Table 2.
Examples of Designed Multi-Target-Directed Ligands
| Compound | Merged Pharmacophores | Additional Activities | References |
|---|---|---|---|
| Dual Acetylcholinesterase and β-amyloid inhibitors (Drugs interacting with Acetyl and/or Butyrylcholinesterases binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) or only to PAS) | |||
| Xanthostigmine | Rivastigmine - xanthone hybrid | [4] | |
| AP2238 | Coumarin - dibenzylamine hybrid | [346] | |
| IQM-622 | Tacrine - 8-hydroxyquinoline hybrid | [347] | |
| Indanone-tacrines | Tacrine - donepezil hybrid | [348] | |
| Pyrano[3,2-c]quinoline tacrines | Tacrine - pyrano[3,2.c]quinoline hybrid | [349] | |
| NP-61 (NP-0361) (Structure not disclosed) | Probable tacrine - indole propionamide hybrid | [350, 351, 352] |
|
| Bis(7)-tacrines | Bis-tacrines | BACE1 inhibitors | [353, 354] |
| Tacrine multimers | [355] | ||
| Huprine-tacrines | Tacrine - huprine hybrids | BACE1 inhibitors | [356, 357] |
| Donepezil-huprine derivatives | Huprine - Donepezil hybrids | BACE1 inhibitors | [358] |
| Indanone-dibenzylamines | AP2238 - Donepezil hybrids | [359] | |
| N-benzylpiperidine purine derivatives | Donepezil analogues | [360] | |
| 9-substituted berberines | [361] | ||
| 9-substituted berberines containing tiazole | [362] | ||
| Isaindigotone derivatives | [363] | ||
| Oxoisoaporphines | [364, 365] | ||
| Oxoisoaporphine-tacrines | Tacrine - oxoisoaporphine hybrids | [366] | |
| Multialkoxybenzene-tacrines | Tacrine – multialkoxybenzene hybrids | [367] | |
| 2,4-disubstituted pyrimidines | [368, 369] | ||
| Piperidinium-type and 1,4-dihydropiridine derivatives | [167, 166] | ||
| Piperidine linked derivatives | [370] | ||
| Glutamic acid linked derivatives | Neuroprotective against free radicals | [371] | |
| Benzofuran-based hybrids | [372] | ||
| Benzophenone linked derivatives | [373] | ||
| Bis-nor-meptazinols | [168] | ||
| Dual Acetylcholinesterase inhibitors and antioxidants | |||
| Lipocrine | 6-Chlorotacrine - α-lipoic acid hybrid | β-amyloid inhibitor | [374] |
| Memoquin and derivatives | Caproctamine - 1,4-benzoquinone hybrid | β-amyloid inhibitor Muscarinic M2 receptor antagonist BACE1 inhibitor |
[375, 376, 377, 378, 379] |
| Benzoquinone curcumin hybrid Benzoquinone SKF64346 hybrid |
[380] | ||
| Tacrine melatonin hybrids | [381, 382] | ||
| Dual Acetylcholinesterase inhibitors and antioxidants | |||
| Tacrine ferulic acid hybrids | [383] | ||
| Cystamine-tacrine dimer | [384] | ||
| N-acylaminophenothiazines | [385, 386] | ||
| Dual Acetylcholinesterase inhibitors and metal chelators | |||
| HLA20A | Carbamoylated 8-hydroxyquinolines | [387, 388] | |
| Indanone derivatives | [389] | ||
| Tacrine-8-hydroxyquinoline hybrids PBT2 | Neuroprotective Antioxidant |
[347, 390] | |
| Dual Acetylcholinesterase and β-secretase (BACE1) inhibitors | |||
| Memoquin | Caproctamine - 1,4-benzoquinone hybrid | β-amyloid inhibitor Muscarinic M2 receptor antagonist Antioxidant | [375, 376, 377, 378, 379] |
| Coumarin derivatives | AP2238 derivatives | [391] | |
| Bis(7)-tacrine | Tacrine homodimers | Calcium channel blocker | [353, 392, 393, 354] |
| Tacrine-chromene hybrids | β-amyloid inhibitor | [394] | |
| Huprine-tacrines | Tacrine - huprine hybrids | [356, 357] | |
| Donepezil-huprine derivatives | Huprine - Donepezil hybrids | [358] | |
| N-benzylpiperidines with BACE1 inhibitory moieties | Donepezil - BACE1 inhibitor hybrid | [395] | |
| Quinoxaline based hybrids | Histamine H3 receptor antagonist | [396] | |
| Dual Acetylcholinesterase and monoaminooxidase B (MAO-B) inhibitors | |||
| Ladostigil | Rasagiline - rivastigmine hybrid | Neuroprotective metal chelator β-amyloid modulator |
[397] [398] [141] |
| Propargylamino -benzylpiperidine hybrids | MAOB pharmacophore – CAS AChE pharmacophore hybrid | [399] | |
| Dual Acetylcholinesterase inhibitors and acetylcholine receptor ligands | |||
| Caproctamine | Muscarinic M2 receptor antagonist | [400] | |
| Huprine X (3-Chloro-9-ethyl) | Tacrine – huperizine A hybrids | Muscarinic M1 and M2 receptors agonist | [401] [402] |
| Bis(12)hupyridone | Huperizine A dimer | α7 nicotinic receptor modulator | [403] |
| Ro-46-5934 | Neostigmine derivative | Muscarinic M2 receptor antagonist | [404] |
| Dual Acetylcholinesterase inhibitors and histamine H3 receptor antagonists | |||
