Smallpox was eradicated >40 years ago but it is not a reason to forget forever about orthopoxviruses pathogenic to humans. Though in 1980 the decision of WHO to cease vaccination against smallpox had seemed logical, it led to the decrease of cross immunity against other infections caused by orthopoxviruses. As a result, in 2022 the multi-country monkeypox outbreak becomes a topic of great concern. In spite of existing FDA-approved drugs for the treatment of such diseases, the search for new small-molecule orthopoxvirus inhibitors continues. In the course of this search a series of novel 2-aryl-1-hydroxyimidazole derivatives containing ester or carboxamide moieties in position 5 of heterocycle has been synthesized and tested for activity against Vaccinia virus in Vero cell culture. Some of the compounds under consideration revealed a selectivity index higher than that of the reference drug Cidofovir. The highest selectivity index SI = 919 was exhibited by ethyl 1-hydroxy-4-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazole-5-carboxylate 1f. The most active compound also demonstrated inhibi-tory activity against the cowpox virus (SI = 20) and the ectromelia virus (SI = 46).

Изучена фармакокинетика субстанции нового противооспенного препарата НИОХ-14 (аналога разработанного в США соединения ST-246) у мышей после однократного перорального введения в дозе 50 мкг/г и перорального введения в течение 10 сут в дозах 50 и 5 мкг/г. Концентрацию активного метаболита (то есть ST-246), в который НИОХ-14 превращается в сыворотке крови и гомогенатах органов мышей, определяли методом LC-MS/MS (тандемной масс-спектрометрии — MS/MS и жидкостной хроматографии — LC). На основании фармакокинетических параметров была определена тканевая доступность субстанции НИОХ-14 для разных органов мыши, которая составила 100; 69,6; 20,3; 26,8 и 63,3 % для легких, печени, селезенки, головного мозга и почек, соответственно.

We compared absolute bioavailability of the chemical substance of the anti-smallpox preparation NIOCH-14 and chemical compound ST-246 active against orthopoxviruses after oral administration to mice in doses of 10 and 50 μg/g and intravenous administration to mice in a dose of 2 μg/g body weight. The absolute bioavailability of NIOCH-14 is comparable with the absolute bioavailability of ST-246.

A series of novel polycyclic N-amidoimides were synthesized by reacting 4-oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione with hydrazides of benzoic acids, arylaminoacetic acid, and oxalic acid. The most pronounced antiviral activities against Vaccinia virus were observed for 4-hydroxy-N-(3,5-dioxo-4-azatetracyclo[5.3.2.02, 6.08, 10]dodec-11-en-4-yl)-3-nitrobenzamide, N-(3,5-dioxo-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-en-4-yl)-N′-[(3-trifluoromethyl)phenyl]ethanediamide, and N-(2,6-dimethylphenyl)-N′-(3,5-dioxo-4-azatetracyclo-5.3.2.02,6,08,10]dodec-11-en-4-yl)ethanediamide.

series of novel polycyclic N -amidoimides were synthesized by reacting 4-oxatetracyclo[5.3.2.0 2,6 .0 8,10 ]dodec-11-ene-3,5-dione with hydrazides of benzoic acids, arylaminoacetic acid, and oxalic acid. The most pronounced antiviral activities against Vaccinia virus were observed for 4-hydroxy- N -(3,5-dioxo-4-azatetracyclo[5.3.2.0 2, 6 .0 8, 10 ]dodec-11-en-4-yl)-3-nitrobenzamide, N -(3,5-dioxo-4-azatetracyclo[5.3.2.0 2,6 .0 8,10 ]dodec-11-en-4-yl)- N′ -[(3-trifluoromethyl)phenyl]ethanediamide, and N -(2,6-dimethylphenyl)- N′ -(3,5-dioxo-4-azatetracyclo-5.3.2.0 2,6 ,0 8,10 ]dodec-11-en-4-yl)ethanediamide.

Синтезированы новые полициклические N-амидоимиды взаимодействием 4-оксатетрацикло[5.3.2.02,6.08,10]додец-11-ен-3,5-диона с гидразидами бензойных кислот, ариламиноуксусной кислоты и щавелевой кислоты. Наиболее выраженную противовирусную активность в отношении вируса осповакцины проявили 4-гидрокси-N-(3,5-диоксо-4-азатетрацикло[5.3.2.02,6.08,10]додец-11-ен-4-ил)-3-нитробензамид, N-(3,5-диоксо-4-азатетрацикло[5.3.2.02,6.08,10]додец-11-ен-4-ил)-N’-[(3-трифторметил)фенил]этандиамид и N-(2,6-диметилфенил)-N’-(3,5-диоксо-4-азатетрацикло-[5.3.2.02,6.08,10]додец-11-ен-4-ил)этандиамид.

