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.