| FUB833 | Tacrine-piperidine hybrids | Histamine N-methyltransferase inhibitor (HNMT) | [405] [406] |
| Dual Acetylcholinesterase inhibitors and histamine H3 receptor antagonists | |||
| Quinoxaline derivatives | Quinoxaline-piperidine hybrids | BACE1 inhibitor | [396] |
| Tacrine – piperidine hybrids | [406] | ||
| Dual Acetylcholinesterase inhibitors and N-methyl-D-aspartic acid (NMDA) receptor channel blockers | |||
| Carbacrine | Tacrine – carvedilol hybrid | β-amyloid inhibitor Antioxidant |
[407] |
| Bis(7)-tacrine | Tacrine homodimers | BACE1 inhibitor | [408] [392] [353] [393] [354] |
| Bivalent β-carbolines | β-carboline homodimers | [409] | |
| Dual Acetylcholinesterase inhibitors and serotonin 5-HT6 antagonists | |||
| Latrepirdine (dimebon) | IMAO-B NMDA receptor inhibitor |
[410, 411, 412, 413] | |
| Dual Acetylcholinesterase inhibitors and serotonin 5-HT3 receptor antagonists | |||
| Tacrine – Arylpiperazine hybrids | [414] | ||
| Dual Acetylcholinesterase inhibitors and cannabinoid receptor antagonists | |||
| Diaryl-pyrazolines and diaryl-imidazolines | Tacrine – CB1 antagonist scaffolds | [415] | |
| Arylbenzofuran-based derivatives | [372] | ||
| Dual Acetylcholinesterase and serotonin transporter inhibitors | |||
| RS-1259 (BCG-20-1259) | Rivastigmine – fluoxetine hybrid | [174] | |
| Dual Acetylcholinesterase and σ 1 receptor inhibitors | |||
| SP-04 | [416] | ||
| Dual Acetylcholinesterase inhibitors and calcium channel blockers | |||
| Bis(7)-tacrine | Tacrine homodimers | BACE1 inhibitor NMDA channel blocker |
[392, 353, 393, 408, 354] |
| Tacripyrines: ITH-4012 | Tacrine – dihydropyridine hybrid | [417] | |
| Tacripyrines: ITH-12118 | Tacrine – dihydropyridine hybrid | [418, 419, 420] | |
| Tacripyrines | [421] | ||
| Dihydropyrimidoquinolinediones | [422] | ||
| Dual Acetylcholinesterase inhibitors and platelet activating factor (PAF) antagonists | |||
| PMS-777 | [423] | ||
| PMS-1339 | [424] | ||
| Dual monoaminooxidase B (MAOB) inhibitors and iron-chelating agents | |||
| VAR 10200 (HLA-20A) | 8-hydroxyquinoline – propargylamino pharmacophore hybrid | [387, 388] | |
| VAR 10300 (M-30D) | 8-hydroxyquinoline – propargylamino pharmacophore hybrid | [425, 426, 427, 398] | |
| Dual monoaminooxidase B (MAOB) inhibitors and adenosine A2 receptor antagonists | |||
| Istradefylline (KW-6002) | Caffeine derivative | [428, 429, 430] | |
| Dual monoaminooxidase B (MAOB) inhibitors and peroxisome proliferator-activated receptor gamma (PPARg) modulators | |||
| Pioglitazone, Rosiglitazone | [431, 432, 433] | ||
| Dual histamine H3 receptor and presynaptic acetylcholine muscarinic M2 receptor antagonists | |||
| 4,4’-bispiperidines | [434] | ||
| Dual NMDA receptor channel and L-type calcium channel blockers | |||
| NGP1-01 (polycyclic cage amines) | Neuroprotective Reduces endothelial iron accumulation |
[435, 436, 437] | |
| Dual NMDA receptor channel blocker and serotonin 5-HT3 antagonist | |||
| Memantine | Tau protein phosphorylation inhibition | [438, 439] | |
| Dual phosphodiesterase-4 inhibitor and α-secretase activator | |||
| Etazolate | GABAA receptor modulator | [440] | |
| Dual β-secretase (BACE1) inhibitor and metal chelator | |||
| 1,3-Diphenylurea derivatives | [441] | ||
| Tryptoline and tryptamine triazole derivatives | Anti-amyloid aggregation | [442, 443] | |
| Dual γ-secretase and peroxisome proliferator-activated receptor gamma (PPARg) modulators | |||
| 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid and derivatives | [176, 444] | ||
| Dual glycogen synthase kinase-3β (GSK-3) and phosphodiesterase-7 (PDE7) inhibitor | |||
| VP1.15 (2,3-diphenyl-1,2,4-thiadiazole derivative) | [445] | ||
| Dual protein kinase C (PCK) activators and histone deacetylase (HDAC) inhibitors | |||
| Hexahydrobenzo[e]1,4diazocin-3-ones | [446] | ||
| Dual β amyloid oligomerization inhibitors and free radical scavengers | |||
| Phenolic bis-styrylbenzenes | [447] | ||
| Curcumin - cholesterol bivalent ligands | [448] | ||
| Metal chelators which also target β amyloid | |||
| EDTA-2-phenylbenzothiazol-derivatives | [449] | ||
| Benzimidazol-derivatives | [450] | ||
| Dual metal chelators and antioxidants | |||
| Deferiprone – BHT hybrids | [451] | ||
| Glucopyranosyl conjugates of deferiprone and of tetrahydrosalen | Pro-drugs | [452, 453] | |