Синтезированы новые полициклические N-амидоимиды взаимодействием 4-оксатетрацикло[5.3.2.02,6.08,10]додец-11-ен-3,5-диона с гидразидами бензойных кислот, ариламиноуксусной кислоты и щавелевой кислоты. Наиболее выраженную противовирусную активность в отношении вируса осповакцины проявили 4-гидрокси-N-(3,5-диоксо-4-азатетрацикло[5.3.2.02,6.08,10]додец-11-ен-4-ил)-3-нитробензамид, N-(3,5-диоксо-4-азатетрацикло[5.3.2.02,6.08,10]додец-11-ен-4-ил)-N’-[(3-трифторметил)фенил]этандиамид и N-(2,6-диметилфенил)-N’-(3,5-диоксо-4-азатетрацикло-[5.3.2.02,6.08,10]додец-11-ен-4-ил)этандиамид.

A series of new 1-aryl-3-{3,5-dioxo-4-azatetracyclo[5.3.2.0 2,6 .0 8,10 ]dodec-11-en-4-yl}ureas have been synthesized by reaction of 4-amino-4-azatetracyclo[5.3.2 2,6 .0 8,10 ]dodec-11-en-3,5-dione (II) with aryl isocyanates and phenyl isothiocyanate. The structures of obtained compounds have been confirmed by means of IR and 1 H NMR spectroscopy. Some of these compounds possess pronounced antiviral activity against smallpox vaccine virus. The maximum level of activity was observed for 3-{3,5-dioxo-4-azatetracyclo[5.3.2.0 2,6 .0 8,10 ]dodec-11-en-4-yl}-1-(4-methylphenyl)urea, 3-{3,5-dioxo-4-azatetracyclo -[5.3.2.0 2,6 .0 8,10 ]dodec-11-en-4-yl}-1-(3-fluorophenyl)urea hydrate, and 3-{3,5-dioxo-4-azatetracyclo [5.3.2.0 2,6 .0 8,10 ]dodec-11-en-4-yl}-1-(phenyl)thiourea.

Синтезированы новые производные 1-арил-3-{3,5-диоксо-4-азатетрацикло[5.3.2.02,6.08,10]-додец-11-ен-4-ил}мочевины и изучена их противовирусная активность в отношении вируса осповакцины. Выраженную активность показали 3-{3,5-диоксо-4-азатетрацикло- [5.3.2.02,6.08,10]додец-11-ен-4-ил}-1-(4-метилфенил)мочевина, гидрат 3-{3,5-диоксо-4-азатетрацикло-[5.3.2.02,6.08,10]додец-11-ен-4-ил}-1-(3-фторфенил)мочевины и 3-{3,5-диоксо-4-азатетрацикло[5.3.2.02,6.08,10]додец-11-ен-4-ил}-1-(фенил)тиомочевина.

A series of 1-aryl-3-(3,5-dioxo-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-en-4-yl)urea derivatives were synthesized and studied for antiviral activity against smallpox vaccine virus. 3-(3,5-Dioxo-4-azatetracyclo-[5.3.2.02,6.08,10]dodec-11-en-4-yl)-1-(4-methylphenyl)urea, 3-(3,5-dioxo-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-en-4-yl)-1-(3-fluorophenyl)urea hydrate, and 3-(3,5-dioxo-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-en-4-yl)-1-(phenyl)thiourea showed pronounced activity.

AIM:Study pharmacodynamic parameters of anti-viral effectiveness of a chemical compound NIOC-14 in experiments in mice infected with ectromelia virus (EV).MATERIALS AND METHODS:EV (K-1 strain) was obtained from the State Collection of Viral Infections and Rickettsioses Causative Agents of the State Scientific Centre of Virology and Biotechnology "Vector". Outbred ICR mice were intranasally infected with EV at a dose of 10 LD50 per animal (10 x 50% lethal doses/animal) and per orally received NIOC-14 or ST-246 as a positive control. Chemical compound NIOC-14 (7-[N'-(4-trifluoromethylbenzoyl)-hidrazincarbonyl]-tricyclo[3.2.2.0(2,4)]non-8-en-6-carbonic acid) was synthesized in Novosibirsk Institute of Organic Chemistry (NIOC). Anti-pox preparation ST-246, developed by SIGA Technologies Inc. (USA), was synthesized in NIOC using the technique described by the authors.RESULTS:50% effective doses against EV in vivo were shown not to differ significantly between the preparations NIOC-14 (3.59 μg/g mouse mass) and ST-246 (5.08 μg/g mouse mass). During determination of therapeutic window, administration of NIOC-14 to mice 1 day or 1 hour before EV infection, as well as 1, 2 and 4 days after EV infection and then for 9 days was found to ensure 100% animal survival. Administration of NIOC-14 as well as ST-246 resulted in the decrease relative to control of EV titers in lungs, nasal cavity, brains, liver, spleen, kidneys and pancreas.CONCLUSION:Anti-viral effectiveness of NIOC-14 against EV in vivo was thus comparable by all the studied pharmacodynamic parameters with anti-viral activity of anti-pox-virus preparation ST-246.

