Chemistry and anti-herpes simplex virus type 1 evaluation of 4-substituted-1H-1,2,3-triazole-nitroxyl-linked hybrids

Cunha, Anna C.; Ferreira, Vı́tor F.; Vaz, Maria G. F.; Cassaro, Rafael A. Allão; Resende, Jackson Antônio Lamounier Camargos; Sacramento, Carolina Q.; Costa, Jessica de Mattos; Abrantes, Juliana L.; Souza, Thiago Moreno L.; Jordão, Alessandro K.

doi:10.1007/s11030-020-10094-2

Cited by 12 publications

(7 citation statements)

References 39 publications

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“…The effectiveness of 1,2,3-triazole derivatives was also reported in the series of 5-(benzylthio)-4-carbamyl-1,2,3-triazoles where the authors obtained EC 50 values around 9.9-16.5 mM against HSV-1 [23]. Recently, Cunha et al [24] showed that a series of 1,2,3-triazole linked nitroxyl radical derived from TEMPOL inhibited in vitro replication of HSV-1. Four hybrids showed important anti-HSV-1 activity with 50% inhibitory concentration (IC 50 ) values that ranged from 0.80 to 1.32 mM.…”

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confidence: 67%

“…Ribavirin, for instance, is a known antiviral against HIV-1, HSV and HCV, and 1,2,3-triazole analogue increased pharmacological activity and reduced ribavirin cytotoxicity [20,21]. Regarding anti-HSV-1 activity, some authors have reported good in vitro activity [22][23][24]. Jordão et al [22], for example, elaborated on a series of arysulfonylhydrazide-1H-1,2,3-triazoles and described 50% effective drug concentration (EC 50 ) values of 1.30 and 1.26 mM against this virus.…”

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confidence: 99%

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Antiviral Activity of 1,4-Disubstituted-1,2,3-Triazoles against HSV-1 in vitro

et al. 2019

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Background: Herpes simplex virus 1 (HSV-1) affects a large part of the adult population. Anti-HSV-1 drugs, such as acyclovir, target thymidine kinase and viral DNA polymerase. However, the emerging of resistance of HSV-1 alerts for the urgency in developing new antivirals with other therapeutic targets. Thus, this study evaluated a series of 1,4-disubstituted-1,2,3-triazole derivatives against HSV-1 acute infection and provided deeper insights into the possible mechanisms of action. Methods: Human fibroblast cells (HFL-1) were infected with HSV-1 17syn+ and treated with the triazole compounds at 50 mM for 24 h. The 50% effective drug concentration (EC 50 ) was determined for the active compounds. Their cytotoxicity was also evaluated in HFL-1 with the 50% cytotoxic concentration (CC 50 ) determined using CellTiter-Glo ® solution. The most promising compounds were evaluated by virucidal activity and influence on virus egress, DNA replication and transcription, and effect on an acyclovir-resistant HSV-1 strain. Results: Compounds 3 ((E)-4-methyl-N'-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol1yl)benzylidene)benzenesulfonohydrazide) and 4 (2,2'-(4,4'-((1,3-phenylen ebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1 diyl))dibenzaldehyde) were the most promising, with an EC 50 of 16 and 21 mM and CC 50 of 285 and 2,593 mM, respectively. Compound 3 was able to inhibit acyclovir-resistant strain replication and to interfere with virus egress. Both compounds did not affect viral DNA replication, but inhibited significantly the expression of ICP0, ICP4 and gC. Compound 4 also affected the transcription of UL30 and ICP34.5. Conclusions: Our findings demonstrated that these compounds are promising antiviral candidates with different mechanisms of action from acyclovir and further studies are merited.

