A versatile salicyl hydrazonic ligand and its metal complexes as antiviral agents

Rogolino, Dominga; Carcelli, Mauro; Bacchi, Alessia; Compari, Carlotta; Contardi, Laura; Fisicaro, E.; Gatti, Anna; Sechi, Mario; Stevaert, Annelies; Naesens, Lieve

doi:10.1016/j.jinorgbio.2015.05.013

Cited by 47 publications

(21 citation statements)

References 54 publications

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“…The coordinating versatility of N′ -acylhydrazone ligands is well-known (Albrecht et al, 2009; Ray et al, 2009; Rogolino et al, 2015). If a 2-hydroxy substituted phenyl ring is present on the backbone of the ligand, it can coordinate one or, depending on denticity, two metal centers (M 1 and M 2 in Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we focused our attention on a family of N′ -acylhydrazones which proved to be versatile chelating inhibitors of the influenza virus PA endonuclease (Carcelli et al, 2016). We also identified some N′ -acylhydrazone metal complexes with promising in vitro antiviral activity against various DNA- and RNA-viruses (Rogolino et al, 2015). Based on the functional similarity between HIV IN, HIV RNase H and the influenza PA endonuclease (Rogolino et al, 2012), we decided to evaluate a panel of N′ -acylhydrazones against both HIV IN and RNase H, with the aim of identifying a unique chelating motif effective across metal-dependent enzymes of diverse viruses.…”

Section: Introductionmentioning

confidence: 99%

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Chelation Motifs Affecting Metal-dependent Viral Enzymes: N′-acylhydrazone Ligands as Dual Target Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain

et al. 2017

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Human immunodeficiency virus type 1 (HIV-1) infection, still represent a serious global health emergency. The chronic toxicity derived from the current anti-retroviral therapy limits the prolonged use of several antiretroviral agents, continuously requiring the discovery of new antiviral agents with innovative strategies of action. In particular, the development of single molecules targeting two proteins (dual inhibitors) is one of the current main goals in drug discovery. In this contest, metal-chelating molecules have been extensively explored as potential inhibitors of viral metal-dependent enzymes, resulting in some important classes of antiviral agents. Inhibition of HIV Integrase (IN) is, in this sense, paradigmatic. HIV-1 IN and Reverse Transcriptase-associated Ribonuclease H (RNase H) active sites show structural homologies, with the presence of two Mg(II) cofactors, hence it seems possible to inhibit both enzymes by means of chelating ligands with analogous structural features. Here we present a series of N′-acylhydrazone ligands with groups able to chelate the Mg(II) hard Lewis acid ions in the active sites of both the enzymes, resulting in dual inhibitors with micromolar and even nanomolar activities. The most interesting identified N′-acylhydrazone analog, compound 18, shows dual RNase H-IN inhibition and it is also able to inhibit viral replication in cell-based antiviral assays in the low micromolar range. Computational modeling studies were also conducted to explore the binding attitudes of some model ligands within the active site of both the enzymes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chelation Motifs Affecting Metal-dependent Viral Enzymes: N′-acylhydrazone Ligands as Dual Target Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain

et al. 2017

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“…The compounds' antiviral activity in cell culture was determined with a broad panel of viruses and using cytopathic effect (CPE) reduction assays described in detail elsewhere [42]. Human influenza A/H1N1 and B viruses were examined on Madin-Darby canine kidney (MDCK) cells [34].…”

Section: Antiviral Assaysmentioning

confidence: 99%

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Tonelli

Naesens

Gazzarrini

et al. 2017

European Journal of Medicinal Chemistry

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We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC = 5.8 μM, SI > 43).

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“…Metal chelating agents represent an important class of viral enzyme inhibitors (29)(30)(31)(32)(33). Chelation of the divalent Mg 2ϩ cofactors of HIV integrase has proven to be a successful strategy for the design of HIV integrase inhibitors and resulted in approval of the chelating inhibitors raltegravir (RAL), elvitegravir (EVG), and dolutagravir (DTG) (for a review, see reference 31).…”

mentioning

confidence: 99%

Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase

Colby-Germinario

Hassounah

et al. 2016

Antimicrob Agents Chemother

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The viral RNA-dependent RNA polymerase (RdRp) activity of the dengue virus (DENV) NS5 protein is an attractive target for drug design. Here, we report the identification of a novel class of inhibitor (i.e., an active-site metal ion chelator) that acts against DENV RdRp activity. DENV RdRp utilizes a two-metal-ion mechanism of catalysis; therefore, we constructed a small library of compounds, through mechanism-based drug design, aimed at chelating divalent metal ions in the catalytic site of DENV RdRp. We now describe a pyridoxine-derived small-molecule inhibitor that targets DENV RdRp and show that 5-benzenesulfonylmethyl-3-hydroxy-4-hydroxymethyl-pyridine-2-carboxylic acid hydroxyamide (termed DMB220) inhibited the RdRp activity of DENV serotypes 1 to 4 at low micromolar 50% inhibitory concentrations (IC 50s of 5 to 6.7 M) in an enzymatic assay. The antiviral activity of DMB220 against DENV infection was also verified in a cell-based assay and showed a 50% effective concentration (EC 50 ) of <3 M. Enzyme assays proved that DMB220 was competitive with nucleotide incorporation. DMB220 did not inhibit the enzymatic activity of recombinant HIV-1 reverse transcriptase and showed only weak inhibition of HIV-1 integrase strand transfer activity, indicating high specificity for DENV RdRp. S600T substitution in the DENV RdRp, which was previously shown to confer resistance to nucleoside analogue inhibitors (NI), conferred 3-fold hypersusceptibility to DMB220, and enzymatic analyses showed that this hypersusceptibility may arise from the decreased binding/incorporation efficiency of the natural NTP substrate without significantly impacting inhibitor binding. Thus, metal ion chelation at the active site of DENV RdRp represents a viable anti-DENV strategy, and DMB220 is the first of a new class of DENV inhibitor. D engue virus (DENV) belongs to the family Flaviviridae, a group of enveloped positive-sense single-stranded RNA viruses that includes the genera Hepacivirus (prototype, hepatitis C virus [HCV]), Flavivirus (prototype, yellow fever virus), and Pestivirus (prototype, bovine viral diarrhea virus) (1). Distinct from the hepaciviruses and pestiviruses that are not arthropodborne, the flaviviruses are transmitted by mosquitos and ticks. Dengue, the most prevalent arthropod-borne viral disease of humans, is caused by four serotypes (DENV1 to -4) and has had a major impact on global public health (2-4).Infection with any of the DENV serotypes may result in a wide spectrum of clinical symptoms ranging from a mild flu-like syndrome (known as dengue fever [DF]) to the most severe forms of the disease, which are characterized by coagulopathy, increased vascular fragility, and permeability (dengue hemorrhagic fever [DHF]). The latter may progress to hypovolemic shock (dengue shock syndrome [DSS]) (3, 5). Among the four serotypes, DENV2 is the most prevalent on a global scale, followed by DENV3, DENV1, and DENV4 (6). Dengue is endemic in over 100 tropical and subtropical countries, and the global incidence of dengue has grown ...

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A versatile salicyl hydrazonic ligand and its metal complexes as antiviral agents

Cited by 47 publications

References 54 publications

Chelation Motifs Affecting Metal-dependent Viral Enzymes: N′-acylhydrazone Ligands as Dual Target Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain

Chelation Motifs Affecting Metal-dependent Viral Enzymes: N′-acylhydrazone Ligands as Dual Target Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase

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