Anti-enteroviral activity of new MDL-860 analogues: Synthesis, in vitro/in vivo studies and QSAR analysis

[Display omitted] •60 analogues of antiviral agent MDL-860 were obtained and 6 diaryl ethers demonstrated high in vitro antiviral activity (SI > 50) against enteroviruses CVB1, CVB3 and PV1.•The most active compounds are low toxic.•QSAR analysis was performed.•X-ray crystallography for one of the...

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Veröffentlicht in:Bioorganic chemistry 2019-04, Vol.85, p.487-497
Hauptverfasser: Nikolova, Ivanka, Slavchev, Ivaylo, Ravutsov, Martin, Dangalov, Miroslav, Nikolova, Yana, Zagranyarska, Irena, Stoyanova, Adelina, Nikolova, Nadya, Mukova, Lucia, Grozdanov, Petar, Nikolova, Rosica, Shivachev, Boris, Kuz'min, Victor E., Ognichenko, Liudmila N., Galabov, Angel S., Dobrikov, Georgi M.
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container_title Bioorganic chemistry
container_volume 85
creator Nikolova, Ivanka
Slavchev, Ivaylo
Ravutsov, Martin
Dangalov, Miroslav
Nikolova, Yana
Zagranyarska, Irena
Stoyanova, Adelina
Nikolova, Nadya
Mukova, Lucia
Grozdanov, Petar
Nikolova, Rosica
Shivachev, Boris
Kuz'min, Victor E.
Ognichenko, Liudmila N.
Galabov, Angel S.
Dobrikov, Georgi M.
description [Display omitted] •60 analogues of antiviral agent MDL-860 were obtained and 6 diaryl ethers demonstrated high in vitro antiviral activity (SI > 50) against enteroviruses CVB1, CVB3 and PV1.•The most active compounds are low toxic.•QSAR analysis was performed.•X-ray crystallography for one of the compounds was performed.•1 compound showed promising in vivo activity. A series of 60 nitrobenzonitrile analogues of the anti-viral agent MDL-860 were synthesized (50 of which are new) and evaluated for their activity against three types of enteroviruses (coxsackievirus B1, coxsackievirus B3 and poliovirus 1). Among them, six diaryl ethers (20e, 27e, 28e, 29e, 33e and 35e) demonstrated high in vitro activity (SI > 50) towards at least one of the tested viruses and very low cytotoxicity against human cells. Compound 27e possesses the broadest spectrum of activity towards all tested viruses in the same way as MDL-860 does. The most active derivatives (27e, 29e and 35e) against coxsackievirus B1 were tested in vivo in newborn mice experimentally infected with 20 MLD50 of coxsackievirus B1. Compound 29e showed promising in vivo activity (protection index 26% and 4 days lengthening of mean survival time). QSAR analysis of the substituent effects on the in vitro cytotoxicity (CC50) and anti-viral activity of the nitrobenzonitrile derivatives was carried out and adequate QSAR models for the anti-viral activity of the compounds against poliovirus 1 and coxsackievirus B1 were constructed.
doi_str_mv 10.1016/j.bioorg.2019.02.020
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A series of 60 nitrobenzonitrile analogues of the anti-viral agent MDL-860 were synthesized (50 of which are new) and evaluated for their activity against three types of enteroviruses (coxsackievirus B1, coxsackievirus B3 and poliovirus 1). Among them, six diaryl ethers (20e, 27e, 28e, 29e, 33e and 35e) demonstrated high in vitro activity (SI &gt; 50) towards at least one of the tested viruses and very low cytotoxicity against human cells. Compound 27e possesses the broadest spectrum of activity towards all tested viruses in the same way as MDL-860 does. The most active derivatives (27e, 29e and 35e) against coxsackievirus B1 were tested in vivo in newborn mice experimentally infected with 20 MLD50 of coxsackievirus B1. Compound 29e showed promising in vivo activity (protection index 26% and 4 days lengthening of mean survival time). QSAR analysis of the substituent effects on the in vitro cytotoxicity (CC50) and anti-viral activity of the nitrobenzonitrile derivatives was carried out and adequate QSAR models for the anti-viral activity of the compounds against poliovirus 1 and coxsackievirus B1 were constructed.</description><identifier>ISSN: 0045-2068</identifier><identifier>EISSN: 1090-2120</identifier><identifier>DOI: 10.1016/j.bioorg.2019.02.020</identifier><identifier>PMID: 30782563</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Anti-enteroviral ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Cell Line ; Coxsackieviruses ; Crystallography, X-Ray ; Humans ; MDL-860 ; Microbial Sensitivity Tests ; Molecular Structure ; Nitriles - chemical synthesis ; Nitriles - chemistry ; Nitriles - pharmacology ; Nitrobenzonitriles ; Poliovirus - drug effects ; QSAR ; Quantitative Structure-Activity Relationship ; Synthesis</subject><ispartof>Bioorganic chemistry, 2019-04, Vol.85, p.487-497</ispartof><rights>2019 Elsevier Inc.</rights><rights>Copyright © 2019 Elsevier Inc. 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A series of 60 nitrobenzonitrile analogues of the anti-viral agent MDL-860 were synthesized (50 of which are new) and evaluated for their activity against three types of enteroviruses (coxsackievirus B1, coxsackievirus B3 and poliovirus 1). Among them, six diaryl ethers (20e, 27e, 28e, 29e, 33e and 35e) demonstrated high in vitro activity (SI &gt; 50) towards at least one of the tested viruses and very low cytotoxicity against human cells. Compound 27e possesses the broadest spectrum of activity towards all tested viruses in the same way as MDL-860 does. The most active derivatives (27e, 29e and 35e) against coxsackievirus B1 were tested in vivo in newborn mice experimentally infected with 20 MLD50 of coxsackievirus B1. Compound 29e showed promising in vivo activity (protection index 26% and 4 days lengthening of mean survival time). QSAR analysis of the substituent effects on the in vitro cytotoxicity (CC50) and anti-viral activity of the nitrobenzonitrile derivatives was carried out and adequate QSAR models for the anti-viral activity of the compounds against poliovirus 1 and coxsackievirus B1 were constructed.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30782563</pmid><doi>10.1016/j.bioorg.2019.02.020</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-8765-6536</orcidid><orcidid>https://orcid.org/0000-0002-0589-7342</orcidid></addata></record>
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source MEDLINE; Access via ScienceDirect (Elsevier)
subjects Anti-enteroviral
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Cell Line
Coxsackieviruses
Crystallography, X-Ray
Humans
MDL-860
Microbial Sensitivity Tests
Molecular Structure
Nitriles - chemical synthesis
Nitriles - chemistry
Nitriles - pharmacology
Nitrobenzonitriles
Poliovirus - drug effects
QSAR
Quantitative Structure-Activity Relationship
Synthesis
title Anti-enteroviral activity of new MDL-860 analogues: Synthesis, in vitro/in vivo studies and QSAR analysis
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