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:
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.