompromised and/or transplanted individuals. Current HSV type-1 (HSV-1) resistance to standard antiviral agents is a therapeutic challenge, especially for treating immunocompromised patients. METHODS: Herein we describe the promising antiviral profile of three 2-aminomethyl-3-hydroxy-1,4-naphthoquinones against HSV-1 using Vero cells. RESULTS: The in silico theoretical analysis indicated that the lowest unoccupied molecular orbital (LUMO) and the conformational features of these molecules are important structural features for modulating their biological activity. Our in vitro results showed that these compounds have significant anti-HSV-1 activity comparable to acyclovir, the antiviral currently used clinically. Importantly two of them showed a lower cytotoxicity profile against Vero cells than acyclovir. The inhibitory mechanism analysis using a time-of-addition assay revealed that all compounds inhibit the late phase of lytic replication. Finally, the highest selectivity index of the first tested compound was almost twice as high as that of acyclovir. CONCLUSIONS: Since resistance is still a problem for treating HSV infections, these compounds present a promising profile toward the development of new strategies for anti-HSV-1 therapy.

Potencial atividade antiviral de plexaurella regia no ciclo replicativo do vírus herpes simples tipo 1 / Potential antiviral activity of plexaurella regia on the replication of herpes simplex virus type 1

Latência e resistência de cepas de Herpes simples tipo 1 (HSV-1) ao aciclovir têm sido associados a sequelas graves em pacientes imunocomprometidos, como pacientes com AIDS. Por essa razão, a pesquisa por novas substâncias com atividade anti-HSV-1 é uma necessidade urgente. Objetivo: Investigar se os extratos obtidos de Plexaurella spp poderiam ser usados em estudos pré-clínicos de drogas contra o vírus herpes simples tipo 1. Métodos: A viabilidade celular e concentrações inibitórias das drogas foram utilizados como testes de triagem para investigar os extratos etil acetato e diclorometano de Plexaurella spp como antivirais. Resultados: Os resultados de viabilidade demonstraram que os extratos de Plexaurella regia e Plexaurella grandflora não foram citotóxicas, mas somente Plexaurella regia alcançou um valor de CC50 expressivo. Nos ensaios antivirais, Plexaurella regia mostraram um resultado ainda mais significante de concentração efetiva (EC50) e índice terapêutico (<2.5 µg/mL e 51.6 µg/mL, respectivamente) comparado com aciclovir (ACV). Conclusão: Estes resultados mostram que os extratos de corais têm atividade anti-herpética e podem contribuir para novas estratégias de redução da incidência de resistência de doenças relacionadas aos herpes vírus

Latency and resistance of acyclovir-resistant strains of Herpes simplex virus type 1 (HSV-1) have been associated with serious sequelae in immunocompromised individuals, such as AIDS patients. Consequently, the search for new substances with anti-HSV activity is both necessary and urgent. Objective: To investigate whether extracts obtained from Plexaurella spp can be used in preclinical studies of drugs against herpes simplex virus type 1. Methods: Cell viability and inhibitory drug concentrations as screening tests were used to investigate ethyl acetate and dichloromethane extracts from Plexaurella spp as antivirals. Results: The results of viability assays demonstrated that extracts from Plexaurella regia and Plexaurella grandiflora showed less cytotoxicity, but only Plexaurella regia reached a very expressive CC50 value. In antiviral assays, Plexaurella regia showed an even more significant result of effective concentration (EC50) and therapeutic index (<2.5 µg/mL and 51.6 µg/mL, respectively) compared with acyclovir (ACV). Conclusion: These results demonstrated that extracts from corals have anti-herpetic activities and could contribute towards new strategies to stop the increasing incidence of resistance in herpes-related diseases.

Molecular modeling of a phenyl-amidine class of NMDA receptor antagonists and the rational design of new triazolyl-amidine derivatives.

Recently, many efforts have been made to develop N-methyl-D-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington's, Parkinson's, and Alzheimer's diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives (1a-1q), reported as N-methyl-D-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines. The best (quantitative) structure-activity relationship model constructed by multiple linear regression analysis presented high data fitting (R = 0.914) was able to explain 83.6% of the biological data variance (R(2) = 0.836), presented a satisfactory internal predictive ability (Q(2) = 0.609) and contained the descriptors (E(HOMO), Ovality and cLogP). Our assays confirmed that glutamate promotes an extensive cell death in avian neurons (77%) and 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively). The results of neurotoxicity and cytotoxicity on Vero cells suggested the favorable profile of 2a and 2b. Also, the molecular modeling used to predict the activity, the interaction with the receptor and the pharmacokinetic and toxicity of the triazolyl-amidines pointed them as a promising class for further exploration as N-methyl-D-aspartic acid receptor antagonists.

Marine natural seaweed products as potential antiviral drugs against Bovine viral diarrhea virus

Bovine viral diarrhea virus (BVDV) is an etiologic agent that causes important economic losses in the world. It is endemic in cattle herds in most parts of the world. The purpose of this study was to evaluate the in vitro cytotoxic effect and antiviral properties of several marine natural products obtained from seaweeds: the indole alkaloid caulerpin (CAV, 1) and three diterpenes: 6-hydroxydichotoma-3,14-diene-1,17-dial (DA, 2), 10,18-diacetoxy-8-hydroxy-2,6-dolabelladiene (DB1, 3) and 8,10,18-trihydroxy-2,6-dolabelladiene (DB3, 4). The screening to evaluate the cytotoxicity of compounds did not show toxic effects to MDBK cells. The antiviral activity of the compounds was measured by the inhibition of the cytopathic effect on infected cells by plaque assay (PA) and EC50 values were calculated for CAV (EC=2,0± 5.8), DA (EC 2,8± 7.7), DB1 (EC 2,0±9.7), and DB3 (EC 2,3±7.4). Acyclovir (EC50 322± 5.9) was used in all experiments as the control standard. Although the results of the antiviral activity suggest that all compounds are promising as antiviral agents against BVDV, the Selectivity Index suggests that DB1 is the safest of the compounds tested.

