Anti-enteroviral activity of new MDL-860 analogues: Synthesis,in vitro/in vivo studies and QSAR analysis |
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| Institution: | 1. Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, bl. 9, Acad. G. Bonchev Str., Sofia 1113, Bulgaria;2. Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, bl. 26, Acad. G. Bonchev Str., Sofia 1113, Bulgaria;3. Institute of Mineralogy and Crystallography, Bulgarian Academy of Sciences, bl. 107, Acad. G. Bonchev Str., Sofia 1113, Bulgaria;4. A.V. Bogatsky Physical-Chemical Institute NAS of Ukraine, Department of Molecular Structure and Chemoinformatics, Odessa, Ukraine;5. Odessa National Polytechnic University, Department of Theoretical Foundation of Chemistry, Odessa, Ukraine;1. National Center for Genetic Engineering and Biotechnology (BIOTEC), 113 Thailand Science Park, Phaholyothin Road, Klong Luang, Pathumthani 12120, Thailand;2. School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan 430074, China;1. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation;2. National University of Science and Technology ‘MISIS’, 119049 Moscow, Russian Federation;3. Kazan National Research Technological University, 420015 Kazan, Russian Federation;1. Laboratory of Organic Chemistry, Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece;2. GlaxoSmithKline, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, USA;1. School of Mechanical Engineering and Automation, Northeastern University, Shenyang 110819, China;2. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;3. Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China |
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| Abstract: | 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. |
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| Keywords: | Coxsackieviruses QSAR Synthesis Nitrobenzonitriles MDL-860 Anti-enteroviral |
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