ABSTRACT
A new class of compounds featuring a camphor moiety has been discovered that exhibits potent inhibitory activity against influenza A(H1N1)pdm09 and A(H5N1) viruses. The synthesized compounds were characterized by spectroscopic analysis; in addition the structures of compound 2 and 14 were elucidated by the X-ray diffraction technique. Structure-activity relationship studies have been conducted to identify the 1,7,7-trimethylbicyclo[2.2.1]heptanes2-ylidene group as the key functional group responsible for the observed antiviral activity. The most potent antiviral compound is imine 2 with therapeutic index more than 500.
Subject(s)
Antiviral Agents/pharmacology , Camphor/pharmacology , Drug Discovery , Imines/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Influenza A Virus, H5N1 Subtype/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Camphor/chemical synthesis , Camphor/chemistry , Dogs , Dose-Response Relationship, Drug , Imines/chemical synthesis , Imines/chemistry , Madin Darby Canine Kidney Cells , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Influenza is a continuing world-wide public health problem that causes significant morbidity and mortality during seasonal epidemics and sporadic pandemics. The purpose of the study was synthesis and investigation of antiviral activity of camphor-based symmetric diimines and diamines. A set of C2-symmetric nitrogen-containing camphor derivatives have been synthesized. The antiviral activity of these compounds was studied against rimantadine- and amantadine-resistant influenza virus A/California/7/09 (H1N1)pdm09 in MDCK cells. The highest efficacy in virus inhibiting was shown for compounds 2a-e with cage moieties bound by aliphatic linkers. The therapeutic index (selectivity index) for 2b exceeded that for reference compounds amantadine, deitiforin and rimantadine almost 10-fold. As shown by structure-activity analysis, the length of the linker has a dramatic effect on the toxicity of compounds. Compound 2e with -C12H24- linker exhibited the lowest toxicity (CTD50=2216µM). Derivatives of camphor, therefore, can be considered as prospective antiinfluenza compounds active against influenza viruses resistant to adamantane-based drugs.
Subject(s)
Antiviral Agents/pharmacology , Camphor/chemistry , Imines/pharmacology , Influenza A virus/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dogs , Dose-Response Relationship, Drug , Imines/chemical synthesis , Imines/chemistry , Madin Darby Canine Kidney Cells , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
The synthesis and biological evaluation of a novel series of dimeric camphor derivatives are described. The resulting compounds were studied for their antiviral activity, cyto- and genotoxicity. Compounds 3a and 3d in which the quaternary nitrogen atoms are separated by the C5H10 and С9H18 aliphatic chain, exhibited the highest efficiency as an agent inhibiting the reproduction of the influenza virus A(H1N1)pdm09. The cytotoxicity data of compounds 3 and 4 revealed their moderate activity against malignant cell lines; compound 3f had the highest activity for the CEM-13 cells. These results show close agreement with the data of independent studies on toxicity of these compounds, in particular that the toxicity of compounds strongly depends on spacer length.
