moiety. Among them, the lead compound **237** (Table 17) exhibited maximum inhibitory activity towards AChE enzyme, with an IC₅₀ value of 2.13 µM, compared to tacrine (IC₅₀ = 0.93 µM) [258]. Moreover, it demonstrated inhibition of Aβ₁.₄₂ aggregation, with 77.1 % inhibitory activity compared to the positive control, curcumin (75.9 %) at 10 µM. Additionally, this hybrid displayed improved antioxidant activities in DPPH assay, with an IC₅₀ as low as 19.5 µM, as well as in FRAP and ORAC assays, with potential up to 1.54 and 6.4 µM Trolox equiv., respectively [258].

### 5.2.1.7. Tacrine-hydroxamate hybrids.
Xu et al. introduced tacrine-hydroxamate hybrid compound **238** (Table 17) that displayed notable multifunctional properties [259]. It exhibited potent inhibition of ChEs (IC₅₀ for AChE = 0.12 nM; for BChE = 361.52 nM), surpassing tacrine in AChE inhibition (IC₅₀ = 69.66 nM; BChE = 10.81 nM). Additionally, this hybrid demonstrated inhibition of histone deacetylase (HDAC1) with an IC₅₀ of 0.23 nM. Furthermore, it exhibited inhibitory activity against Aβ₁.₄₂ self-aggregation (34.2 % at 20 µM) and demonstrated the ability to disaggregate pre-formed Aβ fibrils. It also displayed antioxidant potential (9.05 µM) and metal chelating attributes. Mechanistic studies revealed that it acts as an HDAC pan-inhibitor and a mixed-type AChE blocker, while also possessing BBB penetrance [259].

### 5.2.1.8. Tacrine-O-phosphorylated hybrids.
Przybylowska et al. investigated tacrine-O-phosphorylated hybrid compounds **239–241** (Table 17) [260]. Hybrid **239** exhibited remarkable inhibitory activity against AChE with an IC₅₀ value of 6.11 nM while compound **240** exhibited potent inhibition against BChE with an IC₅₀ value of 1.969 nM. These compounds demonstrated 6- and 12-fold greater potency, respectively, compared to tacrine (IC₅₀ = 23.53 nM). Furthermore, hybrid **241** showed no hepatocytotoxicity on HepG2 cells in the MTT assay, with an IC₅₀ value greater than 600 µM [260].

### 5.2.1.9. Tacrine-resveratrol hybrids.
Jérabek et al. synthesized MTDL **242** (Table 17) by combining tacrine with resveratrol (a naturally occurring anti-oxidant and anti-inflammatory polyphenol [261]). This hybrid emerged as potent inhibitor of hAChE with an IC₅₀ value of 0.80 µM and effectively attenuated self-aggregation of Aβ with an inhibition percentage of 17.6 % at 50 µM *in vitro*. Additionally, it demonstrated notable anti-inflammatory and immunomodulatory properties in neuronal and glial models of AD. Importantly, this MTDL displayed high BBB permeability and low cytotoxicity on primary neurons of HepG2 cells [262].

## 5.3. Linkage, fusion, and incorporation of donepezil pharmacophore with one or more heterocyclic scaffolds

Donepezil, an FDA-approved inhibitor selective to AChE [263] presents a distinct profile compared to tacrine, which concurrently targets both AChE and BChE [264]. This section delves into various MTDLs incorporating the pharmacophores of donepezil, namely N-benzyl piperidine and dimethoxy aryl group, employing linkage, fusion, and incorporation strategies.

### 5.3.1. Donepezil-quinoline/benzimidazole/oxadiazole/triazole/pyridine/pyrimidine hybrids

#### 5.3.1.1. Donepezil-quinoline hybrids.
Gabr et al. developed a structurally rigid donepezil analogue using an incorporation technique [265]. The resulting hybrid, compound **243** (Table 18), featuring a 2-aminoquinoline moiety, demonstrated potent inhibition of AChE with an IC₅₀ value of 14.7 nM and BACE-1 with an IC₅₀ value of 13.1 nM, compared to donepezil (IC₅₀ for AChE = 6.87 nM and for BACE-1 = 231 nM, respectively). Molecular modeling studies suggested a potential dual binding mode of the lead compound to both AChE and BACE-1.

Additionally, it affected the viability of SH-SY5Y cells and demonstrated the ability to cross the BBB (P<sub>e</sub> = 24.29 × 10⁻⁶ cm/s vs. donepezil = 22.91 × 10⁻⁶ cm/s) [265].

#### 5.3.1.2. Donepezil-benzimidazole hybrids.
MTDLs **244** and **245** (Table 18) were developed by linking a hydroxyphenylbenzimidazole moiety to benzylpiperidine, a pharmacophore of donepezil [266]. The lead compound **244**, containing a methoxy group on the benzyl ring, exhibited higher cholinergic AChE activity with an IC₅₀ of 1.87 µM compared to donepezil (IC₅₀ = 26 nM). On the other hand, compound **245**, featuring a three-dentate chelating unit, showed the strongest copper (II) chelation capacity. Additionally, compound **245** demonstrated the greatest reduction of Aβ-induced cell toxicity in cells [266].

#### 5.3.1.3. Donepezil-oxadiazole hybrids.
Waiker et al. reported donepezil-oxadiazole hybrids **246** and **247** (Table 18) that exhibited inhibition of hAChE and hBACE-1 similar to donepezil, with IC₅₀ values of 76 nM and 0.12 µM, respectively, against hAChE, and 1.20 µM and 1.48 µM, respectively, against hBACE-1 [267]. They also showed inhibition of hBChE with IC₅₀ values of 0.23 µM and 0.32 µM, respectively, akin to rivastigmine. Additionally, these compounds significantly reduced Aβ aggregate formation as confirmed through multiple assays and microscopy techniques, along with substantial displacement of PI by 54 % and 51 % at 50 µM concentrations, respectively. In AD mouse models induced by scopolamine and Aβ, both hybrids effectively restored learning and memory behaviors. *Ex vivo* studies on hippocampal and cortex brain homogenates revealed that these hybrids decreased AChE, malondialdehyde, and nitric oxide levels while increasing glutathione levels. They also reduced pro-inflammatory cytokines, specifically TNF-α and IL-6 mRNA levels [267].

#### 5.3.1.4. Donepezil-triazole hybrids.
Rastegari et al. employed a linking strategy to prepare donepezil-linked 1,2,3-triazole-chromenone carboxamide hybrids [268]. Among them, hybrid **248** (Table 18) exhibited the most potent AChE inhibition potential with an IC₅₀ value of 1.80 µM, compared to donepezil with an IC₅₀ of 27 nM. However, it showed no potential towards BChE. Additionally, it demonstrated BACE-1 inhibition activity with an IC₅₀ of 21.13 µM. Furthermore, in PC12 neurons subjected to H₂O₂-induced cell death, it revealed satisfactory neuroprotection at a concentration of 50 µM. Moreover, it exhibited metal chelation towards Fe²⁺, Cu²⁺, and Zn²⁺ ions [268].

