Synthesis and anti-CVB 3 evaluation of substituted 5-nitro-2-phenoxybenzonitriles

Pürstinger, Gerhard; Palma, Armando M. De; Zimmerhofer, Günther; Huber, Simone; Ladurner, Sophie; Neyts, Johan

doi:10.1016/j.bmcl.2008.07.099

Cited by 12 publications

(14 citation statements)

References 22 publications

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“…The required anilines were also mostly prepared by S N Ar chemistry from substituted phenols or thiophenols and 2-fluoro-4-nitro-benzonitrile (Scheme 2). 14 However, when Y was chlorine, substitution of the chlorine was circumvented by copper- catalyzed selective O-arylation of 3-aminophenols, 15 while the corresponding thioethers were prepared using cuprous thiophenolates (Scheme 2). 16 Subsequently, when 3-cyanovinyl-substituted phenols were required, Heck coupling of aryl iodides with acrylonitrile using PdCl 2 (PPh 3 ) 2 as catalyst was effective (Scheme 3).…”

Section: Methodsmentioning

confidence: 99%

Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse Transcriptase

et al. 2011

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Non-nucleoside inhibitors of HIV reverse transcriptase (NNRTIs) are being pursued with guidance from molecular modeling including free energy perturbation (FEP) calculations for protein-inhibitor binding affinities. The previously reported pyrimidinylphenylamine 1 and its chloro analog 2 are potent anti-HIV agents; they inhibit replication of wild-type HIV-1 in infected human T-cells with EC50 values of 2 and 10 nM. However, they show no activity against viral strains containing the Tyr181Cys (Y181C) mutation in HIV-RT. Modeling indicates that the problem is likely associated with extensive interaction between the dimethylallyloxy substituent and Tyr181. As an alternative, a phenoxy group is computed to be oriented in a manner diminishing the contact with Tyr181. However, this replacement leads to a roughly 1000-fold loss of activity for 3 (2.5 μM). The present report details the efficient, computationally-driven evolution of 3 to novel NNRTIs with sub-10 nM potency towards both wild-type HIV-1 and Y181C-containing variants. The critical contributors were FEP substituent scans for the phenoxy and pyrimidine rings and recognition of potential benefits of addition of a cyanovinyl group to the phenoxy ring.

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Section: Methodsmentioning

confidence: 99%

Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse Transcriptase

et al. 2011

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“…MDL-860 is an antipicornavirus compound identified in 1982 by a group of The Dow Chemical Company . MDL-860 showed a broad-spectrum antiviral activity against enteroviruses and rhinoviruses but was not active against other virus families, including positive-sense RNA viruses (feline calicivirus, coronavirus), negative-sense RNA viruses (Newcastle disease virus, vesicular stomatitis virus, and influenza A virus), and a DNA virus (herpes simplex virus type 1). , Effectiveness of MDL-860 in vivo has been shown in mouse models of coxsackievirus infection, , and its potent derivatives have also been synthesized . MDL-860 inhibits some early step of viral replication after uncoating, , but its direct target and the mechanism of action remain unknown.…”

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confidence: 99%

Allosteric Regulation of Phosphatidylinositol 4-Kinase III Beta by an Antipicornavirus Compound MDL-860

et al. 2017

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MDL-860 is a broad-spectrum antipicornavirus compound discovered in 1982 and one of the few promising candidates effective in in vivo virus infection. Despite the effectiveness, the target and the mechanism of action of MDL-860 remain unknown. Here, we have characterized antipoliovirus activity of MDL-860 and identified host phosphatidylinositol-4 kinase III beta (PI4KB) as the target. MDL-860 treatment caused covalent modification and irreversible inactivation of PI4KB. A cysteine residue at amino acid 646 of PI4KB, which locates at the bottom of a surface pocket apart from the active site, was identified as the target site of MDL-860. This work reveals the mechanism of action of this class of PI4KB inhibitors and offers insights into novel allosteric regulation of PI4KB activity.

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“…24 This fact compelled us to replace later guanidine-HCl with another inhibitor of viral RNA synthesis, the compound 2-(3,4-dichlorophenoxy)- 5-nitrobenzonitrile (MDL-860). 25 This Merrill-Dow Pharmaceuticals product (synthesized initially by L. Markley) is notable for its wide anti-EV scope and for its in vivo effects on cardiotropic CVB3 infection in adult mice. 26 In the present work, we investigated the effect of a modified triple combination, pleconaril þ MDL-860 þ oxoglaucine (PMO) on experimental CVB1 neuroinfection in newborn mice.…”

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confidence: 99%

Anti-enteroviral triple combination of viral replication inhibitors: activity against coxsackievirus B1 neuroinfection in mice

Stoyanova

Nikolova

Pürstinger

et al. 2015

Antivir Chem Chemother

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Background: Chemotherapy is an important tool for controlling enterovirus infections, but clinically effective antienterovirus drugs do not currently exist, mainly due to the development of drug resistance. We investigated the combination effects of enterovirus replication inhibitors in order to limit this process. In previous studies, we showed the efficacy of consecutive alternating administration of the triple combinations disoxaril/guanidine/oxoglaucine and pleconaril/guanidine/oxoglaucine against coxsackievirus B1 infection in newborn mice. Drug sensitivity tests of the viral brain isolates showed that these drug combinations prevented the development of drug resistance. Methods: In the current study, we replaced guanidine-HCl with enteroviral RNA synthesis inhibitor MDL-860 to test the effect of a new triple combination-pleconaril/MDL-860/oxoglaucine-applied via consecutive alternating administration in newborn mice infected subcutaneously with 20 MLD 50 of coxsackievirus B1. Results: The pleconaril/MDL-860/oxoglaucine combination via consecutive alternating administration showed high activity at the 75 mg/kg MDL-860 dose: a protective effect of 50% and a pronounced suppression of brain virus titers. Moreover, along with prevention of drug resistance, a phenomenon of increased drug sensitivity was established. MDL-860 sensitivity in pleconaril/MDL-860/oxoglaucine increased 8.2 times vs. placebo (29 times vs. monotherapy) on day 7 and oxoglaucine sensitivity-4.9 times vs. placebo (by 6.8 times vs. monotherapy) on day 13. As concerns pleconaril, a demonstrable prevention of drug resistance was registered without increase of drug sensitivity. Daily, simultaneous administration of pleconaril/MDL-860/oxoglaucine showed no protective effects and led to a rapid development of drug resistance. Conclusions: These results add new support for using consecutive alternating administration treatment courses to achieve clinically effective chemotherapy of enterovirus infections. KeywordsAnimal model, compounds, drug combination, drug resistance, picornaviridaeIn recent decades, the interest on the role of enteroviruses (EVs) in human infectious pathology has increased.1-3 This is in part due to the large number of investigations carried out on a series of EV-induced infections manifested for the first time by epidemic spread in several regions of the globe, for example, the enterovirus 71 (EV 71) epidemic in Southeast Asia 4,5 and EV D68 in the USA. 6 Moreover, EVs are causative agents of an unusual phenomenon for the infectious pathology: one virus, in one region, during one period of time (the summer season), to cause more than 10 different clinical pictures affecting different

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Synthesis and anti-CVB 3 evaluation of substituted 5-nitro-2-phenoxybenzonitriles

Cited by 12 publications

References 22 publications

Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse Transcriptase

Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse Transcriptase

Allosteric Regulation of Phosphatidylinositol 4-Kinase III Beta by an Antipicornavirus Compound MDL-860

Anti-enteroviral triple combination of viral replication inhibitors: activity against coxsackievirus B1 neuroinfection in mice

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