Indole-Based Compounds in the Development of Anti-Neurodegenerative Agents

Abstract

Neurodegeneration is a gradual decay process leading to the depletion of neurons in both the central and peripheral nervous systems, ultimately resulting in cognitive dysfunctions and the deterioration of brain functions, alongside a decline in motor skills and behavioral capabilities. Neurodegenerative disorders (NDs) impose a substantial socio-economic strain on society, aggravated by the advancing age of the world population and the absence of effective remedies, predicting a negative future. In this context, the urgency of discovering viable therapies is critical and, despite significant efforts by medicinal chemists in developing potential drug candidates and exploring various small molecules as therapeutics, regrettably, a truly effective treatment is yet to be found. Nitrogen heterocyclic compounds, and particularly those containing the indole nucleus, which has emerged as privileged scaffold, have attracted particular attention for a variety of pharmacological applications. This review analyzes the rational design strategy adopted by different research groups for the development of anti-neurodegenerative indole-based compounds which have the potential to modulate various molecular targets involved in NDs, with reference to the most recent advances between 2018 and 2023.

Keywords: indole nucleus; multifunctional compounds; neurodegeneration.

Figure 1

Chemical structures of drugs used for AD treatment.

Figure 2

Chemical structures of drugs used for PD treatment.

Figure 3

Chemical structure and biological activity of indole-based dual inhibitor of ChEs 1.

Figure 4

Chemical structures and biological activities of tryptophan-based selective BChE inhibitors 2–10.

Figure 5

SARs of tryptophan-based selective BChE inhibitors.

Figure 6

Chemical structures of indole-based sulfonamide derivatives 11, 11a–d and their biological activity and SARs.

Figure 7

General chemical structure of indole-based hydrazide-hydrazone derivatives 12, chemical structures of derivatives 12a,b and their main interaction in the binding sites of ChEs.

Figure 8

Chemical structure of protein aggregation inhibitor Ro-31-8220 (13).

Figure 9

(a): General chemical structure of indole-based selective MAO-B inhibitors of series 14, chemical structures and biological activities of compounds 14a and 14b; (b): SARs of indole-based selective MAO-B inhibitors of series 14.

Figure 10

(a): General chemical structure of IPP-based A_2AAR antagonists, chemical structures and biological activities of compounds 15–17; (b): SARs of IPP-based A_2AAR antagonists.

Figure 11

Chemical structure of PERK inhibitor 18 (GSK2606414).

Figure 12

(a): Chemical structures of indole-based AMPK activators 19–21; (b): SARs of indole-based AMPK activators.

Figure 13

Design and general chemical structure of indole-based 5-HT₆R antagonists of series 22, chemical structure and biological activity of compounds 22a.

Figure 14

Chemical structure of fascaplysin, general chemical structure of indole-based derivatives of series 23, chemical structures and biological activities of compounds 23a and 23b.

Figure 15

Chemical structures of cryptolepine (24) and 2-bromocryptolepine (25).

Figure 16

Chemical structures and biological activities of reserpine and ajmalicine.

Figure 17

Chemical structures and biological activities of indole-based derivatives 26 and 27a–d.

Figure 18

(a): General chemical structure of indole-based derivatives of series 28, chemical structure and biological activity of compound 28a; (b): SARs of indole-based derivatives of series 28.

Figure 19

Chemical structure of indole-3-carbinol 29.

Figure 20

Chemical structures of monomeric (30a, 30b) and dimeric (31a, 31b) 3-substituted 4,6-dimethoxyindoles-based thiosemicarbazones.

Figure 21

Chemical structures of indole-3-acetic acid (32), indole-3-propionic acid (33), indole-3-lactic acid (34), and indole-3-carboxyaldehyde (35).

Figure 22

Chemical structures of compounds 36 (NC009) and 37a (PIGA1138), general chemical structures of phenylindolylglyoxylamides (PIGAs) 37.

Figure 23

SARs of 1,2,3,4-tetrahydro-β-carboline hybrids of series 38, chemical structures and biological activities of compounds 38a and 38b.

Figure 24

General chemical structure and SARs of 1,2,3,4-tetrahydro-β-carbolines hybrids of series 39, chemical structures and biological activities of compounds 39a and 39b.

Figure 25

General chemical structure of indole-tacrine hybrids of series 40, chemical structure and biological activity of compound 40a.

Figure 26

General chemical structure of indole–spiropyrrolidine hybrids of series 41, chemical structures and biological activities of compound 41a and 41b.

Figure 27

General chemical structure of carbamate-tryptamine hybrids of series 42; chemical structure and biological activity of compound 42a.

Figure 28

General chemical structure and SARs of carbamate N-anthraniloyl tryptamine hybrids of series 43, chemical structure and biological activity of compound 43a.

Figure 29

General chemical structure and SARs of carbamate N-salicyloyl tryptamine hybrids of series 44, chemical structure and biological activity of compound 44a.

Figure 30

General chemical structure and SARs of tryptamine–cinnamic acid hybrids of series 45; chemical structure and biological activity of compound 45a.

Figure 31

General chemical structure, SARs, and biological activities of tryptamine–ferulic acid hybrids 46a–c.

Figure 32

General chemical structure and SARs of indole–diosgenin hybrids of series 47, chemical structure of compound 47a.

Figure 33

Chemical structure of compound 48 (NP61), general chemical structure, SARs, and biological activity of indolyl-piperidine hybrids of series 49, chemical structure and biological activity of compound 49a.

Figure 34

(a): General chemical structures of stilbene mimic derivatives (50a–c and 50d–g), chemical structures and biological activities of compounds 50c and 50d–g; (b): General chemical structure of chalcone–donezepil-like derivatives (51a–e), chemical structures and biological activities of compounds 51b and 51e; (c): General chemical structures of hydrazone containing derivatives 52a–c and 52d–e, chemical structures and biological activities of compounds 52c and 52e.

Figure 35

(a) Chemical structures of donepezil and melatonin and design of the new hybrids of series 53; (b) Chemical structures and biological activities of compounds 53a and 53b.

Figure 36

Chemical structures and biological activities of 1-(phenylsulfonyl)-1H-indole hybrids 54–56.

Figure 37

Chemical structures and biological activities of pleiotropic compound 57, its metabolite 58 and its fumarate salt 59.

Figure 38

General chemical structure of indole–piperazine hybrids of series 60, chemical structure and biological activity of compound 60a.

Figure 39

General chemical structure of derivatives of series 61, chemical structure of ladostigil, chemical structure and biological activity of compound 61a.

Figure 40

(a): General chemical structure of indole–donepezil–chromone trihybrids of series 62; (b): Chemical structure, main interaction in the binding sites of ChEs and MAOs, and biological activity of compound 62a.

Figure 41

General chemical structure, main interactions in the binding sites of ChEs and MAOs of series 63–65 and chemical structures and biological activity of compounds 63a, 65a and 65b.