Quinoline tricyclic derivatives. Design, synthesis and evaluation of the antiviral activity of three new classes of RNA-dependent RNA polymerase inhibitors

Carta, Antonio; Briguglio, Irene; Piras, Sandra; Corona, Paola; Boatto, Gianpiero; Nieddu, Maria; Giunchedi, Paolo; Marongiu, M. E.; Giliberti, Gabriele; Iuliano, Filippo; Blois, Sylvain; Ibba, Cristina; Busonera, Bernardetta; Colla, Paolo La

doi:10.1016/j.bmc.2011.10.009

Cited by 66 publications

(32 citation statements)

References 19 publications

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“…Quinoline derivatives such as triazolo[4,5- g ]quinolines, imidazo[4,5- g ]quinolones, and pyrido[2,3- g ]quinoxalines have also been demonstrated to exhibit antiviral activity against pathogenic viruses in the Flaviviridae family, including Bovine Viral Diarrhoea virus (BVDV, Pestivirus), Yellow Fever (YFV, Flavivirus), and Hepatitis C virus (HCV, Hepacivirus). Enzymatic assays indicated that these quinoline derivatives had a significant inhibitory effect on RNA-dependent RNA polymerase (RdRp) activities of viral NS5 proteins [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity of a Novel Compound CW-33 against Japanese Encephalitis Virus through Inhibiting Intracellular Calcium Overload

Huang

Lien

Chen

et al. 2016

IJMS

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Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, has five genotypes (I, II, III, IV, and V). JEV genotype I circulates widely in some Asian countries. However, current JEV vaccines based on genotype III strains show low neutralizing capacities against genotype I variants. In addition, JE has no specific treatment, except a few supportive treatments. Compound CW-33, an intermediate synthesized derivative of furoquinolines, was investigated for its antiviral activities against JEV in this study. CW-33 exhibited the less cytotoxicity to Syrian baby hamster kidney (BHK-21) and human medulloblastoma (TE761) cells. CW-33 dose-dependently reduced the cytopathic effect and apoptosis of JEV-infected cells. Supernatant virus yield assay pinpointed CW-33 as having potential anti-JEV activity with IC50 values ranging from 12.7 to 38.5 μM. Time-of-addition assay with CW-33 indicated that simultaneous and post-treatment had no plaque reduction activity, but continuous and simultaneous treatments proved to have highly effective antiviral activity, with IC50 values of 32.7 and 48.5 μM, respectively. CW-33 significantly moderated JEV-triggered Ca2+ overload, which correlated with the recovery of mitochondria membrane potential as well as the activation of Akt/mTOR and Jak/STAT1 signals in treated infected cells. Phosphopeptide profiling by LC-MS/MS revealed that CW-33 upregulated proteins from the enzyme modulator category, such as protein phosphatase inhibitor 2 (I-2), Rho GTPase-activating protein 35, ARF GTPase-activating protein GIT2, and putative 3-phosphoinositide-dependent protein kinase 2. These enzyme modulators identified were associated with the activation of Akt/mTOR and Jak/STAT1 signals. Meanwhile, I-2 treatment substantially inhibited the apoptosis of JEV-infected cells. The results demonstrated that CW-33 exhibited a significant potential in the development of anti-JEV agents.

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Section: Discussionmentioning

confidence: 99%

Antiviral Activity of a Novel Compound CW-33 against Japanese Encephalitis Virus through Inhibiting Intracellular Calcium Overload

Huang

Lien

Chen

et al. 2016

IJMS

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“…In recent years, our research group has published several 1(2)H-benzo[d] [1,2,3]triazole, usually called benzotriazole, derivatives that have shown marked antiviral activity against many viruses [15][16][17][18]. The versatile biological behavior of benzotriazole and its derivatives have recently been described in an in-depth review [19].…”

