Discovery and SAR studies of antiviral 4-aminopiperidine derivatives active against SARS-CoV-2
Year: 2025
Type: article
Abstract: Two related families of 4-aminopiperidine compounds active against SARS-CoV-2 in the micromolar range were discovered by screening the CSIC Chemical library. A medicinal chemistry programme was completed to optimize these series. Seventy-four derivatives of the early hits were synthesized which allowed to develop SAR studies and identify new hit compounds with low micromolar in vitro antiviral activity (EC 90 < 2 μM) and improved selectivity indexes in A594-hACE2 cells (from 13- to >28). Compounds which were active against two coronaviruses (SARS-CoV-2 and HCoV-229E) were less effective against the unrelated vesicular stomatitis virus (VSV), suggesting certain selectivity for coronaviruses. Several hit compounds, which are cationic amphiphilic compounds with p K a values mostly >7.6 and > 9, were shown to induce phospholipidosis in A594-hACE2 cells. This suggests that the limited capacity of these molecules to prevent efficient viral propagation, as compared with Remdesivir, is possibly related to a mode of action that involves phospholipid metabolism.
Authors: Sergio Algar, Paula Bueno, Hristo Anatoliev-Dimitrov, Jessy Medina, Valentina Trifero, Victoria Castro, Urtzi Garaigorta, Pablo Gastaminza, Christophe Dardonville
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,650
Awards: G1165171717, G1175115578, G131539442, G1622782223, G210041235, G2261858694, G2262748287, G2551911579, G2601397997, G300979063, G3403529256, G34346518, G3480869486, G3681454997, G4042783231, European Virus Archive GLOBAL, G410571670, G425668148, G4334763888, G451917667, G4584195851, G488842982, G5080475149, G5195188938, G5539308778, G5967599077, G6122222817, G6213874696, G6326031618, G7084143925, G8046220519, G929308097
OpenAlex ID: W4417410490