#### 5.3.1.5. Donepezil-pyridine hybrids.
Palanimuthu et al. utilized thiosemicarbazones derived from 1-benzylpiperidine and linked them to donepezil to create thiosemicarbazone-linked donepezil hybrids targeting five major AD hallmarks: metal dyshomeostasis, low acetylcholine levels, dysfunctional autophagy, protein aggregation, and oxidative stress [269]. Among these hybrids, compound **249** (Table 18) emerged as the most active. This agent exhibited highly promising multi-functional activity, with minimal anti-proliferative activity, significant iron chelation efficacy, suppression of copper-mediated Aβ aggregation, reduction of oxidative stress, moderate AChE inhibition activity, and induction of autophagy [269].

#### 5.3.1.6. Donepezil-pyrimidine hybrids.
Malek et al. synthesized novel MTDLs **250–252** (Table 18), based on dihydropyrimidone via a one-pot three-component Biginelli reaction [270]. These hybrids were designed to target AChE and BChE, as well as exhibit calcium channel antagonism and antioxidant properties. *In vitro* studies revealed that these hybrids displayed promising activities, with IC₅₀ values for AChE inhibition ranging from 342 nM to 462 nM, and for BChE inhibition ranging from 4.78 µM to 6.63 µM. Additionally, these compounds demonstrated calcium channel blockade, antioxidant potential measured by ORAC assay, and activation of the Nrf2-ARE pathway [270].
<table><caption>**Table 18**</caption><caption>Anti-Alzheimer's potential of MTDLs based on donepezil-quinoline/benzimidazole/oxadiazole/triazole/pyridine/pyrimidine/flavonoid/carbazole/indole/coumarin/pyrrolizine/phenothiazine hybrids.</caption><thead><tr><th>Hybrid compounds</th><th>AChE inhibition IC<sub>50</sub> (µM)</th><th>BChE inhibition IC<sub>50</sub> (µM)</th><th>β-Amyloid inhibition (%)</th><th>Antioxidant IC<sub>50</sub> (µM)</th><th>Other activities</th><th>Ref.</th></tr></thead><tbody><tr><td>243</td><td>14.7</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>BACE-1 inhibition IC<sub>50</sub> value of 13.1 nM effected the viability of SH-SY5Y cells and crossed BBB</td><td>[265]</td></tr><tr><td>244</td><td>9.0</td><td>n.t.<sup>a</sup></td><td>38.6<sup>c</sup></td><td>n.t.<sup>a</sup></td><td>Higher capacity for copper chelation, significant neuroprotective effect<br>245 showed a significant neuroprotective effect</td><td>[266]</td></tr><tr><td>245</td><td>1.87</td><td></td><td>43.7<sup>c</sup></td><td></td><td></td><td></td></tr><tr><td>246</td><td>76<sup>c</sup></td><td>0.23</td><td>39.44-56.21<sup>f</sup></td><td>n.t.<sup>a</sup></td><td>Exhibited IC<sub>50</sub> = 0.12 and 1.48 µM, respectively against hBACE-1, displaced PI</td><td>[267]</td></tr><tr><td>247</td><td>0.12</td><td>0.32</td><td>36.03-59.22<sup>f</sup></td><td></td><td></td><td></td></tr><tr><td>248</td><td>1.80</td><td>>100</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>BACE-1 inhibition IC<sub>50</sub> = 21.13 µM, revealed satisfactory neuroprotection, showed metal chelation</td><td>[268]</td></tr><tr><td>249</td><td>4.93</td><td>-</td><td>-</td><td>-</td><td>Low anti-proliferative activity, significant iron chelation efficacy</td><td>[269]</td></tr><tr><td>250</td><td>342<sup>c</sup></td><td>4.78</td><td>n.t.<sup>a</sup></td><td>1.60</td><td>Calcium antagonism (67, 50, 74 % inhibition, respectively), Nrf2 transcriptional activation potencies (CD = 7.1 µM, 7.7 µM, 13.5 µM, respectively)</td><td>[270]</td></tr><tr><td>251</td><td>462<sup>c</sup></td><td>6.63</td><td></td><td>1.85</td><td></td><td></td></tr><tr><td>252</td><td>352<sup>c</sup></td><td>5.43</td><td></td><td>1.41</td><td></td><td></td></tr><tr><td>253</td><td>46<sup>c</sup></td><td>>10000<sup>c</sup></td><td>n.t.<sup>a</sup></td><td>n.a.<sup>b</sup></td><td>Inhibited 5-LOX (IC<sub>50</sub> = 74.3 µM), MAO-A (IC<sub>50</sub> = 15.3 µM), as well as MAO-B (IC<sub>50</sub> = 5.2 µM), protected a neuronal cell line from mitochondrial oxidative stress, possessed BBB permeation</td><td>[272]</td></tr></tbody></table>

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<table><caption>**Table 18 (continued)**</caption><thead><tr><th>Hybrid compounds</th><th>AChE inhibition IC<sub>50</sub> (µM)</th><th>BChE inhibition IC<sub>50</sub> (µM)</th><th>β-Amyloid inhibition (%)</th><th>Antioxidant IC<sub>50</sub> (µM)</th><th>Other activities</th><th>Ref.</th></tr></thead><tbody><tr><td>254: n = 3<br>255: n = 4</td><td>16.5<br>26.5</td><td>0.59<br>0.18</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>Interacted with the Zn<sup>2+</sup> ion, 254 demonstrated inhibition effect against BACE-1 (24.5 %)</td><td>[273]</td></tr><tr><td>256</td><td>13<sup>d</sup></td><td>89.9<sup>c</sup></td><td>53.5<sup>b</sup></td><td>n.t.<sup>a</sup></td><td>Potential against 5-HT<sub>6</sub>R with the K<sub>i</sub> = 4.8 nM, demonstrated good reliability in mouse liver microsomes, a favorable safety pattern, and brain permeation</td><td>[274]</td></tr><tr><td>257</td><td>36<sup>c</sup></td><td>9.83</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>Inhibited PDE5 IC<sub>50</sub> = 0.15 µM, BBB permeation</td><td>[275]</td></tr><tr><td>258</td><td>32<sup>c</sup></td><td>3.88</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>Inhibited PDE5 IC<sub>50</sub> = 1.53 µM, BBB permeation, reversed the cognitive dysfunction</td><td>[275]</td></tr><tr><td>259</td><td>&gt;100</td><td>0.96</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>Inhibited hMAO-A having IC<sub>50</sub> = 2.13 µM, hMAO-B with the IC<sub>50</sub> = 21 nM</td><td>[276]</td></tr><tr><td>260</td><td>9.10</td><td>5.90</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>Potent and selective hMAO-B inhibition with the IC<sub>50</sub> = 0.30 µM, SI = &gt;33</td><td>[276]</td></tr><tr><td>261</td><td>1.31</td><td>32.33</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>Possessed low cytotoxicity and acute toxicity, good BBB permeability, inhibited BACE-1 (IC<sub>50</sub> = 1.23 µM), GSK-3β (19.30 % inhibition)</td><td>[277]</td></tr><tr><td>262</td><td>37.3<sup>c</sup></td><td>2.32</td><td>62.1<sup>b</sup></td><td>n.t.<sup>a</sup></td><td>Showed IC<sub>50</sub> = 1.57 µM for hMAO-B, showed a low neurotoxicity, cross the BBB and neuroprotection</td><td>[278]</td></tr><tr><td>263</td><td>4.17</td><td>&gt;50</td><td>0.42<sup>c</sup></td><td>n.t.<sup>a</sup></td><td>Counteract the neurotoxic effects of Aβ, showed less cytotoxicity and could help mice with cognitive impairment</td><td>[279]</td></tr></tbody></table>

