Background: Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals,
as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the
fungi Metarhizium spp., we previously identified tyrosine betaine as a major constituent.
Methods: Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for
the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to
in vitro NEP inhibition assays and to molecular modeling studies.
Results: In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate
inhibitory activities (IC50 ranging from 170.0 to 52.9 µM). However, they enclose structural features required
to hinder passive blood brain barrier permeation (BBB).
Conclusions: Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the
low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is
associated to an increment in the Aβ levels and, accordingly, with a higher risk for the onset of Alzheimer's disease.