Indole Alkaloids and Semisynthetic Indole Derivatives as Multifunctional Scaffolds Aiming the Inhibition of Enzymes Related to Neurodegenerative Diseases – A Focus on Psychotria L. Genus

Abstract

Indole alkaloids and synthetic indole derivatives are well known for their therapeutic importance. In fact, preclinical and clinical studies had already demonstrated several pharmacological activities for these compounds. Here, we overview the multifunctional potential of these molecules for the inhibition of enzymes related to neurodegenerative disease: acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidases A and B (MAO-A and MAO-B). A focus will be given on Psychotria L. genus, considering its reported central effects. Finally, three Psychotria alkaloids, namely desoxycordiofoline (61), bahienoside A (64) and bufotenine (65), along with the synthetic indole derivatives (5S)- 5-(1H-indol-3-ylmethyl)imidazolidine-2,4-dione (66), 5-(1H-indol-3-ylmethyl)-2-thioxoimidazolin-4-one (67), 5-(1Hindol- 3-ylmethyl)-3-methyl-2-thioxoimidazolidin-4-one (68), and methyl 2-(aminoN-(2-(4-methylcyclohex-3-enyl)propan- 2-yl)methanethioamino)-3-(1H-indol-3-yl)propanoate (69), were evaluated in vitro regarding their interactions with AChE, BChE, MAO-A and MAO-B. It was observed that 66 and 68 were able to inhibit MAO-A activity with IC50 value of 8.23 and 0.07 μM. Molecular docking calculations were performed in order to understand the interactions between both ligands (66 and 68) and MAO-A. It was observed that the indole scaffold of both compounds bind into the MAO-A active site in the same orientation, establishing van der Waals contacts with lipophilic amino acids. Additionally, the hydantoin ring of 66 is able to interact by hydrogen bonds with two conserved water molecules in the MAO-A active site, while the methyl-thiohydantoin ring of 68 is within hydrogen bond distance from the hydrogen atom attached to the (N-5) of FAD cofactor. Taking together, our findings demonstrate that the indolyl-hydantoin and indolylmethyl-thiohydantoin rings might consists of good scaffolds for the development of new MAO-A inhibitors possessing neuroprotective properties.

Kororamides, Convolutamines, and Indole Derivatives as Possible Tau and Dual-Specificity Kinase Inhibitors for Alzheimer’s Disease: A Computational Study

“…Indole alkaloids are marine natural products that show specific biological activities, such as anti-inflammatory and serotonin antagonism [ 41 ]. Moreover, the therapeutic importance of this kind of indole scaffolds is well known, as demonstrated by clinical and preclinical studies showing pharmacological activities over neurodegenerative diseases, such as AD [ 41 , 50 ]. Within the group of compounds containing the indole moiety are meridianins, for instance.…”

Assessments of iodoindoles and abamectin as inducers of methuosis in pinewood nematode, Bursaphelenchus xylophilus

“…Recently, the potential therapeutic effects of halogenated indoles, indole alkaloids, and semisynthetic indole derivatives have attracted considerable research interest 35–37 . For example, halogen substituted indoles have been shown to eliminate Escherichia coli and Staphylococcus aureus persister cells 37 .…”

Role of Plant Derived Alkaloids and Their Mechanism in Neurodegenerative Disorders

“…AChE existence majorly contributes in the pathogenesis of AD which is more often associated with the formation of neurofibrillary tangles and Aβ plaques 147 . Harmine has been reported to target the pathogenesis of AD because of its efficacy to potentially penetrate the BBB, the parenchyma cells of brain as well as constrain the activity of AChE 193 which is the key enzyme involved in the metabolism and breakdown of a neurotransmitter known as ACh 194 . An experimental study suggested that harmine at the dose of 20 mg/kg could efficiently augment spatial cognition as well as amend compromised memory via cholinergic neurotransmission improvement 193 .…”

“…Harmine has been reported to target the pathogenesis of AD because of its efficacy to potentially penetrate the BBB, the parenchyma cells of brain as well as constrain the activity of AChE 193 which is the key enzyme involved in the metabolism and breakdown of a neurotransmitter known as ACh 194 . An experimental study suggested that harmine at the dose of 20 mg/kg could efficiently augment spatial cognition as well as amend compromised memory via cholinergic neurotransmission improvement 193 . Another pathological feature in AD is the aggregation and accumulation of tau proteins as well as the overexpression of brain proliferative agent named as tyrosine-phosphorylation regulated kinase (DYRK1A) 195 .…”