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<table><caption>**Table 18 (continued)**</caption><thead><tr><th>Hybrid compounds</th><th>AChE<br>inhibition<br>IC<sub>50</sub> (µM)</th><th>BChE<br>inhibition<br>IC<sub>50</sub> (µM)</th><th>β-Amyloid<br>inhibition (%)</th><th>Antioxidant<br>IC<sub>50</sub> (µM)</th><th>Other activities</th><th>Ref.</th></tr></thead><tbody><tr><td>264</td><td>0.73</td><td>0.74</td><td>1.67<sup>c</sup></td><td>n.t.<sup>a</sup></td><td></td><td></td></tr><tr><td>265</td><td>0.22</td><td>4.97</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>265 Showed IC<sub>50</sub> = 0.28 µM and 266 showed IC<sub>50</sub> = 0.53 µM for PDE<sub>9</sub>A, low neurotoxicity, good BBB penetrability, alleviated scopolamine-induced learning deficits</td><td>[280]</td></tr><tr><td>266</td><td>48<sup>c</sup></td><td>2.88</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td></td><td></td></tr><tr><td>267: n = 1<br>268: n = 2</td><td>1.75<br>0.60</td><td>1.20<br>4.33</td><td>43<sup>i</sup><br>60<sup>i</sup></td><td>0.13<br>0.23</td><td>Suppressed the target FAAH (IC<sub>50</sub> = 5.06 and 9.65 µM, respectively</td><td>[282]</td></tr></tbody></table>

### 5.3.2. Donepezil-flavonoids/carbazole/indole/coumarin/pyrrolizine/phenothiazine hybrids

#### 5.3.2.1. Donepezil-flavonoid hybrids.
Valencia et al. employed a linkage strategy to combine donepezil with a flavonoid, resulting in the synthesis of compound 253 (Table 18). This hybrid demonstrated a unique biological profile, showing affinity for σ1R (K<sub>i</sub> = 37.4 nM), along with inhibition of AChE (IC<sub>50</sub> = 46 nM). Additionally, this hybrid exhibited inhibitory activity against 5-lipoxygenase (IC<sub>50</sub> = 74.3 µM), MAO A (IC<sub>50</sub> = 15.3 µM), and MAO B (IC<sub>50</sub> = 5.2 µM). Furthermore, it demonstrated neuroprotective effects against mitochondrial oxidative stress in a neuronal cell line, facilitated the maturation of neural stem cells into a neuronal phenotype, and displayed BBB permeation with a rate of 5.9 x 10<sup>-6</sup> cm/s [271,272].

#### 5.3.2.2. Donepezil-carbazole hybrids.
Sadeghian et al. synthesized donepezil-carbazole hybrids 254 and 255 (Table 18) by linking benzylpiperidine to carbazole that exhibited the highest inhibitory activities against AChE, with IC<sub>50</sub> values of 16.5 µM and 26.5 µM, respectively [273]. Additionally, they displayed potent inhibition of BChE, with IC<sub>50</sub> values of 0.59 µM and 0.18 µM, respectively. Both compounds also interacted with the Zn<sup>2+</sup> ion. Compound 254 showed moderate inhibition against BACE-1, with a 24.5 % inhibition at a concentration of 50 µM. Kinetic and docking studies suggested that these compounds act as

non-competitive inhibitors capable of interacting with both the PAS and CAS of AChE [273].

#### 5.3.2.3. Donepezil-indole hybrids.
Wichur et al. presented donepezil-indole hybrid 256 (Table 18) a fused-type multifunctional ligand, that exhibited remarkable and balanced potential against BChE (IC<sub>50</sub> = 89.9 nM) and 5-HT6R (Ki = 4.8 nM), along with inhibition against Aβ aggregation (53.5 % at 10 µM) [274]. Additionally, this hybrid demonstrated good reliability in mouse liver microsomes, a favorable safety pattern, and brain permeation with a brain to plasma ratio of 6.79 after oral administration in mice, as evidenced by in vitro ADMET and in vivo pharmacokinetic studies [274]. Similarly, Mao et al. evaluated a series of novel tadalafil derivatives to identify dual-target AChE/PDE5 inhibitors [275]. Two ligands, compounds 257 and 258 (Table 18), were identified as selective dual-target AChE/PDE5 inhibitors (IC<sub>50</sub> = 36 nM and 32 nM, respectively, for AChE; IC<sub>50</sub> = 0.153 µM and 1.530 µM, respectively, for PDE5) and exhibited efficient BBB permeation (P<sub>e</sub> = 7.67 x 10<sup>-6</sup> cm/s and 9.25 x 10<sup>-6</sup> cm/s, respectively). Notably, hybrid 258 reversed the cognitive dysfunction of scopolamine-induced AD mice. The SAR studies of tadalafil analogues indicated that the substituent group at the N-atom of piperazine-2,5-dione could be replaced for PDE5 inhibitory activity. Thus, the tadalafil parent nucleus was retained to preserve PDE5 inhibitory activity while varying the substituent group at the N-atom of piperazine-2,5-dione, aiming to obtain good dual-target

<footnote>a Not tested.</footnote>

<footnote>b Tested but not active</footnote>

<footnote>c nM.</footnote>

<footnote>d Percent inhibition.</footnote>

<footnote>e 40 µM.</footnote>

<footnote>f 5-20 µM.</footnote>

<footnote>g 50 µM.</footnote>

<footnote>h 20 µM.</footnote>

<footnote>i 10 µM.</footnote>
AChE/PDE5 inhibitors with improved BBB penetrability and excellent pharmacological activity [275].

