Table 1.
Examples of Multi-Target-Directed Ligands with Origin on Natural Products and Semi Synthetic Analogs
| Compound | AChE Inhibitor | Tau Hyperphos-Phorylation Inhibitor |
β-amyloid Anti-Aggregation, Clearance, or Secretion | Antioxidant | Other Activities | Clinical Status (Phase) |
References |
|---|---|---|---|---|---|---|---|
| Alkaloids | |||||||
| Physostigmine | ♦ | ♦nicotinic receptor agonist | [265] | ||||
| Phenserine | ♦ | ♦ | ♦ | ♦neurotrophic ukinase modulator uNMDA receptor modulator | I/III | [266] [267] [268] | |
| Galantamine | ♦ | ♦nicotinic receptor allosteric modulator uanti-apoptotic | IV | [134] [269] | |||
| Huperzines A, B | ♦ | ♦NMDA receptor modulator uneuroprotective uanti-apoptotic | II | [270] [271] | |||
| Berberine | ♦ | ♦ | ♦ | ♦ IMAO uanti-neuroinflammatory ucholesterol regulator ♦ insulin regulator | [272] [273] | ||
| Epiberberine | ♦ | ♦ | ♦ | [274] | |||
| Coptisine | ♦neurotrophic ♦ IMAO-A | [274] | |||||
| Groenlandicine | ♦ | ♦ | ♦ | ♦ | [274] [275] | ||
| Jatrorrhizine | ♦ | ♦ | [274] | ||||
| Manzamine | ♦ | ♦anti-neuroinflammatory ukinase modulator | [276] | ||||
| Harmine, Harmaline | ♦ | ♦ | ♦ | ♦ increase dopamine release uIMAOs uNMDA receptor modulators ukinase modulators | [277] [278] | ||
| (10-hydroxy)-Infractopicrin | ♦ | ♦ | [279] | ||||
| Trigonelline | ♦ | ♦neurotrophic umemory enhancement | [280] [281] | ||||
| Nantenine | ♦ | ♦ | ♦adrenergic α1 and serotonin 5-HT2A receptors antagonist | [282] | |||
| Crebanine | ♦ | ♦ α7-nACh receptor modulator | [283] | ||||
| Nicotine | ♦ | ♦ | ♦nicotinic receptor agonist ♦ neuroprotective ♦ anti-apoptotic | [271] | |||
| Caffeine | ♦adenosine A2 receptor antagonist uIMAO-B | [284] [285] [286] | |||||
| Alkaloids | |||||||
| Vincamine | ♦ brain circulation modulator ♦ voltage Na+ channel modulator | [271] | |||||
| Cyclobuxidine F derivatives |
♦ | ♦ | [287] | ||||
| Polyphenols | |||||||
| Luteolin | ♦ | ♦ | ♦ | ♦ | ♦kinase modulator umitochondrial protector | [288] [289] [290] | |
| Myricetin | ♦ | ♦ | ♦anti-neuroinflammatory uNMDA receptor modulator uBACE-1 inhibitor | [291] [292] [293] | |||
| Plant derived Coumarins: Decursinol, Mesuagenin |
♦ | ♦ | ♦ | ♦anti-neuroinflammatory uIMAOs | [294] [295] [296] | ||
| Ensaculin | ♦ | ♦serotonin 5-HT1A agonist ♦ NMDA receptor modulator (antag.) udopamine D2 receptor antagonist | II | [297] [298] | |||
| Epigallocatechin gallate | ♦ | ♦ | ♦BACE-1 inhibitor (?) uα-secretase inhibitor ukinase modulator uα-synuclein inhibitor umetal chelator uanti-inflammatory | II -III | [299] [300] [301] [302] [303] | ||
| Ferulic acid | ♦ | ♦ | ♦BACE-1 inhibitor uprotective against PSEN1 expression (transgenic mice) | [304] [305] [306] | |||
| Rosmarinic acid | ♦ | ♦ | ♦ | ♦ | ♦anti-apoptotic uneuroprotective ubinds to muscarinic M1, nicotinic, serotonin 5-HT1A, serotonin 5-HT2A and histamine H3 receptors | [291] [307] [293] [271] | |
| Nordihydroguaiaretic acid | ♦ | ♦ | [293] | ||||
| Curcumin | ♦ | ♦ | ♦ | ♦anti-inflammatory uBACE-1 inhibitor uα-secretase inhibitor utau dimerization inhibitor umetal chelator uneuroprotective ♦ NMDA receptor modulator (antag.) | II | [308] [309] [310] [311] [312] [313] | |
| Polyphenols | |||||||
| Resveratrol | ♦ | ♦ | ♦ | ♦ SIRT1-ROCK1 signaling pathway regulator uBACE-1 inhibitor uapoptosis modulator uanti-inflammatory | III (n) | [314] [310] [315] [316] [317] [318] | |
| Vitisin A, Heyncanol A | ♦ | ♦ | [319] | ||||
| Hopeahainol | ♦ | ♦ | ♦ | ♦neuroprotective | [320] [321] | ||
| Apocynin | ♦ | ♦anti-inflammatory uNADPH oxidase inhibitors | [225] | ||||
| Honokiol, Magnolol | ♦anti-apoptotic uneuroprotective | [322] | |||||
| Cannabinoids | |||||||
| Cannabidiol | ♦ | ♦neuroprotective usedative | [271] | ||||
| Terpenoids | |||||||
| Niloticane | ♦ | ♦ COX-1 inhibitor ♦ COX-2 inhibitor | [323] | ||||
| Timosaponin AIII & BII | ♦ (AIII) | u(BII) | u(BII) | ♦anti-inflammatory uBACE-1 inhibitor (BII) | [324] [325] | ||
| Withanolide | ♦ | ♦ | ♦ | ♦neurotrophic uBACE-1 inhibitor uα-secretase inhibitor uLDL receptor-related protein enhancer | [326] [327] [328] [329] | ||
| Asiatic acid | ♦ | ♦ | ♦ | ♦BACE-1 inhibitor uanti-apoptotic uanti-inflammatory uα-secretase inhibitor ukinase modulator | [330] [329] [331] | ||
| Sage monoterpenoids | ♦ | ♦ | ♦anti-inflammatory | [271] | |||
| Ginsenosides | ♦ | ♦ | ♦ | ♦neuroprotective ♦ NMDA receptor modulator (antag.) | [271] [275] | ||
| Diverse Compounds | |||||||
| Bryostatin | ♦ | ♦α-secretase inhibitor ukinase modulator | I-II | [332] | |||
| Epothilone | ♦ | ♦ microtubule stabilizer | [333] | ||||
| Diverse Compounds | |||||||
| Geldanamycin | ♦ | ♦ proteasome activator | [208] | ||||
| Rapamycin | ♦ | ♦immunosuppressant | [334] | ||||
| Zeatin | ♦ | ♦ | ♦neuroprotective | [335] [336] | |||
| Butylphtalide (NBP) | ♦ | ♦ | ♦ | ♦αAPPs increased release uanti-inflammatory ukinase modulator uanti-apoptotic | [337] | ||
| Minocycline | ♦ | ♦ | ♦ | ♦BACE-1 inhibitor uanti-apoptotic uanti-inflammatory uneurogenic | [338] [339] [340] [341] | ||
| Geniposide, Gardenoside | ♦ memory enhancement uanti-apoptotic uneurogenic | [342] [343] | |||||
| WIN-026 (KRWAR-026; INM-176) | ♦ | ♦ | ♦ | III | [344] [345] | ||