Caulerpin as a potential antiviral drug against herpes simplex virus type 1

About 80% of the human adult population is infected with HSV-1. Although there are many anti-HSV-1 drugs available (acyclovir, ganciclovir, valaciclovir, foscarnet), their continuous use promotes the selection of resistant strains, mainly in ACV patients. In addition to resistance, the drugs also have toxicity, particularly when administration is prolonged. The study of new molecules isolated from green algae with potential antiviral activity represents a good opportunity for the development of antiviral drugs. Caulerpin, the major product from the marine algae Caulerpa Lamouroux (Caulerpales), is known for its biological activities such as antioxidant, antifungal, acetylcholinesterase inhibitor (AChE) and antibacterial activity. In this work, we show that caulerpin could be an alternative to acyclovir as an anti-HSV-1 drug that inhibits the alpha and beta phases of the replication cycle.

Oxoquinoline acyclonucleoside phosphonate analogues as a new class of specific inhibitors of human immunodeficiency virus type 1.

The emergence of a multidrug-resistant HIV-1 strain and the toxicity of anti-HIV-1 compounds approved for clinical use are the most significant problems facing antiretroviral therapies. Therefore, it is crucial to find new agents to overcome these issues. In this study, we synthesized a series of new oxoquinoline acyclonucleoside phosphonate analogues (ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a-3k), which contained different substituents at the C6 or C7 positions of the oxoquinoline nucleus and an N1-bonded phosphonate group. We subsequently investigated these compounds' in vitro inhibitory effects against HIV-1-infected peripheral blood mononuclear cells (PBMCs). The most active compounds were the fluoro-substituted derivatives 3f and 3g, which presented excellent EC(50) values of 0.4±0.2 µM (3f) and 0.2±0.005 µM (3g) and selectivity index values (SI) of 6240 and 14675, respectively.

Evaluation of the acute toxicity of dolabelladienotriol, a potential antiviral from the brown alga Dictyota pfaffii, in BALB/c mice

Dolabelladienotriol is a product extracted from the brown marine alga Dictyota pfaffii from Brazil that has been shown to have antiviral activity and low cytotoxicity. Our studies have evaluated the acute toxicity of dolabelladienotriol in BALB/c mice for ten days after administration of a single dose. Among the parameters considered were behavior, weight, biochemical and histological analyses of blood samples taken at three different times (Bs.0, Bs.1 and Bs.2) and optical microscopic examination of organs like liver, kidney, stomach and small intestine. Mice deaths were not observed at any dose during the ten day period. There were some changes in the biochemical analysis results for urea nitrogen (BUN) and alanine aminotransferase (ALT), but the changes were not significantly different from the reference levels of the animals before administration of the substance. Histological analyses of tissues were very similar for all animals. The alterations in liver and kidney tissues did not affect the animals´ behavior at any concentration, not even at 50 mg/kg, where the most significant changes in tissues were seen. This study indicates that dolabelladienotriol has low toxicity in administered dose range.

Synthesis, antiviral activity and molecular modeling of oxoquinoline derivatives.

In the present article, we describe the synthesis, anti-HIV1 profile and molecular modeling evaluation of 11 oxoquinoline derivatives. The structure-activity relationship analysis revealed some stereoelectronic properties such as LUMO energy, dipole moment, number of rotatable bonds, and of hydrogen bond donors and acceptors correlated with the potency of compounds. We also describe the importance of substituents R(2) and R(3) for their biological activity. Compound 2j was identified as a lead compound for future investigation due to its: (i) high activity against HIV-1, (ii) low cytotoxicity in PBMC, (iii) low toxic risks based on in silico evaluation, (iv) a good theoretical oral bioavailability according to Lipinski 'rule of five', (v) higher druglikeness and drug-score values than current antivirals AZT and efavirenz.

SAR of a series of anti-HSV-1 acridone derivatives, and a rational acridone-based design of a new anti-HSV-1 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine series.

Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we assess the structural features and electronic properties of a series of ten 1-hydroxyacridone derivatives (1a-j) recently described as a new class of non-nucleoside inhibitors of Herpes Simplex Virus-1 (HSV-1). Based on these molecules, we applied rigid analogue and isosteric replacement approaches to design and synthesize nine new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivatives (2a-i). The biological and computational results of these new molecules were compared with 1-hydroxyacridones. An inhibitory profile was observed in 10-Cl substituted 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivative (2f), which presents the same substituent at the analogous position of 1-hydroxyacridone derivative (1b). The structure-activity relationship (SAR) studies pointed out the 10-position next to nitrogen atom as important for the anti-HSV-1 profile in the pyrazolo-naphthyridine derivatives tested, which reinforced the promising profile for further experimental investigation. The most potent acridone and pyrazolo-naphthridine derivatives were also submitted to an in silico ADMET screening in order to determine their overall drug-score, which confirmed their potential antiviral profile.