5.3.2.4. *Donepezil-coumarin hybrids.* Joubert et al. investigated 7-substituted coumarin hybrids linked to benzyl- and *N*-benzylpiperidine, resembling the *N*-benzylpiperidine function of donepezil, connected *via* an alkyl ether linkage at the 7th position of coumarin to assess ChE and MAO-B inhibition potential [276]. Among the hybrids, compound 259 (Table 18), the coumarin-benzyl hybrid, displayed the most potent multifunctional activities, inhibiting *eqBChE* (IC₅₀ = 0.96 µM), *hMAO-A* (IC₅₀ = 2.13 µM), and *hMAO-B* (IC₅₀ = 21 nM) more potent than reference selegiline IC₅₀ = 8 nM). Conversely, compound 260 (Table 18), the coumarin-*N*-benzylpiperidine hybrid, exhibited good *eeAChE* and *eqBChE* inhibition (IC₅₀ = 9.10 µM and 5.90 µM, respectively) along with relatively potent and selective *hMAO-B* inhibition (IC₅₀ = 0.30 µM, SI = >33). Molecular modeling suggested that compound 260 can bind to the CAS, mid-gorge, and PAS of AChE and BChE simultaneously, potentially impeding AChE-induced *A*β aggregation [276]. Likewise, Liu et al. explored coumarin derivatives for their inhibitory effects on AChE, BChE, GSK-3β, and BACE-1 [277]. Compound 261 (Table 18) displayed a multifunctional profile, targeting AChE (IC₅₀ = 1.31 µM) with good selectivity over BChE (SI = 24.62), as well as inhibition of GSK-3β (19.30% inhibition at 20 µM) and BACE-1 (IC₅₀ = 1.22 µM). This hybrid exhibited reasonable cytotoxicity profiles in HepG2, SH-SY5Y, HL-7702 cells, and good BBB permeation. Acute toxicity tests indicated its non-toxic nature at a dosage of 1000 mg/kg, and ADME prediction suggested satisfactory physicochemical characteristics [277]. Similarly, *N*-benzyl pyridinium-coumarin hybrids with ChE and MAO-B inhibitory potential were designed [278]. Hybrid 262 (Table 18) displayed the highest inhibition potential for *hMAO-B*, along with balanced inhibition of ChEs and *hMAO-B*. It exhibited IC₅₀ = 37.3 nM vs donepezil 47.4 nM for *eeAChE*; 2.32 µM vs donepezil 4.6 µM for *eqBChE* and IC₅₀ = 1.57 µM vs iproniazid 7.89 µM for *hMAO-B*. Molecular modeling and kinetic findings indicated that this hybrid is a mixed-type inhibitor that binds to the CAS and PAS of AChE simultaneously and competitively inhibits the active site of MAO-B. Additionally, it effectively inhibited *A*β₁.₄₂ self-aggregation (62.1% at 20 µM) and crossed the BBB without toxicity on PC12 cells [278].

5.3.2.5. *Donepezil-pyrrolizine hybrids.* Pyrrolizine-based MTDLs **263** and **264** (Table 18) have shown promise as potential anti-Alzheimer agents due to their preference for *hAChE* over *hBChE* and their ability to suppress *in vitro* self-induced *A*β aggregation [279]. The *hAChE*-selective hybrid, **263**, containing a –CONH₂ group, exhibited an IC₅₀ value of 4.17 µM for *hAChE* and an IC₅₀ value of >50 µM for *hBChE*. In contrast, compound **264** displayed dual inhibitory activity on *hAChE* and *hBChE* at sub-micromolar concentrations, with IC₅₀ values of 0.73 µM and 0.74 µM, respectively. These findings highlight pyrrolizine-donepezil hybrids as potentially useful novel scaffolds for counteracting the neurotoxic effects of *A*β. Kinetic analyses revealed competitive type inhibition of both *hAChE* and *hBChE* by both hybrids. Furthermore, the cytotoxicity of these hybrids towards SH-SY5Y and healthy human hepatic (THLE2) cell lines was comparable to or less than that of donepezil. *In vivo* studies demonstrated that both compounds could alleviate cognitive impairment induced by scopolamine in mice. Finally, molecular docking simulations of these hybrids in the *hAChE* active site provided agreement with the obtained pharmacological results [279]. Similarly, Hu et al. developed a series of dual-target AChE/PDE9A inhibitors [280]. Compounds **265** and **266** (Table 18) exhibited excellent and balanced dual-target inhibitory activities against AChE and PDE9A, with IC₅₀ values of 0.22 µM and 48 nM for AChE, and 0.28 µM and 0.53 µM for PDE9A, respectively. These hybrids also showed low neurotoxicity and good BBB penetrability. Both hybrids alleviated scopolamine-induced learning deficits and improved cognitive and spatial memory in *A*β₂₅.₃₅-induced cognitive deficit mice, as

demonstrated in the Morris water-maze test [280].

5.3.2.6. *Donepezil-phenothiazine hybrids.* Carocci et al. proposed MTDLs formed by combining a phenothiazine moiety, (known for its antioxidant properties [281]), with *N*-benzylpiperidine or *N*-benzylpiperazine fragments resembling the fundamental scaffold of donepezil, using a linkage approach [282]. Their investigation for the derived hybrids, **267** and **268** (Table 18), revealed that besides their antioxidant properties, they also exhibited activity against some AD-related targets. These targets included the inhibition of both AChE and BChE, *in vitro* *A*β₁.₄₀ aggregation, and suppression of the novel target fatty acid amide hydrolase (FAAH), with IC₅₀ values of 5.06 µM and 9.65 µM, respectively, for these two hybrids. Both hybrids exhibited intriguing multi-target profiles, with all assayed activities falling in the low micromolar range. Specifically, they inhibited AChE with IC₅₀ values of 1.75 µM and 0.60 µM, respectively, and BChE with IC₅₀ values of 1.20 µM and 4.33 µM, respectively. Additionally, compound **267** showed *A*β₁.₄₀ inhibition of 43 %, while hybrid **268** showed 60 % inhibition at 10 µM. Compound **268** was inactive in the DPPH assay but performed well in *in vitro* antioxidant cell assays on both HepG2 and SHSY-5Y cell lines [282].

