The evaluation of isatin analogues as inhibitors of monoamine oxidase

The small molecule, isatin, is a well‐known reversible inhibitor of the monoamine oxidase (MAO) enzymes with IC₅₀ values of 12.3 and 4.86 μM for MAO‐A and MAO‐B, respectively. While the interaction of isatin with MAO‐B has been characterized, only a few studies have explored structure–activity relationships (SARs) of MAO inhibition by isatin analogues. The current study therefore evaluated a series of 14 isatin analogues as in vitro inhibitors of human MAO‐A and MAO‐B. The results indicated good potency MAO inhibition for some isatin analogues with five compounds exhibiting IC₅₀ < 1 μM. 4‐Chloroisatin (1b) and 5‐bromoisatin (1f) were the most potent inhibitors with IC₅₀ values of 0.812 and 0.125 μM for MAO‐A and MAO‐B, respectively. These compounds were also found to be competitive inhibitors of MAO‐A and MAO‐B with K_i values of 0.311 and 0.033 μM, respectively. Among the SARs, it was interesting to note that C5‐substitution was particularly beneficial for MAO‐B inhibition. MAO inhibitors are established drugs for the treatment of neuropsychiatric and neurodegenerative disorders, while potential new roles in prostate cancer and cardiovascular disease are being investigated.