Section: Introductionmentioning

confidence: 99%

5,6-Dichloro-2-Phenyl-Benzotriazoles: New Potent Inhibitors of Orthohantavirus

Sanna

Piras

Madeddu

et al. 2020

Viruses

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Orthohantaviruses, previously known as hantaviruses (family Hantaviridae, order Bunyavirales), are emerging zoonoses hosted by different rodent and insectivore species. Orthohantaviruses are transmitted by aerosolized excreta (urine, saliva and feces) of their reservoir hosts. When transmitted to humans, they cause hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe and hantavirus (cardio) pulmonary syndrome (HPS) in the Americas. Clinical studies have shown that early treatments of HFRS patients with ribavirin (RBV) improve prognosis. Nevertheless, there is the need for urgent development of specific antiviral drugs. In the search for new RNA virus inhibitors, we recently identified a series of variously substituted 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazole derivatives active against the human respiratory syncytial virus (HRSV). Interestingly, several 2-phenyl-benzotriazoles resulted in fairly potent inhibitors of the Hantaan virus in a chemiluminescence focus reduction assay (C-FRA) showing an EC50 = 4–5 µM, ten-fold more active than ribavirin. Currently, there are no FDA approved drugs for the treatment of orthohantavirus infections. Antiviral activities and cytotoxicity profiles suggest that 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazoles could be promising candidates for further investigation as a potential treatment of hantaviral diseases.

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“…In the framework of a long-lasting antiviral research program, our group designed and synthesised a series of angular and linear N-polycyclic derivatives active against BVDV, YFV, HCV and other related viruses [23 -30]. The molecular target for BVDV inhibition was identified in the viral RNA dependent RNA polymerase (RdRp) [24,28,31,32]. Imidazo[4,5-g]quinoline derivatives were published as interesting BVDV inhibitors and the most active derivative of that series, 4-(4-chloro-3H-imidazo[4,5-g]quinolin-2yl)benzonitrile (A) (EC 50 0.3µM; CC 50 >100 µM) [32,33] was docked and scored for affinity towards the binding site of the BVDV RdRp, the resulting receptor/ligand complex was relaxed by energy minimisation, followed by MD simulation.…”

Section: Introductionmentioning

confidence: 99%

Anti-BVDV Activity Evaluation of Naphthoimidazole Derivatives Compared with Parental Imidazoquinoline Compounds

Ibba¹,

Piras²,

Delogu³

et al. 2020

TOMCJ

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Background: Pestivirus genus includes animal pathogens which are involved in economic impact for the livestock industry. Among others, Bovine Viral Diarrhoea Virus (BVDV) establish a persistent infection in cattle causing a long list of symptoms and a high mortality rate. In the last decades, we synthesised and reported a certain number of anti-BVDV compounds. Methods: In them, imidazoquinoline derivatives turned out as the most active. Their mechanism of actions has been deeply investigated, BVDV RNA-dependent RNA polymerase (RpRd) resulted as target and the way of binding was predicted in silico through three main H-bond interaction with the target. The prediction could be confirmed by target or ligand mutation. The first approach has already been performed and published confirming the in silico prediction. Results: Here, we present how the ligand chemical modification affects the anti-BVDV activity. The designed compounds were synthesised and tested against BVDV as in silico assay negative control. Conclusion: The antiviral results confirmed the predicted mechanism of action, as the newly synthesised compounds resulted not active in the in vitro BVDV infection inhibition.

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Quinoline tricyclic derivatives. Design, synthesis and evaluation of the antiviral activity of three new classes of RNA-dependent RNA polymerase inhibitors

Cited by 66 publications

References 19 publications

Antiviral Activity of a Novel Compound CW-33 against Japanese Encephalitis Virus through Inhibiting Intracellular Calcium Overload

Antiviral Activity of a Novel Compound CW-33 against Japanese Encephalitis Virus through Inhibiting Intracellular Calcium Overload

5,6-Dichloro-2-Phenyl-Benzotriazoles: New Potent Inhibitors of Orthohantavirus

Anti-BVDV Activity Evaluation of Naphthoimidazole Derivatives Compared with Parental Imidazoquinoline Compounds

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