Conclusions

A systematic rational search for newly designed rasagiline derivatives is presented. It was performed using the CADMA-Chem computer-assisted protocol. A total of 361 derivatives were generated by adding, or modifying, functional groups in the rasagiline molecular framework.
A selection score (SS) was built to sample the search space, simultaneously considering ADME (absorption, distribution, metabolism, excretion) properties, toxicity, and manufacturability (i.e., synthetic accessibility). It was used to characterize the whole set of designed derivatives and allowed the selection of a reduced subset of ten compounds expected to be the most promising, regarding drug-like behavior.
For this subset, several reactivity indices were estimated, as well as their pKa values. These indices account for electron and H donor capabilities. Thus, they are expected to reflect free radical scavenging behavior through single electron transfer (SET) and formal hydrogen transfer (HAT) mechanisms. According to the gathered data, three rasagiline derivatives were identified as the most likely candidates to act as chemical antioxidants (by directly scavenging free radicals). They are: dR-113, dRI-49 and dRII-22 in that order. All of them are predicted to be better for that purpose than rasagiline itself. In addition, since the made structural modifications are mild, they are expected to retain the neuroprotection of the parent molecule. The findings from this work are expected to motivate further investigations on these molecules, using both theoretical and experimental approaches.