5.4. *Linkage, fusion, and incorporation of donepezil pharmacophore with non-heterocyclic scaffold*

Ferulic acid-O-alkylamine hybrid linked to donepezil, compound **269** (Table 19) was emerged as the potent inhibitor of BChE, exhibiting an IC₅₀ value of 21 nM for *eqBChE*, 8.63 µM for *ratBChE*, and 70 nM for *hBChE* [283]. Additionally, it demonstrated significant inhibition of AChE with IC₅₀ values of 2.13 µM for *eeAChE*, 1.8 µM for *ratAChE*, and 3.82 µM for *hAChE*. Moreover, this hybrid showed noteworthy inhibitory effects on self-induced *A*β₁.₄₂ aggregation (50.8 %) along with the disaggregation of self-induced *A*β₁.₄₂ aggregation (38.7 %) at 25 µM. Although it exhibited moderate antioxidant potential (0.55 equiv. of Trolox), it provided a protective role against H₂O₂-induced PC12 cell injury and showed low toxicity. Furthermore, it was able to cross the BBB *in vitro*, did not demonstrate toxic effects in mice at doses up to 1000 mg/kg, and significantly reversed scopolamine-induced memory deficits in mice, as revealed by the step-down passive avoidance test [283]. Similarly, *N*-benzylpiperidine derivatives were characterized for their ability to inhibit both HDAC6 and AChE [284]. Compounds **270** and **271** (Table 19) demonstrated dual enzyme inhibitions, with IC₅₀ values indicating potent inhibition of HDAC6 (0.17 µM for **270**; 0.45 µM for **271**) and moderate inhibition of AChE (6.89 µM for **270**; 3.22 µM for **271**). Additionally, both compounds showed activities in scavenging free radicals, metal chelating, and inhibiting *A*β aggregations, along with appealing neuroprotective activities in PC12 cells and good AChE selectivity [284]. Similarly, donepezil-butylated hydroxytoluene hybrid **272** (Table 19) displayed a balanced multi-functional profile [285]. It exhibited intriguing AChE inhibition (IC₅₀ = 75 nM for *eeAChE*, 0.75 µM for *hAChE*) and inhibition of MAO-B (IC₅₀ = 7.4 µM), along with excellent antioxidant activity and inhibitory effects on *A*β aggregation. This hybrid also showed neuroprotective properties against oxidative stress and inflammation, crossed the BBB, demonstrated good metabolic continuity, and reversed scopolamine-induced memory deficits in mice without causing toxic effects [285]. Furthermore, in another study, among several piperidine derivatives, hybrid **273** (Table 19) was identified as a MTDL, inhibiting both ChEs and FAAH [286]. While hybrid **274**, a piperazine derivative, exhibited potent and selective inhibition of AChE (IC₅₀ = 0.8 nM) compared to donepezil (IC₅₀ = 17 nM), along with the ability to bind bivalent copper cations. Importantly, both lead compounds showed no significant cytotoxicity on SH-SY5Y and HepG2 cells at the highest tested concentration (100 µM) [286].

Shahrivar-Gargari et al. investigated MTDLs containing indanone, the pharmacophore of donepezil, and carbamate moieties [287]. The hybrid **275** (Table 19), bearing a methoxy substituent, exhibited potent
<table><caption>**Table 19**
Anti-Alzheimer's potential of MTDLs based on donepezil pharmacophore hybridization with non-heterocyclic scaffolds.</caption><thead><tr><th>Hybrid compounds</th><th>AChE inhibition IC<sub>50</sub> (μM)</th><th>BChE inhibition IC<sub>50</sub> (μM)</th><th>β-Amyloid inhibition (%)</th><th>Antioxidant IC<sub>50</sub> (μM)</th><th>Other activities</th><th>Ref.</th></tr></thead><tbody><tr><td>269</td><td>1.8</td><td>21<sup>c</sup></td><td>50.8<sup>d</sup></td><td>0.55</td><td>Low in toxicity, crossed the BBB, significantly reversed scopolamine-induced memory deficit</td><td>[283]</td></tr><tr><td>270</td><td>6.89</td><td>n.a.<sup>b</sup></td><td>11.48<sup>f</sup></td><td>9.23</td><td>Enzyme inhibitions (270:HDAC6 IC<sub>50</sub> = 0.17 μM 271:=0.45 μM), metal chelation, demonstrated appealing neuroprotective activities</td><td>[284]</td></tr><tr><td>271</td><td>3.22</td><td>n.a.<sup>b</sup></td><td>13.16<sup>f</sup></td><td>11.75</td><td></td><td></td></tr><tr><td>272</td><td>75<sup>c</sup></td><td>47.95<sup>d</sup></td><td>n.t.<sup>a</sup></td><td>1.64</td><td>Showed MAO-B inhibition, crossed the BBB, demonstrated good liver microsomal metabolic continuity, reversed scopolamine-induced memory deficits</td><td>[285]</td></tr><tr><td>273</td><td>1.68</td><td>5.61</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>Showed FAAH inhibition 273 with IC<sub>50</sub> = 20.9, 274 = 41.6 μM, both compounds did not exhibit a significant cytotoxicity</td><td>[286]</td></tr><tr><td>274</td><td>0.8<sup>c</sup></td><td>1.41</td><td></td><td></td><td></td><td></td></tr><tr><td>275</td><td>1.20</td><td>0.30</td><td>86.8<sup>g</sup></td><td>n.t.<sup>a</sup></td><td>Good neuroprotective activities</td><td>[287]</td></tr><tr><td>276</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>1.8<sup>h</sup></td><td>n.t.<sup>a</sup></td><td>Showed neuroprotective properties, crossed the BBB, good MAO-B inhibitor (IC<sub>50</sub> = 31 nM)</td><td>[288]</td></tr><tr><td>277</td><td>18.7</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>b</sup></td><td>n.t.<sup>a</sup></td><td></td><td>[289]</td></tr></tbody></table>

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<figure><img src="image_18.png" /></figure>