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confidence: 67%

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confidence: 99%

Antiviral Activity of 1,4-Disubstituted-1,2,3-Triazoles against HSV-1 in vitro

et al. 2019

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“…ACV toxicity in the host is generally low because of the requirement of viral TK for the first phosphorylation. Nonetheless, host TKs are able to perform the first phosphorylation of ACV at an extremely low level; typically, ACV-TP is found at a 40–100× greater concentration in infected cells than in uninfected cells [ 8 ], reflective of a measured selectivity index of 869 [ 12 ]. Furthermore, the toxicity of ACV is also abrogated because ACV-TP is a poor inhibitor of host DNA polymerase [ 13 ].…”

Section: Acyclovir the First In Its Class Of Antiherpetic Drugsmentioning

confidence: 99%

Current Drugs to Treat Infections with Herpes Simplex Viruses-1 and -2

Sadowski

Upadhyay

Greeley

et al. 2021

Viruses

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Herpes simplex viruses-1 and -2 (HSV-1 and -2) are two of the three human alphaherpesviruses that cause infections worldwide. Since both viruses can be acquired in the absence of visible signs and symptoms, yet still result in lifelong infection, it is imperative that we provide interventions to keep them at bay, especially in immunocompromised patients. While numerous experimental vaccines are under consideration, current intervention consists solely of antiviral chemotherapeutic agents. This review explores all of the clinically approved drugs used to prevent the worst sequelae of recurrent outbreaks by these viruses.

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“…Moreover, some chemical modifications confer to the biological activity of these derivatives against Alzheimer’s disease and the HIV-1 enzyme reverse transcriptase (RT) [ 33 , 34 ]. In fact, the antiviral activity of the 1 H -pyrazolo[3,4- b ]pyridine and thieno[2,3- b ]pyridine derivative systems was described by our group [ 35 , 36 , 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Pyrazolopyridine Derivatives on Different Steps of Herpes Simplex Virus Type-1 In Vitro Replicative Cycle

Miranda

Chaves

Rosa

et al. 2022

IJMS

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Herpes simplex virus type-1 (HSV-1) infection causes several disorders, and acyclovir is used as a reference compound. However, resistant strains are commonly observed. Herein, we investigate the effects of N-heterocyclic compounds (pyrazolopyridine derivatives), named ARA-04, ARA-05, and AM-57, on HSV-1 in vitro replication. We show that the 50% effective concentration (EC50) values of the compounds ARA-04, ARA-05, and AM-57 were 1.00 ± 0.10, 1.00 ± 0.05, and 0.70 ± 0.10 µM, respectively. These compounds presented high 50% cytotoxic concentration (CC50) values, which resulted in a selective index (SI) of 1000, 1000, and 857.1 for ARA-04, ARA-05, and AM-57, respectively. To gain insight into which step of the HSV-1 replication cycle these molecules would impair, we performed adsorption and penetration inhibition assays and time-of-addition experiments. Our results indicated that ARA-04 and ARA-05 affected viral adsorption, while AM-57 interfered with the virus replication during its α- and γ-phases and decreased ICP27 content during initial and late events of HSV-1 replication. In addition, we also observed that AM-57 caused a strong decrease in viral gD content, which was reinforced by in silico calculations that suggested AM-57 interacts preferentially with the viral complex between a general transcription factor and virion protein (TFIIBc-VP16). In contrast, ARA-04 and ARA-05 interact preferentially in the proteins responsible for the viral adsorption process (nectin-1 and glycoprotein). Thus, our results suggest that the 1H-pyrazolo[3,4-b]pyridine derivatives inhibit the HSV-1 replicative cycle with a novel mechanism of action, and its scaffold can be used as a template for the synthesis of promising new molecules with antiviral effects, including to reinforce the presented data herein for a limited number of molecules.

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Chemistry and anti-herpes simplex virus type 1 evaluation of 4-substituted-1H-1,2,3-triazole-nitroxyl-linked hybrids

Cited by 12 publications

References 39 publications

Antiviral Activity of 1,4-Disubstituted-1,2,3-Triazoles against HSV-1 in vitro

Antiviral Activity of 1,4-Disubstituted-1,2,3-Triazoles against HSV-1 in vitro

Current Drugs to Treat Infections with Herpes Simplex Viruses-1 and -2

The Role of Pyrazolopyridine Derivatives on Different Steps of Herpes Simplex Virus Type-1 In Vitro Replicative Cycle

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