Effect of New Antiviral Agent Camphecin on Behavior of Mice.

We studied the effect of camphecin (1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol) on mouse behavior in the open-field test. Camphecin possesses antiviral activity and inhibits viral replication, but its influence on the nervous system is poorly studied. Single camphecin injection produced no significant changes in behavioral patterns. Chronic camphecin administration (5 times over 2 weeks) to mice of different strains had no significant influence on open field behavior (motor, exploratory activity, anxiety, emotional state and vegetative functions). The findings are discussed in the context of neutral influence of camphecin on animal behavior.

[Curare-Like Camphor Derivatives and Their Biological Activity].

The synthesis and evaluation of muscle relaxant activity of series of dimeric camphor derivatives are described. Compounds in which the quaternary nitrogen atoms are separated by aromatic chain exhibited the highest efficiency as muscle relaxant. It was shown the screening of a charged atom and counter-ion does not have a significant role on the activity of the studied agents.

Synthesis of non-symmetric N-benzylbispidinol amides and study of their inhibitory activity against the main protease of the SARS-CoV-2 virus.

Based on the data obtained by molecular modeling of the non-covalent interaction of non-symmetric N-benzylbispidin-9-ol amides with the active site of the main protease 3CLpro of the SARS-CoV-2 virus, a series of compounds was synthesized, and their inhibitory activity against 3CLpro was studied and compared with that of the known inhibitor ML188 (IC50 = 1.56±0.55 µmol L-1). It was found that only compound 1g containing the 1,4-dihydroindeno[1,2-c]pyrazole fragment showed moderate activity (IC50 = 100±5.7µmol L-1) and was characterized by the highest calculated binding energy among the studied bispidine derivatives according to molecular docking data.

Synthesis of N-heterocyclic amides based on (+)-camphoric acid and study of their antiviral activity and pharmacokinetics.

Efficient conditions for the synthesis of nitrogen-containing heterocyclic derivatives of (1R,3S)(+)-camphoric acid were selected. A series of heterocyclic compounds based on (+)-camphoric acid bearing pharmacophoric fragments was synthesized using the developed methodology. The compounds were tested for their antiviral activity against SARS-CoV-2 and H1N1 influenza viruses, and efficient inhibitors were identified that are of significant interest for further studies. The stability of the compounds and pharmaco-kinetics of the leader compound were studied when administered intragastrically and intramuscularly to mice at a dose of 200 mg kg-1 using the HPLC-MS/MS method.

Synthesis of conjugates of (aR,7S)-colchicine with monoterpenoids and investigation of their biological activity.

Conjugates of the natural alkaloid (aR,7S)-colchicine with bicyclic monoterpenoids and their derivatives were synthesized for the first time. Molecular docking of the synthesized agents in the active site of the main viral protease of the SARS-CoV-2 virus was carried out. The cytotoxic properties of the agents against different cell lines and the ability to inhibit the main viral protease 3CLPro were studied.

N-Heterocyclic borneol derivatives as inhibitors of Marburg virus glycoprotein-mediated VSIV pseudotype entry.

There is currently no approved antiviral therapy for treatment of Marburg virus disease (MVD). Although filovirus infection outbreaks are quite rare, the high mortality rates in such outbreaks make the development of anti-filoviral drugs an important goal of medical chemistry and virology. Here, we performed screening of a large library of natural derivatives for their virus entry inhibition activity using pseudotype systems. The bornyl ester derivatives containing saturated N-heterocycles exhibited the highest antiviral activity. It is supposed that compounds with specific inhibitory activity toward MarV-GP-dependent virus entry will inhibit the rVSIV-ΔG-MarV-GP pseudotype much more efficiently than the control rVSIV-ΔG-G pseudotype. At the same time, the compounds similarly inhibiting both pseudotypes will likely affect rVSIV capsid replication or the cellular mechanisms common to the entry of both viruses. Borneol itself is not active against both pseudotypes and is nontoxic, whereas its derivatives have varying toxicity and antiviral activity. Among low-toxic borneol derivatives, six compounds turned out to be relatively specific inhibitors of MarV-GP-mediated infection (SC > 10). Of them, compound 6 containing a methylpiperidine moiety exhibited the highest virus-specific activity. Notably, the virus-specific activity of this compound is twice as high as that of the reference.

Synthesis and in vitro study of novel borneol derivatives as potent inhibitors of the influenza A virus.

Herein, we present the design and synthesis of a series of novel heterocyclic derivatives of (-)-borneol and (-)-isoborneol as potent inhibitors of the influenza A virus. All compounds were tested for their toxicity against MDCK cells and for virus-inhibiting activity against the influenza virus A/Puerto Rico/8/34 (H1N1). Compounds 7, 16 and 26 containing a morpholine fragment exhibited the highest efficiency as agents inhibiting the replication of the influenza virus A(H1N1) with selectivity indices of 82, 45 and 65, correspondingly. Derivatives 9 (SI = 23) and 18 (SI = 25) containing a 1-methylpiperazine motif showed moderate antiviral activity. Structure-activity analysis of this new series of borneol derivatives revealed that a 1,7,7-trimethylbicyclo[2.2.1]heptan scaffold is required for the antiviral activity.

Broad range of inhibiting action of novel camphor-based compound with anti-hemagglutinin activity against influenza viruses in vitro and in vivo.

Influenza virus continues to remain one of the leading human respiratory pathogens causing significant morbidity and mortality around the globe. Due to short-term life cycle and high rate of mutations influenza virus is able to rapidly develop resistance to clinically available antivirals. This makes necessary the search and development of new drugs with different targets and mechanisms of activity. Here we report anti-influenza activity of camphor derivative 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol (camphecene). In in vitro experiments it inhibited influenza viruses A(H1, H1pdm09, H3 and H5 subtypes) and B with EC50's lying in micromolar range. Due to low cytotoxicity it resulted in high selectivity indices (74-661 depending on the virus). This effect did not depend on susceptibility or resistance of the viruses to adamantane derivatives amantadine and rimantadine. The compound appeared the most effective when added at the early stages of viral life cycle (0-2h p.i.). In direct hemagglutinin inhibition tests camphecene was shown to decrease the activity of HA's of influenza viruses A and B. The activity of camphecene was further confirmed in experiments with influenza virus-infected mice, in which, being used orally by therapeutic schedule (once a day, days 1-5 p.i.) it decreased specific mortality of animals infected with both influenza A and B viruses (highest indices of protection 66.7% and 88.9%, respectively). Taken together, these results are encouraging for further development of camphecene-based drug(s) and for exploration of camphor derivatives as highly prospective group of potential antivirals.