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<table><caption>**Table 19 (continued)**</caption><thead><tr><th>Hybrid compounds</th><th>AChE<br>inhibition IC<sub>50</sub><br>(μM)</th><th>BChE<br>inhibition IC<sub>50</sub><br>(μM)</th><th>β-Amyloid<br>inhibition (%)</th><th>Antioxidant<br>IC<sub>50</sub> (μM)</th><th>Other activities</th><th>Ref.</th></tr></thead><tbody><tr><td><img src="image_278.png" alt="278" style="vertical-align: middle; text-align: center;"></td><td>n.t.<sup>b</sup></td><td></td><td>81.6<sup>a</sup></td><td></td><td></td><td></td></tr><tr><td><img src="image_279.png" alt="279" style="vertical-align: middle; text-align: center;"></td><td>0.44</td><td>4.22</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>Inhibited hMAO-B IC<sub>50</sub> = 6.43</td><td>[292]</td></tr></tbody></table>

inhibitory potential against both AChE and BChE with IC<sub>50</sub> values of 1.20 μM and 0.30 μM, respectively. Moreover, this hybrid significantly inhibited Aβ self-aggregation (86.8 % at 10 μM) and demonstrated remarkable neuroprotective activity against H<sub>2</sub>O<sub>2</sub>-induced cell death in PC12 cells. Kinetic studies suggested a partial non-competitive mixed type of inhibitory effects for both AChE and BChE, and molecular docking predicted a potential allosteric binding mode with both enzymes [287]. Similarly, Wang et al. explored indanone-chalcone hybrid 276 (Table 19) as multi-functional agent that exhibited potent inhibitory activity against Aβ<sub>1-42</sub> aggregation (IC<sub>50</sub> = 1.8 μM) and disaggregation (IC<sub>50</sub> = 7.9 μM), along with selective inhibition of MAO-B (IC<sub>50</sub> = 31 nM vs rasagiline IC<sub>50</sub> = 88 nM) and neuroprotective effects against Aβ<sub>1-42</sub>-induced toxicity [288]. Compound 276's lipophilicity suggests its potential to pass through the BBB [288]. Similarly, Azimian et al. utilized molecular hybridization and bioisosteric replacement strategies to develop potential agents for treating AD based on the structure of donepezil [289]. Hybrid 277 (Table 19) exhibited inhibitory activity characterized by an IC<sub>50</sub> value of 18.7 μM against AChE. Furthermore, the researchers assessed the Aβ<sub>1-40</sub> aggregation inhibitory properties and found that the hybrid 278 could inhibit Aβ<sub>1-40</sub> aggregation by 81.6 % at the concentration of 10 μM [289].

Ladostigil, a dual ChE inhibitor and a brain-selective MAO-A and MAO-B inhibitor, has demonstrated promise in the treatment of dementia [290,291]. Guieu et al. synthesized racemic trans 279 (Table 19), a hybrid molecule that represents a structural compromise between donepezil and rasagiline and evaluated its biological activity. This compound exhibited inhibitory effects against hAChE (IC<sub>50</sub> = 0.44 μM), hMAO-B (IC<sub>50</sub> = 6.43 μM), and hBChE (IC<sub>50</sub> = 4.22 μM). While compound 279 shares functional similarities with ladostigil, particularly in its dual targeting of AChE and MAO-B, however it is structurally distinct from ladostigil [292].

### 5.5. Fusion and incorporation of rivastigmine pharmacophore into one or more heterocyclic scaffolds

Rivastigmine, an FDA-approved dual inhibitor of both AChE and BChE [293,294], serves as a pivotal scaffold in the development of multifunctional drugs targeting Alzheimer's disease. Its mechanism of action involves covalent inhibition, wherein the carbamate moiety forms a stable covalent bond with the active site serine residue of AChE

and BChE, resulting in prolonged enzyme inhibition. This unique feature underscores the importance of the carbamate moiety in facilitating specific and potent cholinesterase inhibition, thereby enhancing cognitive function in Alzheimer's patients.

#### 5.5.1. Rivastigmine/quinoline/benzimidazole/pyrazine/pyrazoline/pyrrolidine hybrids

##### 5.5.1.1. Rivastigmine-quinoline hybrids.
Using a MTDLs strategy, quinoline-O-carbamate derivative 280 (Table 20), based on the pharmacophore of rivastigmine, was designed via an incorporation approach [295]. This hybrid emerged as a reversible dual inhibitor of eeAChE and eqBChE, with IC<sub>50</sub> values of 1.3 μM and 0.81 μM, respectively. Additionally, it demonstrated a significant neuroprotective effect against Aβ<sub>25-35</sub>-induced PC12 cell injury. Moreover, this hybrid exhibited good stability in artificial gastrointestinal fluids and liver microsomes in vitro, as well as in plasma. Importantly, it improved the AlCl<sub>3</sub>-induced zebrafish AD model by increasing the level of AChE [295].

##### 5.5.1.2. Rivastigmine-benzimidazole hybrids.
Vicente-Zurdo et al. designed rivastigmine-benzimidazole hybrids 281a and 281b (Table 20) by combining the active moiety of rivastigmine with hydroxyphenylbenzimidazole units [296]. The hybrid compound 281a exhibited notable inhibition against BChE with an IC<sub>50</sub> value of 0.30 μM. Additionally, both these hybrids demonstrated good inhibition capacity against self-induced (42.1 %, 58.7 %) and Cu<sup>2+</sup>-induced (40.3 %, 60.8 %) Aβ aggregation at 20 μM, as well as moderate inhibition against amyloid fibrils (22.4 %–42.6 %) at same concentration. Furthermore, both hybrids prevented the toxicity induced in SH-SY5Y cells by Aβ<sub>42</sub> and oxidative stress [296].

##### 5.5.1.3. Rivastigmine-pyrazine hybrids.
Scutellarein hybrid 282 (Table 20) containing trimethylpyrazine and carbamate moieties effectively inhibited AChE (IC<sub>50</sub> = 6.72 μM for eeAChE, and IC<sub>50</sub> = 8.91 μM for eeAChE), self- and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation (91.85 % and 85.62 %, respectively at 25 μM) [297]. It also promoted the disassembly of self- and Cu<sup>2+</sup>-generated Aβ fibrils (84.54 % and 83.49 %, respectively) at same concentration, demonstrating significant neuroprotective effects both in vitro and in vivo. Additionally, this hybrid inhibited platelet aggregation and substantially lowered tau protein

