Synthesis and bioactivity of phenyl substituted furan and oxazole carboxylic acid derivatives as potential PDE4 inhibitors

PDE4 Inhibitors: Profiling Hits through the Multitude of Structural Classes

“…The IC50 values recorded on PDE4 for 36-38 are in the micromolar range, i.e., 9.6, 2.8 and 1.4 μM, respectively [78]. Through docking studies, it has been possible to define relevant features of the binding mode of this class of inhibitors, such as: (1) the presence of an amide function linked to the heterocycle (in 37 and 38) can strengthen the binding with PDE4 by forming a hydrogen bond with Gln443 in the hydrophobic region and, therefore, enhance the activity; (2) the thiazolidine ring contributes to the formation of hydrophobic interactions with Phe446 in the active site; (3) the oxygen of the p-methoxyphenyl group fills the ion pocket and may contribute to increase the inhibitory activity by interacting with the metal ions (i.e., Zn 2+ and Mg 2+ ) [78]. Due to their moderate activity, these new inhibitors need further development in terms of structural optimization, enabling to explore possibilities of clinical efficacy, if any.…”

“…In 2020, compounds 36, 37 (based on a 2,5-disubstituted furan) and 38 (based on 2,4-disubstitued oxazole) (Figure 11) were reported as PDE4 inhibitors generated through a lead optimization research program focusing on SCH 351591 7 (i.e., a quinoline-based agent; Figure 3) [54]. The IC50 values recorded on PDE4 for 36-38 are in the micromolar range, i.e., 9.6, 2.8 and 1.4 μM, respectively [78]. Through docking studies, it has been possible to define relevant features of the binding mode of this class of inhibitors, such as: (1) the presence of an amide function linked to the heterocycle (in 37 and 38) can strengthen the binding with PDE4 by forming a hydrogen bond with Gln443 in the hydrophobic region and, therefore, enhance the activity; (2) the thiazolidine ring contributes to the formation of hydrophobic interactions with Phe446 in the active site; (3) the oxygen of the p-methoxyphenyl group fills the ion pocket and may contribute to increase the inhibitory activity by interacting with the metal ions (i.e., Zn 2+ and Mg 2+ ) [78].…”

“…(3) the oxygen of the p-methoxyphenyl group fills the ion pocket and may contribute to increase the inhibitory activity by interacting with the metal ions (i.e., Zn 2+ and Mg 2+ ) [78]. Due to their moderate activity, these new inhibitors need further development in terms of structural optimization, enabling to explore possibilities of clinical efficacy, if any.…”