Novel indole–flutimide heterocycles with activity against influenza PA endonuclease and hepatitis C virus

As hepatitis C virus (HCV) is one of the major health problems in many countries, interest has been aroused in the design, synthesis, and optimization of novel NS5A inhibitors, outside the chemical space of currently available direct acting antivirals (DAAs). Two series of symmetric molecules with core scaffold 3,3′-(buta-1,3-diyne-1,4-diyl)dianiline or 4,4′-(buta-1,3-diyne-1,4-diyl)dianiline, coupled on its nitrogen as amide with different end caps, were synthesized and tested for their activities against HCV by using cell-based antiviral assays. Molecules with the 3,3′-(buta-1,3-diyne-1,4-diyl)dianiline core were more active than their 4,4′-congeners. Only the 3,3′-derivatives showed noncoplanarity of core phenyls that mostly led to a better interaction with the target protein and appears to be a crucial element for efficient inhibition of HCV replication. Compounds 2f and 2q exhibited potent inhibition of genotype (GT) 1b HCV replication with EC 50 values in the picomolar range and selectivity index greater than 6 orders of magnitude. The compounds seem more selective toward GT 1b and 4a . In conclusion, novel symmetric molecules with a 3,3′-(buta-1,3-diyne-1,4-diyl)dianiline core are potent and selective inhibitors that provide new extension to explore the structure–activity relationship of NS5A targeting DAAs.

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“…Rice, The Rockefeller University, NY) 27 of HCV 3a (strain S52) and 4a (strain ED43), respectively. 28…”

Section: Experimental Sectionmentioning

confidence: 99%

Symmetric Anti-HCV Agents: Synthesis, Antiviral Properties, and Conformational Aspects of Core Scaffolds

et al. 2019

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“…It is noteworthy that the activity of 18 (EC 50 = 0.25 μM) was 12-fold better than lead compound 16 (EC 50 = 2.92 μM). A marked improvement was also observed on the EC 50 value of 16 (43-fold lower), compared to the structurally related fused indole-flutimide analogue I (EC 50 = 126.3 μM), 56 validating the idea of incorporating a spiro connection between hydantoin and the indane ring. Introduction of a methyl substituent on the amide nitrogen atom of the 2,4diketoimidazolidine scaffold of 16 led to a 2-fold increase in the activity (EC 50 16a = 1.41 μM).…”

Section: Biologymentioning

confidence: 53%

“…Rational designtheoretical calculations Previous studies by our group have resulted in compounds carrying metal chelating moieties that demonstrated a highly promising inhibition capacity against either pathogenic viruses, including influenza and HCV, 56 or parasites of the Trypanosoma genus. 57,58 The two above-mentioned series of analogues, although structurally diverse, were based on rational incorporation of metal chelating moieties on scaffolds with pronounced drug-likeness, such as the combination of flutimide with the indole system (I) or incorporation of the acetohydroxamic acid moiety on a 2,6-diketopiperazine (2,6-DKP) scaffold (II) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…[47][48][49][50][51][52][53] It has been proved that the vast majority of metalloenzyme inhibitors are chelating agents employing metal binding groups to coordinate the active site metal ion. 54,55 As a continuation of our research on metal chelating agents, 56,57 we were interested in developing novel combined scaffolds demonstrating both antiviral and antiparasitic properties. In this study, we report the rational design and synthesis of novel spiro-hydantoin analogues, attached by the acetohydroxamic acid moiety (CH 2 CONHOH) as the potential metal binding functional group (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Scaffold hybridization strategy towards potent hydroxamate-based inhibitors ofFlaviviridaeviruses andTrypanosomaspecies

et al. 2019

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“…Compounds #1, 41–45, 78–91, 138–140, and 190 were reported previously (Cai et al, 2014). Compounds #236–241 were synthesized as previously reported (Zoidis et al, 2016). Compounds #128, 132, 191, 197, 198, 204, 206, 208, 211, and 217 were purchased commercially.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of hepatitis B virus replication by N -hydroxyisoquinolinediones and related polyoxygenated heterocycles

et al. 2017

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We previously reported low sensitivity of the hepatitis B virus (HBV) ribonuclease H (RNaseH) enzyme to inhibition by N-hydroxyisoquinolinedione (HID) compounds. Subsequently, our biochemical RNaseH assay was found to have a high false negative rate for predicting HBV replication inhibition, leading to underestimation of the number of HIDs that inhibit HBV replication. Here, 39 HID compounds and structurally related polyoxygenated heterocycles (POH), N-hydroxypyridinediones (HPD), and flutimides were screened for inhibition of HBV replication in vitro. Inhibiting the HBV RNaseH preferentially blocks synthesis of the positive-polarity DNA strand and causes accumulation of RNA:DNA heteroduplexes. Eleven HIDs and one HPD preferentially inhibited HBV positive-polarity DNA strand accumulation. EC50s ranged from 0.69 μM to 19 μM with therapeutic indices from 2.4 – 71. Neither the HIDs nor the HPD had an effect on the ability of the polymerase to elongate DNA strands in capsids. HBV RNaseH inhibition by the HIDs was confirmed with an improved RNaseH assay and by detecting accumulation RNA:DNA heteroduplexes in HBV capsids from cells treated with a representative HID. Therefore, the HID scaffold is more promising for anti-HBV drug discovery than we originally reported, and the HPD scaffold may hold potential for antiviral development. The preliminary structure-activity relationship will guide optimization of the HID/HPDs as HBV inhibitors.

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Novel indole–flutimide heterocycles with activity against influenza PA endonuclease and hepatitis C virus

Abstract: Structure-based design and synthesis of novel indole–flutimide derivatives with antiviral activity.

Cited by 25 publications

References 46 publications

Symmetric Anti-HCV Agents: Synthesis, Antiviral Properties, and Conformational Aspects of Core Scaffolds

Symmetric Anti-HCV Agents: Synthesis, Antiviral Properties, and Conformational Aspects of Core Scaffolds

Scaffold hybridization strategy towards potent hydroxamate-based inhibitors ofFlaviviridaeviruses andTrypanosomaspecies

Inhibition of hepatitis B virus replication by N -hydroxyisoquinolinediones and related polyoxygenated heterocycles

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