In the experiments using intranasal (i/n) infection of mice with the ectromelia virus (EV) in a dose 10 LD50/head (10 x 50% lethal doselhead) or with the monkaypox virus (MPXV) in a dose 10 ID50/head (10 x 50% infective dose/ head) it was demonstrated that the antiviral efficiency of chemical compounds - the condensed derivatives of pyrrolidin-2,5-dion, as well as their predecessors and the nearest analogues, synthesized in Novosibirsk Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences (NIOCH SB RAS) was observed. As a positive control we used the antipoxvirus chemical preparation ST-246 available from SIGA Technologies Inc. (USA), synthesized in NIOCH SB RAS by the technique suggested by the authors. It was demonstrated that the compound NIOCH-14 (7-[N'-(4-Trifluoromethylbenzoil)-hydrazidecarbonil]-tricyclo[3.2.2.02,4]non-8-en-6-carbonic acid) possessed comparable with ST-246 antiviral activity concerning EV and MPXV on all indicators used. Therefore, at infection of mice with EV (strain K-1) and peroral administration of NIOCH-14 and ST-246 in a dose 50 mkg/g of mouse weight (12-14 g) within 10 days the survival rate and average life expectancy of mice authentically exceeded the control levels. EV titers in lungs through 6 days after infection in the same groups were lower than in the control. In addition to that, after 7 days of infection of mice with MPXV (strain V79-1-005) and daily peroral administration of NIOCH-14 and ST-246 in a dose 60 mkg/g of mouse weight (9-11 g) authentic decrease in a part of infected animals and MPXV titers in lungs was observed.

Interaction of 3-aryl-1,2,4-triazin-5(4H)-ones with indole and its methyl derivative in the presence of N-substituted amino acids activated with dicyclohexylcarbodiimide or ethyl chloroformate led to the formation of 1-acyl-6-indolyl-3-phenyl-1,6-dihydro-1,2,4-triazin-5(4H)-ones. The cytotoxic and antiviral actions of the 12 resulting compounds were studied using vaccinia virus.

New pyrazoles; 1,2,4-triazoles; β- and γ-glycols; amidrazones; and amines of the adamantane series have been synthesized. Their activity with respect to smallpox vaccine virus has been studied. High anti-smallpox activity was observed for ethyl-3-(1-adamantyl)-5-(4-methylphenyl)-1H-pyrazole-4-carboxylate (VI) and 1,4-bis(1-adamantyl)-1,4-butanediol (XII).

The antiviral activity of 2-substituted and 2,6-disubstituted quinoline-4-carboxylic acids and their derivatives has been studied against orthopoxviruses on Vero and MK-2 cell cultures. High activity has been found for 2-(1,1′-biphenyl-4-yl)quinoline-4-carboxylic acid.

AIM:To study efficacy of Ingavirin in vitro and in vivo against strains of pandemic influenza virus A(H1N1/09)v and influenza virus A(H5N1) and A(H3N2).MATERIALS AND METHODS:Changes in hemagglutinating and cytopathic activity of influenza virus strains A(H1N1/09)v, A(H5N1) and A(H3N2) during their incubation in the presence of Ingavirin or Remantadin on MDCK cell culture were studied. In mice infected by influenza strains A(H1N1/09)v and A(H3N2) and orally treated with Ingavirin, Tamiflu or Remantadin virus titers in lungs were measured.RESULTS:There was decrease in hemagglutinating and cytopathic activity of influenza virus strains after incubation with Ingavirin in vitro. Ingavirin effectively inhibited reproduction of influenza virus strains A(H1N1/09)v and A(H3N2) in lungs of infected mice. Titers of these strains in lung homogenates decreased when Ingavirin was orally administered to infected mice.CONCLUSION:Strains of influenza virus A(H1N1/09)v were susceptible to Ingavirin and Tamiflu but resistant to Remantadin. Reference strains of A(H5N1) and A(H3N2) were susceptible to Ingavirin, Tamiflu and Remantadin.

Изучена противовирусная активность некоторых 2- и 2,6-дизамещенных 4-хинолинкарбоновых кислот и их производных в отношении ортопоксвирусов на культуре клеток Vero и MK-2. Высокая противовирусная активность выявлена для 2-(1,1'-бифенил-4-ил)-4-хинолинкарбоновой кислоты.

Ingavirin was shown to be efficient in inhibition of the pandemic influenza virus strains A/California/04/2009 (H1N1)v, A/California/07/2009 (H1N1)v, A/Moscow/225/2009 (H1N1)v and A/Moscow/226/2009 (H1N1)v. as well as the influenza virus strain A/Aichi/2/68 (H3N2) in the lungs of the infected mice. After oral administration of Ingavirin the titers of the influenza virus strains in the lung homogenates lowered.