Recent updates on structural insights of MAO-B inhibitors: a review on target-based approach

Abstract

Parkinson's disease is a neurodegenerative disorder characterized by slow movement, tremors, and stiffness caused due to loss of dopaminergic neurons caused in the brain's substantia nigra. The concentration of dopamine is decreased in the brain. Parkinson's disease may be happened because of various genetic and environmental factors. Parkinson's disease is related to the irregular expression of the monoamine oxidase (MAO) enzyme, precisely type B, which causes the oxidative deamination of biogenic amines such as dopamine. MAO-B inhibitors, available currently in the market, carry various adverse effects such as dizziness, nausea, vomiting, lightheadedness, fainting, etc. So, there is an urgent need to develop new MAO-B inhibitors with minimum side effects. In this review, we have included recently studied compounds (2018 onwards). Agrawal et al. reported MAO-B inhibitors with IC₅₀ 0.0051 µM and showed good binding affinity. Enriquez et al. reported a compound with IC₅₀ 144 nM and bind with some critical amino acid residue Tyr60, Ile198, and Ile199. This article also describes the structure-activity relationship of the compounds and clinical trial studies of related derivatives. These compounds may be used as lead compounds to develop potent compounds as MAO-B inhibitors.

Keywords: Brain; Clinical trial; Dopamine; MAO-B inhibitors; Parkinson’s disease; Structure–activity relationship.

Fig. 1

Normal neurons v/s neurons in Parkinson’s disease

Fig. 2

Approved drugs to treat Parkinson’s disease

Fig. 3

Mechanism of action of Drugs which are used in Parkinson’s disease. COMT catechol-O-methyl transferase, DA dopamine, DDC dopa-decarboxylase, DOPAC 3,4-dihydroxyphenylacetic acid, HVA homovanillic acid, L-DOPA levodopa, MAO-B monoamine oxidase B, 3-MT 3-methoxytyramine, 3-O-MD 3-O-methyldopa, DAT dopamine transporter

Fig. 4

4-(benzyloxy)phenyl derivatives as MAO-B inhibitors

Fig. 5

Prenylated chalcone derivatives as MAO-B inhibitors

Fig. 6

Isoxazole carbohydrazide derivatives as MAO-B inhibitors

Fig. 7

Oxygenated chalcone derivatives as MAO-B inhibitors

Fig. 8

3-thiophenylcoumarins derivatives as MAO-B inhibitors

Fig. 9

Coumarin-pyridazine derivatives as MAO-B inhibitors

Fig. 10

Benzylamine-sulphonamide derivatives as MAO-B inhibitors

Fig. 11

Methylthiosemicarbazone derivatives as MAO-B inhibitors

Fig. 12

1-(3-(4-tert-butylphenoxy)propyl)piperidine derivatives as MAO-B inhibitors

Fig. 13

Pyrazolo[1,5-a]qunoxalin-4-ones derivatives as MAO-B inhibitors

Fig. 14

Pyridoxine-resveratrol derivatives as MAO-B inhibitors

Fig. 15

Thiosemicarbazide derivatives as MAO-B inhibitors

Fig. 16

The 2,3-dihydro coumarin derivatives as MAO-B inhibitors

Fig. 17

Pyridazinone/dithiocarbamate derivatives as MAO-B inhibitors

Fig. 18

Biphenylpiperazine derivatives as MAO-B inhibitors

Fig. 19

1,3,4-oxadiazole derivatives as MAO-B inhibitors

Fig. 20

Pyridazinone derivatives as MAO-B inhibitors

Fig. 21

Safinamide derivatives as MAO-B inhibitors

Fig. 22

Dimethoxy-halogenated chalcone derivatives as MAO-B inhibitors

Fig. 23

Pyridazinone derivatives as MAO-B inhibitors