Design, synthesis, biological evaluation and docking studies of sulfonyl isatin derivatives as monoamine oxidase and caspase-3 inhibitors

Abstract

The aim of this study was to design novel multifunctional neuroprotective agents that would slow down or halt neurodegeneration through inhibition of MAO-A, MAO-B and caspase-3. We focused on pharmacophoric groups of known MAO-inhibitors including selegiline (propargylamine moiety) and safinamide (fluorobenzyl moiety), and isatin sulfonamide caspase-3 inhibitors. The synthesised compounds consisted of the isatin nucleus conjugated to a fluorophenylsulfonyl moiety at position 5 and on selected compounds a propargylamine moiety was introduced at the Nposition of isatin. All the compounds showed promising MAO-A inhibitory activity (IC 50 : 4 -22 µM). The compounds without the propargylamine moiety showed better MAO-B inhibition (IC 50 : 5 -8 µM) and caspase-3 inhibition (IC 50 : 25 -29 µM). The fluorophenylsulfonyl moiety in the synthesized compounds was significant for their multifunctional activity. In general the active compounds showed similar or improved inhibitory activities when compared to the reference compounds isatin (MAO-A and -B) and Z-VAD-FMK (caspase-3). Possible binding orientations of selected isatin analogues within the active site cavities of MAO-A, -B and caspase-3 are proposed and in silico ADMET studies were also done. N-[(3-Fluorophenyl)methyl]-N -methyl-2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonamide (4) and N-[(4fluorophenyl)methyl]-N-methyl-2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonamide (5) showed the best multifunctional neuroprotective potential and can be considered as new lead compounds for the development of alternative treatment options for neurodegenerative disorders such as AD, PD and HD.

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

“…Notably, intepirdine exhibited no glioprotective properties. 11 Similarly, although neuroprotective activity of selegiline was established in several in vitro models [45][46][47] , this irreversible MAO-B inhibitor did not reduce gliotoxicity induced by 6-OHDA in both cell-based assays ( Fig. 5A and 5B).…”

Synthesis, in vitro enzyme activity and molecular docking studies of new benzylamine-sulfonamide derivatives as selective MAO-B inhibitors

“…In our recent study 2 , we reported a new benzothiazole-benzylamine hybrid compound, 2-((5-chlorobenzothiazol-2-yl)thio)- N -(4-fluorophenyl)- N -(3-nitrobenzyl)acetamide ( BB-4h ), as shown in Figure 1 , with significant IC 50 (2.95 ± 0.09 µM) against MAO-B. Moreover, sulphonamides and various heterocyclic ring systems have been identified as inhibitors of MAO in previous studies 3 , 16–19 . Therefore, we considered the compound ( BB-4h ) as a lead compound, and we performed some modifications, such as removing nitro and fluoro groups, introducing a sulphonamide group, and changing heterocyclic rings in order to improve biological activity.…”

An Update of Synthetic Approaches and Structure‐Activity Relationships of Various Classes of Human MAO‐B Inhibitors

“…They carried out an extensive work on the designing of five different categories of isatin scaffold based derivatives as MAO‐B inhibitors and synthesized many of them as well (Wang et al ., 2017). One of the derivative with 3,4‐dichlorobenzyloxy ( 37 ) moiety at the 5 position of isatin possessed excellent potency with IC 50 of 0.003 μM [144,145] …”