<footnote>a Not tested.</footnote>

<footnote>b Tested but not active.</footnote>

<footnote>c nM.</footnote>

<footnote>d Percent inhibition.</footnote>

<footnote>e 25 μM.</footnote>

<footnote>f 20 μM.</footnote>

<footnote>g 10 μM.</footnote>

<footnote>h μM.</footnote>
<table><caption>**Table 20**
Anti-Alzheimer's potential of MTDLs based on rivastigmine-heterocyclic/non-heterocyclic scaffold hybrids.</caption><thead><tr><th>Hybrid compounds</th><th>AChE<br>inhibition IC<sub>50</sub><br>(µM)</th><th>BChE<br>inhibition<br>IC<sub>50</sub> (µM)</th><th>β-Amyloid<br>inhibition (%)</th><th>Antioxidant<br>IC<sub>50</sub> (µM)</th><th>Other activities</th><th>Ref.</th></tr></thead><tbody><tr><td>280</td><td>1.3</td><td>0.81</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>Anti-inflammatory potency, good stabilities in artificial gastrointestinal fluids, liver microsomes in vitro and plasma and improved the AlCl<sub>3</sub>- induced zebrafish AD model</td><td>[295]</td></tr><tr><td>281a: n = 1<br>281b: n = 3</td><td>31.7<br>21.4</td><td>0.30<br>1.7</td><td>58.7<sup>d</sup><br>42.1<sup>d</sup></td><td>n.a.<sup>b</sup></td><td>Neuroprotective effect, reduction of ROS</td><td>[296]</td></tr><tr><td>282</td><td>8.91</td><td>n.t.<sup>a</sup></td><td>91.85<sup>d</sup></td><td>n.t.<sup>a</sup></td><td>Decreased lactate dehydrogenase levels, increased cell viability, enhanced expression of relevant apoptotic proteins</td><td>[297]</td></tr><tr><td>283a</td><td>34.5<sup>c</sup></td><td>3.3</td><td>n.a.<sup>b</sup></td><td>n.a.<sup>b</sup></td><td>Best inhibition against PDE9A with the IC<sub>50</sub> values of 14 nM and 17 nM, respectively both compounds found to be non-toxic</td><td>[298]</td></tr><tr><td>283b</td><td>5.34<sup>c</sup></td><td>0.96</td><td>n.a.<sup>b</sup></td><td>n.a.<sup>b</sup></td><td></td><td></td></tr><tr><td>284</td><td>4.91</td><td>n.a.<sup>b</sup></td><td>89.5<sup>e</sup></td><td>2.83</td><td>Selective MAO-B antagonist with the IC<sub>50</sub> = 0.29 µM, bio metal chelator, crossed the BBB</td><td>[299]</td></tr><tr><td>285</td><td>6.80</td><td>16.1</td><td>77.9<sup>e</sup></td><td>1.3</td><td>Improved AlCl<sub>3</sub>-induced zebrafish AD, protected Aβ<sub>1-40</sub>-mediated zebrafish vascular injury and improved scopolamine-induced cognitive deficits</td><td>[300]</td></tr><tr><td>286</td><td>26.2<sup>c</sup></td><td>3.1</td><td>63.9<sup>e</sup></td><td>1.3</td><td>MAO-B inhibition IC<sub>50</sub> value of 1.3 and 3.7 µM respectively, neuroprotectant, as well as a preferential metal chelator</td><td>[301]</td></tr><tr><td>287</td><td>35.54<sup>c</sup></td><td>1.2</td><td>53.1<sup>e</sup></td><td>0.35</td><td></td><td></td></tr><tr><td>288</td><td>5.6</td><td>85.2</td><td>n.t.<sup>a</sup></td><td>1.2</td><td>MAO-B inhibition IC<sub>50</sub> = 2.9 µM, metal chelation, favorable drug-like properties, and good BBB permeation</td><td>[302]</td></tr></tbody></table>

<footnote>a Not tested.</footnote>

<footnote>b Tested but not active.</footnote>

<footnote>c Percent inhibition.</footnote>

<footnote>d 20 µM.</footnote>

<footnote>e 25 µM.</footnote>
hyperphosphorylation produced by Aβ<sub>25-35</sub>. A neuroprotective assay
revealed that pre-treatment of PC12 cells with this compound reduced
lactate dehydrogenase levels, increased cell viability, boosted the pro-
duction of relevant apoptotic proteins (Bcl-2, Bax and caspase-3), and
hindered RSL3-induced PC12 cell ferroptosis while maintaining an
optimal BBB. Moreover, *in vivo* investigations demonstrated that it could
dramatically reduce learning and memory deficits in an AD mouse
model. Notably, this hybrid significantly decreased β-APP and BACE-1
expressions of proteins in scopolamine-treated mice brain tissue [297].

5.5.1.4. *Rivastigmine-pyrazoline*- hybrids. An *in vitro* evaluation of rivastigmine-pyrazolopyrimidinone hybrids highlighted compounds 283a and 283b (Table 20) as promising multi-targeting agents exhibiting potent inhibition against PDE9A, with IC<sub>50</sub> values of 14 nM and 17 nM, respectively [298]. Additionally, these hybrids demonstrated significant inhibitory activity against BChE, with IC<sub>50</sub> values of 3.3 µM and 0.96 µM, respectively. Importantly, their inhibitory potential against BChE was even higher than that of rivastigmine (2.89 µM). Both hybrids exhibited selectivity for BChE over AChE. Molecular docking studies provided insights into their binding patterns, elucidating the impact of configuration and substitutions on PDE9A and BChE inhibition. Furthermore, both hybrids were found to be non-toxic [298].

5.5.1.5. *Rivastigmine-pyrrolidine hybrids.* Xiao et al. developed a series of 4'-aminochalcone-rivastigmine hybrids, extending studies on the conjugation of chalcone and cholinesterase inhibitor rivastigmine [299]. Among these hybrids, compound 284 (Table 20) exhibited the most promising inhibitory potential against AChE, with an IC<sub>50</sub> value of 4.91 µM, along with significant antioxidative activity (2.83-fold of Trolox). At a concentration of 25 µM, this hybrid suppressed self-induced Aβ<sub>1-42</sub> aggregation by 89.5 % and Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation by 79.7 %. Moreover, it functioned as a selective MAO-B antagonist, with an IC<sub>50</sub> of 0.29 µM, and acted as a preferential bio-metal chelator. Importantly, it also demonstrated the ability to cross the BBB *in vitro* [299].

5.6. *Fusion and incorporation of rivastigmine pharmacophore into non-heterocyclic scaffolds*

5.6.1. *Rivastigmine-apigenin/chalcone/phenol hybrids*

5.6.1.1. *Rivastigmine-apigenin hybrids.* Sang et al. reported that compound 285 (Table 20), rivastigmine-apigenin hybrid, exhibited a significant antioxidant potential (ORAC = 1.3 equivalent), and a reversible hAChE inhibition with the IC₅₀ = 6.80 µM and hBChE inhibitory potential with the IC₅₀ = 16.1 µM [300]. This compound also acted as a selective metal chelator, significantly inhibited and disaggregated self-mediated and Cu²⁺-mediated Aβ₁₄₂ aggregation, as well as hAChE-mediated induced Aβ₁₄₂ aggregation. Furthermore, this hybrid demonstrated an exceptional neuroprotective and hepatoprotective activities along with the favorable BBB permeation *in vitro* as well as drug-like properties. Additionally, the *in vivo* assay revealed the remarkable dyskinesia recovery rate and feedback efficiency in AD zebrafish, as well as a remarkable protective effect against Aβ₁₄₀-mediated zebrafish vascular injury. More interestingly, at doses up to 2000 mg/kg, it showed no obvious toxic effect and could improve scopolamine-induced cognitive deficits [300].

