Dimerization of highly pyramidalized 3,4,8,9-tetramethyltetracyclo[4.4.0.03,9.04,8]dec-1(6)-ene to a hydrocarbon featuring four cyclohexane rings in boat conformation

The synthesis, chemical trapping, and dimerization of a highly pyramidalized alkene is reported. Its dimer is a unique nonacycle featuring three planar cyclobutane rings, four cyclopentane rings, and four cyclohexane rings in boat conformations. The X-ray diffraction analysis showed a H-H distance between the flagpole hydrogen atoms of 1.999 and a separation of 2.619 between the two flagpole carbon atoms. The three cyclobutane rings of the dimer were thermally stabl

New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode

Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.02,10.03,7.09,11]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.02,5.03,11.04,9.06,17.012,16]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant

New polycyclic amines with biological activity

[cat] La grip presenta un greu problema arreu del món, com les pandèmies del segle XX han demostrat. S’han pres algunes mesures per lluitar-hi que han realment disminuït els efectes devastadors de la malaltia, com son la hospitalització moderna, la vacunació i les noves medicines. Tot i així, l’amenaça d’un virus recombinant mutant que pugui afectar a milions de persones i la recentment descoberta resistència d’algunes soques del virus als tractaments actuals, han provocat que la necessitat per a noves maneres de lluitar contra la grip A sigui urgent. En la present Tesi, hem pres amantadina com a model, un medicament antiviral actualment en desús degut a l’aparició de soques resistents, que té com a diana un canal de protons del virus anomenat M2. Així doncs, hem sintetitzat i avaluat diverses amines policícliques com a potencials blocadors del canal salvatge M2 i mutants resistents a amantadine, com el V27A, també. Hem tingut èxit en l’obtenció de potents inhibidors del canal salvatge i del V27A i lo més destacable és que alguns han mostrat una activitat dual en ambos canals M2. Cap remarcar que, entre els compostos preparats,una guanidina policíclica va presentar l’activitat més alta mai enregistrada contra el mutant V27A. Seguint amb les molècules policícliques però des d’un punt de vista més teòric, el monomer, dimer i dihidrodimer de un alqué altament piramidalitzat van ser sintetitzats i completament caracteritzats. Cal subratllar que, el dimer posseïa quatre ciclohexans en conformació bot congelat i mostrava interaccions entre els hidrògens flagpole que eren rellevants per als químics orgànics teòrics[eng] Influenza is a major health problem worldwide, as the periodic pandemics of the 20th century have highlighted. Some countermeasures have been developed and have indeed diminish the devastating effects of the disease, such as modern health care, vaccination and novel medicines. Yet, the threat of a recombinant mutant virus that could affect millions of people and the recently discovered resistance of some virus strains to the current available treatments, render the need for new ways of fighting influenza A virus urgent. In the present dissertation we have taken amantadine as a model, an antiviral drug in disuse at the moment due to the appearance of resistant strains, that targets a viral proton channel named M2. Thus, we have synthesized and evaluated several polycyclic amines as potential wild-type M2 channel blockers and amantadine-resistant mutants, like V27A, as well. We have succeeded in the obtention of highly potent wild-type and V27A inhibitors and most remarkable, some of them exhibited a dual activity on both M2 channels. Noteworthy, among the prepared compounds, a polycyclic guanidine presented the higher activity ever recorded against the V27A mutant. Again working with polycyclic molecules but from a more theoretical point of view, the monomer, dimer and dihydrodimer of a highly strained pyramidalized alkene were synthesized and fully characterized. Importantly, the dimer featured four cyclohexanes in a frozen boat conformation and possessed hydrogen flagpole interactions that were relevant to theoretical organic chemists

Inhibitors of the M2 channel of influenza A virus

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/32392Influenza is a highly contagious, major respiratory tract disease affecting millions of people each year. At present, two classes of antivirals are available: the neuraminidase inhibitors and the M2 proton channel blockers amantadine and rimantadine. However, rapid emergence of M2 blockers resistance makes imperative the development of new anti-influenza drugs. In the last few years several groups have synthesized and evaluated several analogs of amantadine. While several of them are active against wild-type M2 channel only a few are able to inhibit the mutant ion channels that lead to amantadine-resistance

Azapropellanes with anti-influenza a virus activity

The synthesis of several [4,4,3], [4,3,3], and [3,3,3]azapropellanes is reported. Several of the novel amines displayed low-micromolar activities against an amantadine-resistant H1N1 strain, but they did not show activity against an amantadine-sensitive H3N2 strain. None of the tested compounds inhibit the influenza A/M2 proton channel function. Most of the compounds did not show cytotoxicity for MDCK cells.status: publishe

Inhibitors of the M2 channel of influenza A virus

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/32392Influenza is a highly contagious, major respiratory tract disease affecting millions of people each year. At present, two classes of antivirals are available: the neuraminidase inhibitors and the M2 proton channel blockers amantadine and rimantadine. However, rapid emergence of M2 blockers resistance makes imperative the development of new anti-influenza drugs. In the last few years several groups have synthesized and evaluated several analogs of amantadine. While several of them are active against wild-type M2 channel only a few are able to inhibit the mutant ion channels that lead to amantadine-resistance

New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode

Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.02,10.03,7.09,11]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.02,5.03,11.04,9.06,17.012,16]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant