Azapropellanes with Anti-Influenza A Virus Activity

Abstract

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. KEYWORDS: Amantadine, influenza, M2 channel, hemagglutinin, propellane H uman influenza A virus, a member of the Orthomyxoviridae, causes significant morbidity and mortality, particularly in infants, elderly people, and those suffering from previous pathology or immunodeficiency. 1 Its capacity to cause widespread epidemics is related to its fast droplet transmission and ability to escape from existing immunity.The life cycle of influenza viruses is well documented and most viral proteins are regarded as potential therapeutic targets. 2−6 However, presently available drugs for the treatment of influenza virus infections only comprise the M2 ion channel blockers amantadine (Amt) and rimantadine (Chart 1), 7,8 and the neuraminidase inhibitors oseltamivir, zanamivir, peramivir, and laninamivir. 5 Taking into account that most of the currently circulating influenza strains are resistant to the M2 ion channel blockers and as resistance to the neuraminidase inhibitors (in particular oseltamivir) is also rising, 9,10 novel antiinfluenza virus drugs, preferably with a novel mechanism of action, are urgently needed.The influenza virus enters its target cells by receptormediated endocytosis, which is followed by acid-induced fusion of the viral and endosomal membranes. This fusion event is mediated by a conformational change of the influenza hemagglutinin (HA) protein, triggered by the low pH in the endosomal lumen. 11 The endosomal acidic pH also activates the membrane-spanning A/M2 protein, which acts as a proton channel to conduct protons into the virion interior. The decrease in intravirion pH results in uncoating of the viral ribonucleoprotein, which is transferred, through the fusion pore, to the cytoplasm. 12 Since this endosomal escape of the virus critically depends on the activity of the M2 proton channel and the HA protein, dually acting agents which combine blockade of the M2 channel with an inhibitory effect on HA refolding, appear highly attractive. This dual approach could also, at least in theory, increase the barrier for selecting Amt resistance. 13 Optimized Amt analogues might be able to exert this dual pharmacological effect, provided that both the M2 and HA inhibition occur at similar and clinically relevant compound

Isocyanides as Influenza A Virus Subtype H5N1 Wild‐Type M2 Channel Inhibitors

“…According to the reported SAR data and the size of the M2 channel, drug activity is thus dependent on the size of the hydrophobic moiety and the length of the linker that connects the moiety with the amine. This conclusion is continuously confirmed by the recently reported active amines …”

“…This result can be explained by the size of the scaffold, as it has a perpendicular dimension of 4.0 Å and a horizontal length of 7.1 Å, which allows the molecule to fit in the channel in the perpendicular direction. For comparison, azapropellane amine 39 did not inhibit the A/M2 channel well, despite the fact that moderate activity against H1N1 was reported . Azapropellane amine 39 has respective dimensions of 4.9 and 5.8 Å in the horizontal and perpendicular directions, and the size of both sides are longer than 4.2 Å (the radius of M2 channel) (Figure ).…”

“…This conclusion is continuously confirmed by the recently reported active amines. [8,29] The channel size limitation was also demonstrated by compound 38;i ts M2 blockinga ctivity in TEVC experiments has been confirmed; [8] however, larger azapropellanes did not block the A/M2 proton channel even though the compounds exhibiteda ctivity against the H1N1 strain. [29] Thus, the M2 activity seems to be very sensitivet ot he size of the hydrophobic moiety.…”

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

“…Based on the chemical resemblance, we deemed interesting to assess if our 4,6-diamino-1,2-dihydrotriazines (1, 14 and 16) were also able to inhibit the A/ M2 proton channel expressed in Xenopus oocytes using the TEVC assay. At 100 mM, neither of the three compounds significantly inhibited the wild type or S31N mutant M2 channel [38], thus excluding M2 inhibition as the antiviral mechanism of action in virus-infected MDCK cells (data not shown).…”

Bridgehead vicinal diallylation of norbornene derivatives and extension to propellane derivatives via ring-closing metathesis

“…In this study, we have also revised the configuration of our earlier reported molecules containing allyl groups and oxa-bowl/propellane hybrids. Since non-flattened molecules are implicated in biological systems, our results would be useful in drug design [42]. …”