Synthesis, biochemistry, and in silico investigations of isatin-based hydrazone derivatives as monoamine oxidase inhibitors

다국어 초록 (Multilingual Abstract)

Ten isatin-based hydrazone derivatives were synthesized using two subseries,
IA
(isatin + acetophenone) and
IB
(isatin + benzaldehyde), and evaluated for their monoamine oxidases (MAOs) inhibitory activity. All the compounds showed stronger MAO-A inhibition than MAO-B, and the
IB
series showed more effective MAO-A inhibitory activity than
IA
series. Compound
IB4
most potently inhibited MAO-A (half maximal inhibitory concentration IC
50
 = 0.015 µM), followed by
IB3
(IC
50
 = 0.019 µM). On the contrary, compound
IB3
showed the highest MAO-B inhibition (IC
50
 = 0.068 µM), followed by
IB4
(IC
50
 = 1.87 µM). Compound
IB3
and
IB4
had low selectivity indices of 3.68 and 8.50, respectively. Structurally, the methyl group of
IA
series decreased the inhibition of both MAO-A and MAO-B. Among them,
IB3
and
IB4
(4-Cl and 4-Br in B-ring, respectively) showed higher MAO-A and MAO-B inhibition than the other substitutions. Inhibition constant K
i
values of
IB3
and
IB4
for MAO-A were 0.0088 and 0.0063 µM, respectively, and those for MAO-B were 0.048 and 0.060 µM, respectively.
IB3
and
IB4
were competitive, reversible inhibitors of MAO-A and MAO-B. Molecular docking analysis predicted that
IB3
and
IB4
formed stable hydrogen bonds between Asn181 and the NH atom of isatin in the ligand-protein complex. Dynamic analysis revealed that
IB3
and
IB4
are stable with both MAO isoforms. These observations suggest
IB3
and
IB4
are potent and reversible MAO-A and MAO-B inhibitors and both compounds can be used as therapeutic agents for neurological disorders.

다국어 초록 (Multilingual Abstract)

Ten isatin-based hydrazone derivatives were synthesized using two subseries, IA (isatin + acetophenone) and IB (isatin + benzaldehyde), and evaluated for their monoamine oxidases (MAOs) inhibitory activity. All the compounds showed stronger MAO-A inhibition than MAO-B, and the IB series showed more effective MAO-A inhibitory activity than IA series. Compound IB4 most potently inhibited MAO-A (half maximal inhibitory concentration IC50 = 0.015 μM), followed by IB3 (IC50 = 0.019 μM). On the contrary, compound IB3 showed the highest MAO-B inhibition (IC50 = 0.068 μM), followed by IB4 (IC50 = 1.87 μM). Compound IB3 and IB4 had low selectivity indices of 3.68 and 8.50, respectively. Structurally, the methyl group of IA series decreased the inhibition of both MAO-A and MAO-B.
Among them, IB3 and IB4 (4-Cl and 4-Br in B-ring, respectively) showed higher MAO-A and MAO-B inhibition than the other substitutions. Inhibition constant Ki values of IB3 and IB4 for MAO-A were 0.0088 and 0.0063 μM, respectively, and those for MAO-B were 0.048 and 0.060 μM, respectively. IB3 and IB4 were competitive, reversible inhibitors of MAO-A and MAO-B. Molecular docking analysis predicted that IB3 and IB4 formed stable hydrogen bonds between Asn181 and the NH atom of isatin in the ligand-protein complex. Dynamic analysis revealed that IB3 and IB4 are stable with both MAO isoforms. These observations suggest IB3 and IB4 are potent and reversible MAO-A and MAO-B inhibitors and both compounds can be used as therapeutic agents for neurological disorders.