《N-Benzyl-4,4-disubstituted piperidines as a potent class of influenza H1N1 virus inhibitors showing a novel mechanism of hemagglutinin fusion peptide interaction》 was published in European Journal of Medicinal Chemistry in 2020. These research results belong to de Castro, Sonia; Ginex, Tiziana; Vanderlinden, Evelien; Laporte, Manon; Stevaert, Annelies; Cumella, Jose; Gago, Federico; Camarasa, Maria Jose; Luque, F. Javier; Naesens, Lieve; Velazquez, Sonsoles. Safety of 1-Methyl-4-piperidone The article mentions the following:
Herein, N-benzyl-4,4,-disubstituted piperidines I (R1 = H, Me, cyclohexyl, Ph, PhCH2, PhCH2CH2; R2 = t-Bu, cyclohexyl, PhCH2, 4-MeC6H4SO2CH2; R3 = H, Me, cyclopropyl, PhCH2, 4-FC6H4CH2, etc.; R4 = Me, MeO2CCH2, PhCH2, etc.; R5 = H, Boc, Cbz) have been designed, synthesized and identified as influenza A virus fusion inhibitors with specific activity against the H1N1 subtype. A diverse library of piperidines I was synthesized using the highly efficient one-step Ugi four-component reaction. Mechanistic studies, including resistance selection with the most active compound I [R1 = R2 = PhCH2; R3 = 4-FC6H4CH2; R4 = MeO2CCH2; R5 = Boc; (II)], demonstrated that it acts as an inhibitor of the low pH-induced HA-mediated membrane fusion process. Computational studies identified an as yet unrecognized fusion inhibitor binding site, which is located at the bottom of the HA2 stem in close proximity to the fusion peptide. A direct π-stacking interaction between the N-benzylpiperidine moiety of the compound II and F9HA2 of the fusion peptide, reinforced with an addnl. π-stacking interaction with Y119HA2, and a salt bridge of the protonated piperidine nitrogen with E120HA2, were identified as important interactions to mediate ligand binding. This site rationalized the observed SAR and provided a structural explanation for the H1N1-specific activity of our inhibitors. Furthermore, the HA1-S326V mutation resulted in resistance to II was close to the proposed new binding pocket. These findings point to the N-benzyl-4,4-disubstituted piperidines as an interesting class of influenza virus inhibitors and represent the first example of fusion peptide binders with great potential for anti-influenza drug development. In the experimental materials used by the author, we found 1-Methyl-4-piperidone(cas: 1445-73-4Safety of 1-Methyl-4-piperidone)
1-Methyl-4-piperidone(cas: 1445-73-4) is a member of piperidine. Piperidine is a key saturated heterocyclic scaffold found in several of the top-selling small molecule pharmaceuticals and natural alkaloids, with a diverse range of biological activities. Hence, continuous efforts have been made to develop convenient methods to prepare piperidine derivatives.Safety of 1-Methyl-4-piperidone
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem