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Review
. 2020 Aug 19;21(17):5965.
doi: 10.3390/ijms21175965.

Merged Tacrine-Based, Multitarget-Directed Acetylcholinesterase Inhibitors 2015-Present: Synthesis and Biological Activity

Todd J Eckroat  1 , Danielle L Manross  1 , Seth C Cowan  1
Affiliations
Review

Merged Tacrine-Based, Multitarget-Directed Acetylcholinesterase Inhibitors 2015-Present: Synthesis and Biological Activity

Todd J Eckroat et al. Int J Mol Sci. .

Abstract

Acetylcholinesterase is an important biochemical enzyme in that it controls acetylcholine-mediated neuronal transmission in the central nervous system, contains a unique structure with two binding sites connected by a gorge region, and it has historically been the main pharmacological target for treatment of Alzheimer's disease. Given the large projected increase in Alzheimer's disease cases in the coming decades and its complex, multifactorial nature, new drugs that target multiple aspects of the disease at once are needed. Tacrine, the first acetylcholinesterase inhibitor used clinically but withdrawn due to hepatotoxicity concerns, remains an important starting point in research for the development of multitarget-directed acetylcholinesterase inhibitors. This review highlights tacrine-based, multitarget-directed acetylcholinesterase inhibitors published in the literature since 2015 with a specific focus on merged compounds (i.e., compounds where tacrine and a second pharmacophore show significant overlap in structure). The synthesis of these compounds from readily available starting materials is discussed, along with acetylcholinesterase inhibition data, relative to tacrine, and structure activity relationships. Where applicable, molecular modeling, to elucidate key enzyme-inhibitor interactions, and secondary biological activity is highlighted. Of the numerous compounds identified, there is a subset with promising preliminary screening results, which should inspire further development and future research in this field.

Keywords: Alzheimer’s disease; Friedländer reaction; acetylcholinesterase; multitarget-directed ligand; pyranopyrazole; tacrine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Hydrolysis of acetylcholine (ACh) to choline and acetate catalyzed by acetylcholinesterase (AChE). (B) View of the hAChE (PDB:4EY4) active site with key amino acid residues color coded by region (reprinted from [3], with permission from Elsevier). (C) Surface representation of the hAChE (PDB:4EY4) active site looking down the gorge with regions color coded as in (B) (reprinted from [3], with permission from Elsevier).
Figure 2
Figure 2
Structures of clinically used Alzheimer’s disease (AD) drugs. Tacrine (discontinued), donepezil, galantamine, and rivastigmine are all AChEi. Memantine is an N-methyl-d-aspartate receptor (NMDAR) antagonist. The tricyclic rings of tacrine are labeled A–C for discussion purposes.
Figure 3
Figure 3
Tacrine-based multitarget-directed ligand (MTDLs) can be classified as “linked” or “merged” based on the degree of overlap of the pharmacophores (adapted with permission from [57], copyright (2005) American Chemical Society).
Scheme 1
Scheme 1
(A) Structure of pyranopyrazole tacrines 1a–z and 2a–ax [63,64,65,66,67]. (B) Synthesis of pyranopyrazole tacrines 1a–z. (C) Synthesis of pyranopyrazole tacrines 2a–ax. Reagents and conditions: (i) Ultrasonic irradiation, (S)-Pro, H2O/EtOH, rt, 10–35 min, 77–95%; (ii) cyclohexanone or cycloheptanone or tetrahydro-4H-thiopyran-4-one, AlCl3, DCE or DCM, Δ (12–24 h, 65–95%) or MWI (53–90%); (iii) DCE, Δ, 3–4 h, quant.; (iv) DABCO, EtOH, rt, 12 h, quant.
Figure 4
Figure 4
Molecular modeling of 2u in the substrate active site (CAS) of TcAChE (adapted from [66], with permission from Elsevier). The pyrazole ring forms key H-bonds with Glu199 and Tyr130 and π-π stacking with Trp84. The 4-fluorophenyl moiety forms an amide-π stacking interaction with Gly119.
Scheme 2
Scheme 2
(A) Structure of pyranopyranone tacrines 5a–o and 6a–l [68,69]. (B) Synthesis of pyranopyranone tacrines 5a–o. (C) Synthesis of pyranopyranone tacrines 6a–l. Reagents and conditions: (i) DABCO (rt, 12 h, quant.) or Et3N (Δ, 5 min, 63–77%), EtOH, rt; (ii) cyclohexanone, AlCl3, DCE or 1,4-dioxane, Δ, 2–18 h, 50–87%.
Figure 5
Figure 5
Molecular modeling of (R)-6d in the second distinct site (PAS) of hAChE (adapted from [69]). Important interactions include π-π stacking with Trp286 and Tyr341 and H-bonds of the primary hydroxyl group with Tyr72 and the tacrine-like amino group with Tyr124.
Scheme 3
Scheme 3
(A) Structure of pyranonaphthalene (9a–c, 10a,b), pyranoquinoline (10c–p), and pyranonaphthoquinone tacrines 11a–t [71,72,73,74]. (B) Synthesis of pyranonaphthalene (9a–c, 10a,b), pyranoquinoline (10c–p), and pyranonaphthoquinone tacrines 11a–t. Reagents and conditions: (i) 2-Naphthol, piperidine, EtOH, Δ, 12 h, 72%; (ii) cyclopentanone or cyclohexanone or cycloheptanone, AlCl3, DCE or 1,4-dioxane, Δ (2–24 h, 40–95%) or MWI (3 h, 9–70%); (iii) 1-naphthol or 8-hydroxyquinoline, piperidine, EtOH, Δ, 15 min–12 h, 47–93%; (iv) 2-hydroxy-1,4-naphthoquinone, piperidine, EtOH, Δ, 2–6 h, quant.
Scheme 4
Scheme 4
(A) Structure of other pyranotacrines 15a–ad and 16a–t [71,77,78,79]. (B) Synthesis of pyranotacrines 15a–ad. (C) Synthesis of pyranotacrines 16a–e. (D) Synthesis of sulfamoyl-containing pyranotacrines 16f–t. Reagents and conditions: (i) Ethyl benzoylacetate (R2 = CO2Et, R3 = Ph), piperidine, EtOH, Δ, 3 h, quant.; (ii) ethyl acetoacetate (R2 = CO2Et, R3 = Me) or acetylacetone (R2 = COMe, R3 = Me), piperidine, EtOH, rt, 12 h, 78–93%; (iii) cyclopentanone or cyclohexanone or cycloheptanone, AlCl3, DCE or toluene, Δ (3–24 h, 32–87%) or MWI (10 min, 70–83%); (iv) dimedone, piperidine, EtOH, rt, 12 h, 69–76%; (v) (a) SOCl2, MWI, 30 min, 88%; (b) hydroxybenzaldehyde derivative, pyridine, DCM, rt, 12 h, 85–93%; (vi) dimedone, K2CO3, EtOH, MWI, 6 min, 85–89%.
Scheme 5
Scheme 5
(A) Structure of pyridino- (19a–j), indolo- (20a–c), and quinoxalinotacrines 21 [80,81,82]. (B) Synthesis of pyridinotacrines 19a–j. (C) Synthesis of indolotacrines 20a–c. (D) Synthesis of quinoxalinotacrine 21. Reagents and conditions: (i) Piperidine, EtOH, rt; (ii) acetone or cyclohexanone or cycloheptanone, NH4OAc, AcOH, Δ; (iii) cyclohexanone or cycloheptanone, AlCl3, DCE, Δ (18 h, 72–95%) or MWI (2 h, 16–88%); (iv) TFAA, TEA, THF, rt, 12 h, 97–99%; (v) L-Pro or picolinic acid, K2CO3, CuI, DMSO/H2O, 60 °C (12 h, 48–90%) or MWI (12 h, 26%); (vi) (a) benzaldehyde, MeOH, rt, 12 h, 97%; (b) NaBH3CN, AcOH/MeOH, rt, 12 h, 75%; (vii) (a) TEA, DMF, rt, 1.5 h, 75%; (b) Na2S2O4, H2O/MeOH, 50 °C, 3 h, 87% [83].
Scheme 6
Scheme 6
(A) Structure of pyrrolo- (22a–i), pyrazolo- (22j–n), and furanotacrines 22o, as well as pyrazolophthalazine tacrines 23a–u [84,85]. (B) Synthesis of pyrrolo- (22a–i), pyrazolo- (22j–n), and furanotacrine 22o. (C) Synthesis of pyrazolophthalazine tacrines 23a–u. Reagents and conditions: (i) EtOH, rt, 30 min, >80%; (ii) X-CH2-R2 (where X = Cl or Br, Y = CN, CO2Et, or 4-Br-Bz) TEA, Δ, 15–30 min, 63–91%; (iii) cyclopentanone or cyclohexanone, AlCl3, DCE or DCM, Δ (8–24 h, 30–95%) or MWI (30–32 min, 45–87%); (iv) malononitrile, 10% KOH, EtOH, rt, 30 min, 80%; (v) TEA, EtOH, Δ, 2 h, 67%; (vi) NiCl2·6H2O, EtOH, Δ, 4 h.
Scheme 7
Scheme 7
(A) Structure of pyrazolotacrines 24a–d, 25a,b, 26a–e, and 27a,b [86]. (B) Synthesis of pyrazolotacrines 24a–d, 25a,b, 26a–e, and 27a,b. Reagents and conditions: (i) R-CHO, piperidine, EtOH, Δ, 4 h, 80–90%; (ii) R1-NCS, EtOH, Δ, 4–6 h, 83–89%; (iii) R2-COCH2Br, NaOAc, 1,4-dioxane, Δ, 4–6 h, 60–92%; (iv) ethyl bromoacetate, NaOAc, 1,4-dioxane, Δ, 4–6 h, 68–79%.
Figure 6
Figure 6
Molecular modeling of 27a (rose) and 27b (purple) with hAChE showing the interaction with the PAS (adapted from [86], with permission from Elsevier). Key interactions noted are the tricyclic core showing favorable hydrophobic interactions with Tyr341, Tyr337, Phe338, and Val294, the 4-chlorophenyl substituent showing hydrophobic interactions with Tyr341 and Trp286, the quinolinyl nitrogen showing an H-bond with Arg296, and the thiazolidinone moiety showing favorable interactions with Glu292 and Ser293.
Scheme 8
Scheme 8
(A) Structure of thiourea tacrines 28a–l, 29a–c, 31, and 33 and urea tacrines 30 and 32 [89,90]. (B) Synthesis of thiourea tacrines 28a–l. (C) Synthesis of thiourea and urea tacrines 29a–c and 30–33. Reagents and conditions: (i) Thiourea, NaOMe, EtOH, Δ, 12 h, 10–29%; (ii) cyclohexanone, AlCl3, DCE, MWI, 1–2 h, 46–70%; (iii) SCN-R, pyridine, Δ, 10 h, 85–86%; (iv) urea or thiourea, 300 °C, 1 h, 64–74%; (v) urea or thiourea, 200 °C, 1 h, 76–83%.
Scheme 9
Scheme 9
(A) Structure of amido- (36a–p), amino- (37 and 39a–e), and iminotacrines 38a,b [90,94]. (B) Synthesis of amidotacrines 36a–p. (C) Synthesis of amino- (37 and 39a–e) and iminotacrines 38a,b. Reagents and conditions: (i) BF3·Et2O, toluene, Δ, 4 h, 84%; (ii) 1-methylpyrazole-4-boronic acid pinacol ester or 5-pyrimidineboronic acid pinacol ester, Na2CO3, Pd(PPh3)4, 1,4-dioxane/H2O, Δ, 2 h, 52%; (iii) NH4OH or N2H4·H2O, MeOH, 60 °C, 2–3 h, 73–85%; (iv) LiOH·H2O, THF/H2O/MeOH, rt, 3 h, 79–90%; (v) benzylamine or phenylethylamine or phenylpropylamine, T3P, TEA, DMF, 60 °C, 4 h, 59–67%; (vi) 5-amino-1-methyl-1H-pyrazole, HATU, DIPEA, DMF, rt, 12 h, 63–71%; (vii) 70% H2SO4, Δ, 5 h; (viii) R-C6H4-CHO, pyridine, Δ, 6 h, 87–90%; (ix) NH2NH-Bz, Δ, 1 h, 84%; (x) X-R (where X = Cl or Br), 1,4-dioxane, Δ, 5–10 h, 69–89%.
Figure 7
Figure 7
Molecular modeling of 36c with TcAChE showing the interaction with the CAS (adapted from [94], with permission from Elsevier). Key interactions noted are the tacrine moiety π-π stacking with Trp84 and Tyr337 and H-bonding to His447 and the hydrazide H-bonding with Tyr337.
Scheme 10
Scheme 10
(A) Structure of naphthalene pyranopyrimidinones 42a–i and 43a–i, naphthoquinone pyranopyrimidinones 44a–l, and naphthalene pyrimidinimines 42j–o and 43j–o [95,96,97]. (B) Synthesis of naphthalene pyranopyrimidinones 42a–i and 43a–i and naphthoquinone pyranopyrimidinones 44a–l. (C) Synthesis of naphthalene pyranopyrimidinimines 42j–o and 43j–o. Reagents and conditions: (i) 2-Naphthol or 1-naphthol, piperidine, EtOH, MWI, 10 min, 68–95%; (ii) γ-butyrolactam or δ-valerolactam or ε-caprolactam, POCl3, DCE or PhBr, MWI, 15 min, 70–96%; (iii) potassium phthalimide-N-oxyl, H2O, Δ, 30–60 min, >90%.
Figure 8
Figure 8
Molecular modeling of (S)-42n with hAChE showing the interaction with the mid-gorge region (adapted from [96], © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim). Key interactions noted are the π-π stacking between Trp86 and the benzochromeno moiety and an H-bond between Asp74 and the imino moiety.
Scheme 11
Scheme 11
(A) Structure of 2-methoxyhuprine (50) ((−)-huperine A shown for reference) and propargyl tacrines 51a–c and propargyl ethylenediamine tacrines 52a,b [106,107]. (B) Synthesis of 2-methoxyhuprine (50). (C) Synthesis of propargyl tacrines 51a–c. (D) Synthesis of propargyl ethylenediamine tacrines 52a,b. Reagents and conditions: (i) 1 M NaOH, 1,4-dioxane, Δ, 18 h, 82%; (ii) 5% Pd/C, H2, EtOH, rt, 2 h, quant.; (iii) AlCl3, DCE, MWI, 2 h, 80%; (iv) propargyl bromide (1.1 eq), KOH or K2CO3, MeCN, rt, 12–36 h, 35–82%; (v) propargyl bromide (2.1 eq), KOH or K2CO3, MeCN, rt, 12–36 h, 35–82%.
Scheme 12
Scheme 12
(A) Structure of semicarbazone tacrines 53a,b and indenoquinolines 54a–o [108,111]. (B) Synthesis of semicarbazone tacrines 53a,b. (C) Synthesis of indenoquinolines 54a–o. Reagents and conditions: (i) 1,4-Doxane, Δ, 24 h, 80%; (ii) thiosemicarbazide hydrochloride or semicarbazide hydrochloride, EtOH, Δ, 3 h, 75–79%; (iii) (a) InCl3, toluene, Δ, 24 h; (b) 2 M NaOH, Δ, 24 h, 13–50%; (iv) PhB(OH)2 (1.3 or 2.6 eq.), Pd(PPh3)4, K2CO3, 1,4-dioxane, Δ, 4 h, 80–96%.
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