Results and discussion
The data on the compounds used as references are reported in Table S1
and Table S2, Supporting Information. The data on the designed
rasagiline derivatives are provided in Table S3, and their estimated
properties in Table S4.
Three central matters were addressed in this investigation:
- building the candidate molecules,
- sampling the search space in a suitable maner, and
- assessing their potential for the intended purpose.
Following the CADMA-Chem protocol, above-explained; -OH,
-NH2, -SH and -COOH functional groups were inserted in
sites R1 to R4 of R, RIand RII, This led to 361 rasagiline derivatives. and are
considered as the first two rasagiline derivatives, 48 compounds have
only one functional group insertion (all possible species within the
used scheme), 288 compounds have two functional groups substituted using
any possible combination, and 23 have three added functional groups. The
latter were built from the most promising bi-functionalized species.
ADME properties, toxicity values, and synthetic accessibility (Table S4)
are used in the selection score (SS), as previously
described140-142. The higher the value of
SS (Table S5) the more probable that a rasagiline
derivative presents a drug-like behavior. Equations on how
SS has been constructed considering ADME (absorption,
distribution, metabolism, excretion) properties, toxicity (T), and
synthetic accessibility (SA) can be found in Appendix S1.
Figure 1 presents the selection score (SS) of
rasagiline derivatives designed in this work. The values of individual
properties used to assess SS are presented in Table
S4, while the reference values to compare with are those reported in
Tables S1 and S2. In general, the molecules with higher
SS values are likely to have lower toxicity, improved
synthetic accessibility, and enhanced ADME properties. Based on this
criterion, sixteen rasagiline derivatives (Scheme 3) were chosen for the
next stage, i.e., to determine their potential as antioxidants based on
electronic structure calculations. Additionally, even though
1-(R)-aminoindan does not present a selection score value high enough to
belong to the subset group, it has been included for comparison purposes
on its own subfamily of derivatives.