Tick-borne flavivirus reproduction inhibitors based on isoxazole core linked with adamantane
Vasilenko D. A., Dueva E. V., Kozlovskaya L. I., Zefirov N. A., Grishin Y. K., Butov G. M., Palyulin V. A., Kuznetsova T. S., Karganova G. G., Zefirova O. N., Osolodkin D. I., Averina E. B.
Bioorganic Chemistry
Vol.87, P. 629-637
Опубликовано: 2019
Тип ресурса: Статья
DOI:10.1016/j.bioorg.2019.03.028
Аннотация:
Infections caused by flaviviruses pose a huge threat for public health all over the world. The search for therapeutically relevant compounds targeting tick-borne flaviviruses requires the exploration of novel chemotypes. In the present work a large series of novel polyfunctionalized isoxazole derivatives bearing substituents with various steric and electronic effects was obtained by our unique versatile synthetic procedure and their antiviral activity against tick-borne encephalitis, Omsk hemorrhagic fever, and Powassan viruses was studied in vitro. The majority of studied isoxazoles showed activity in low micromolar range. No appreciable cytotoxicity was observed for tested compounds. The lead compounds, 5-aminoisoxazole derivatives containing adamantyl moiety, exhibited strong antiviral activity and excellent therapeutic index. © 2019 Elsevier Inc.
Ключевые слова:
Adamantane derivatives; Aminoisoxazoles; Flavivirus; Omsk hemorrhagic fever virus; Powassan virus; Tick-borne encephalitis virus
1 adamantyl 5 aminoisoxazole 3 carboxylate; 1 adamantylmethyl 5 amino 4 (2 phenylethyl)isoxazole 3 carboxylate; 1 adamantylmethyl 5 amino 4 methylisoxazole 3 carboxylate; 2 (1 adamantyl)ethyl 5 aminoisoxazole 3 carboxylate; 2 (1 adamantyloxy)ethyl 5 aminoisoxazole 3 carboxylate; 2 adamantyl 5 aminoisoxazole 3 carboxylate; 3 (acetylamino) 5,7 dimethyl 1 adamantyl 5 aminoisoxazole 3 carboxylate; 3 (i propoxycarbonyl) 1 adamantyl 5 aminoisoxazole 3 carboxylate; 3 (methoxycarbonyl) 1 adamantyl 5 aminoisoxazole 3 carboxylate; 3,5 dimethyl 1 adamantyl 5 aminoisoxazole 3 carboxylate; 4 (1 adamantyl)benzyl 5 aminoisoxazole 3 carboxylate; 7 (methoxycarbonyl)bicyclo[3.3.1]non 3 yl 5 aminoisoxazole; adamantane derivative; antivirus agent; isoxazole derivative; unclassified drug; animal cell; antiviral activity; Article; blood brain barrier; carbon nuclear magnetic resonance; CC50; controlled study; cytotoxicity; EC50; elemental analysis; embryo; in vitro study; lipophilicity; mass spectrometry; m
Язык текста: Английский
ISSN: 1090-2120
Vasilenko D. A.
Dueva E. V.
Kozlovskaya L. I. Lyubov` Igorevna 1984-
Zefirov N. A.
Grishin Y. K.
Butov G. M.
Palyulin V. A.
Kuznetsova T. S.
Karganova G. G. Galina Grigoryevna 1956-
Zefirova O. N.
Osolodkin D. I. Dmitrij Ivanovich 1985-
Averina E. B.
Василенко Д. А.
Дуева Е. В.
Козловская Л. И. Любовь Игоревна 1984-
Зефиров Н. А.
Гришин Y. К.
Бутов Г. М.
Палюлин В. А.
Кузнецова Т. С.
Карганова Г. Г. Галина Григорьевна 1956-
Зефирова О. Н.
Осолодкин Д. И. Дмитрий Иванович 1985-
Аверина Е. Б.
Tick-borne flavivirus reproduction inhibitors based on isoxazole core linked with adamantane
Текст визуальный непосредственный
Bioorganic Chemistry
Academic Press
Vol.87 P. 629-637
2019
Статья
Adamantane derivatives Aminoisoxazoles Flavivirus Omsk hemorrhagic fever virus Powassan virus Tick-borne encephalitis virus
1 adamantyl 5 aminoisoxazole 3 carboxylate 1 adamantylmethyl 5 amino 4 (2 phenylethyl)isoxazole 3 carboxylate 1 adamantylmethyl 5 amino 4 methylisoxazole 3 carboxylate 2 (1 adamantyl)ethyl 5 aminoisoxazole 3 carboxylate 2 (1 adamantyloxy)ethyl 5 aminoisoxazole 3 carboxylate 2 adamantyl 5 aminoisoxazole 3 carboxylate 3 (acetylamino) 5,7 dimethyl 1 adamantyl 5 aminoisoxazole 3 carboxylate 3 (i propoxycarbonyl) 1 adamantyl 5 aminoisoxazole 3 carboxylate 3 (methoxycarbonyl) 1 adamantyl 5 aminoisoxazole 3 carboxylate 3,5 dimethyl 1 adamantyl 5 aminoisoxazole 3 carboxylate 4 (1 adamantyl)benzyl 5 aminoisoxazole 3 carboxylate 7 (methoxycarbonyl)bicyclo[3.3.1]non 3 yl 5 aminoisoxazole adamantane derivative antivirus agent isoxazole derivative unclassified drug animal cell antiviral activity Article blood brain barrier carbon nuclear magnetic resonance CC50 controlled study cytotoxicity EC50 elemental analysis embryo in vitro study lipophilicity mass spectrometry
Infections caused by flaviviruses pose a huge threat for public health all over the world. The search for therapeutically relevant compounds targeting tick-borne flaviviruses requires the exploration of novel chemotypes. In the present work a large series of novel polyfunctionalized isoxazole derivatives bearing substituents with various steric and electronic effects was obtained by our unique versatile synthetic procedure and their antiviral activity against tick-borne encephalitis, Omsk hemorrhagic fever, and Powassan viruses was studied in vitro. The majority of studied isoxazoles showed activity in low micromolar range. No appreciable cytotoxicity was observed for tested compounds. The lead compounds, 5-aminoisoxazole derivatives containing adamantyl moiety, exhibited strong antiviral activity and excellent therapeutic index. © 2019 Elsevier Inc.