5.6.1.2. *Rivastigmine-chalcone hybrids.* Sang et al. designed chalcone-O-carbamate derivatives 286 and 287 (Table 20) employing the fusion strategy to develop multi-targeting agents [301]. These hybrids emerged as highly selective BChE inhibitors with IC₅₀ values of 3.1 µM and 1.2 µM, respectively, and displayed high selectivity towards MAO-B with IC₅₀ values of 1.3 µM and 3.7 µM, respectively. Moreover, both hybrids inhibited self-induced Aβ₁₄₂ aggregation with inhibition rates of 63.9 %

and 53.1 %, respectively at concentration of 25 µM. Hybrid **286** exhibited robust antioxidant and neuroprotective properties, along with preferential metal chelation targeting Cu<sup>2+</sup> and Al<sup>3+</sup>. Additionally, it could inhibit and disaggregate Cu<sup>2+</sup>-induced Aβ<sub>1-42</sub> aggregation, and both compounds were capable of crossing the BBB. Notably, *in vivo* studies revealed that compound **286** alleviated scopolamine-induced memory loss [301].

5.6.1.3. *Rivastigmine-phenol hybrids.* Deng et al. employed a MTDL strategy to design a rivastigmine-2-acetylphenol hybrid **288** (Table 20) that notably exhibited *in vitro* bioactivity, functioning as a pseudo-irreversible and selective inhibitor of eeAChE with an IC₅₀ of 5.6 µM [302]. Additionally, it displayed strong inhibition of MAO-B, with an IC₅₀ value of 2.9 µM. Furthermore, this hybrid demonstrated selective metal chelation, favorable drug-like properties, and good BBB permeation (P<sub>e</sub> = 13.1 × 10<sup>-6</sup> cm/s *in vitro*). Moreover, it exhibited significant antioxidant activity with an ORAC value of 1.2 equivalent and showed substantial neuroprotective effects against H₂O₂-induced cell injury in PC12 cells [302].

5.7. *Linkage of memantine pharmacophore into heterocyclic or non-heterocyclic scaffolds*

Memantine, an FDA-approved anti-AD drug functions as an antago-
nist for the NMDA receptor [303,304]. Its therapeutic potential extends
further as a versatile platform for formulation, where small molecules
can be incorporated into the amantadine core of memantine. These
molecules exhibit diverse chemical attributes, including antioxidant and
anti-aggregating activity, as well as inhibition of AChE and MAO. This
multifaceted approach enables the creation of single entities with potent
neuroprotective properties, acting through various mechanisms to
combat AD progression [305].

5.7.1. *Memantine-hydroxycinnamic acids/tacrine/carbazole hybrids*

5.7.1.1. *Memantine-hydroxycinnamic acid hybrids.* Chochkova et al. introduced a novel multitargeted chemical entity framework by combining substituted cinnamic acids (having antioxidant, anti-aggregating and amyloid β-fibrillization activities [306,307]) with memantine, an NMDA receptor antagonist. Among the tested hybrids, N-sinapoyl amide of memantine, compound 289 (Table 21), exhibited the most potent antioxidant activity in all tests. *In vitro* studies demonstrated that this hybrid effectively inhibited NMDA with an EC₅₀ of 14.90 µM. Additionally, it showed moderate neuroprotection, although weaker than the positive control memantine. It displayed promising activities against various detrimental factors including Aβ toxicity, excitotoxicity, oxidative stress damage, hypoxia injury, and neuro-inflammation [308].

5.7.1.2. *Memantine-tacrine hybrids.* Gazova et al. developed 7-methoxy-tacrine-memantine heterodimer 290 (Table 21) based on the MTDL theory [309]. This hybrid displayed effective inhibition of both BChE (IC₅₀ = 0.11 µM) and AChE (IC₅₀ = 0.47 µM). Furthermore, it demonstrated significant inhibition of Aβ₁₄₀ peptide amyloid fibrillization (IC₅₀ = 66.5 µM) and BACE-1 activity (IC₅₀ = 224.7 µM). In addition, it acted as an antagonist of both M1 muscarinic receptors (IC₅₀ = 4.02 µM) and muscle-type nicotinic receptors (nAChR) (IC₅₀ = 0.90 µM). Additionally, it is likely an NMDA receptor open-channel blocker with a mechanism of action similar to memantine. Moreover, it demonstrated sufficient BBB permeation and neuroprotective activities [309].

5.7.1.3. *Memantine-carbazole hybrids.* Bachurin et al. designed a group of therapeutic agents based on conjugates of aminoadamantane and carbazole using a linkage approach [310]. The leading compound 291 (Table 21) exhibited promising effects on BChE with an IC₅₀ of 5.43 µM.
<table><caption>**Table 21**
Anti-Alzheimer's potential of MTDLs based on memantine-hydroxycinnamic acid/tacrine/carbazoles hybrids.</caption><thead><tr><th>Hybrid compounds</th><th>AChE<br>inhibition IC<sub>50</sub><br>(µM)</th><th>BChE<br>inhibition IC<sub>50</sub><br>(µM)</th><th>β-Amyloid<br>inhibition (%)</th><th>Antioxidant<br>IC<sub>50</sub> (µM)</th><th>Other activities</th><th>Ref.</th></tr></thead><tbody><tr><td>289</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td></td><td>NMDA inhibition with the EC<sub>50</sub> = 14.90 µM,<br>moderate neuroprotection, TNF-α (IC<sub>50</sub> = 0.16 µM,<br>IL-6 (IC<sub>50</sub> = 0.19 µM)</td><td>[308]</td></tr><tr><td>290</td><td>0.47</td><td>0.11</td><td>66.5<sup>b</sup></td><td>n.t.<sup>a</sup></td><td>BACE-1 activity (IC<sub>50</sub> = 224.7 µM), antagonist of<br>M1 muscarinic (IC<sub>50</sub> = 4.02 µM) and nAChR (IC<sub>50</sub><br>= 0.90 µM)</td><td>[309]</td></tr><tr><td>291</td><td>&gt;20</td><td>5.43</td><td>n.t.<sup>a</sup></td><td>n.t.<sup>a</sup></td><td>Blocked NMDA receptors (IC<sub>50</sub> = 27.4 µM), exerted<br>microtubules stabilizing properties</td><td>[310]</td></tr><tr><td>292</td><td>8.8</td><td>5.43</td><td>n.t.<sup>a</sup></td><td>48.4<sup>c</sup></td><td>CaE inhibition (16.5 %), stimulated tubulin<br>polymerization</td><td>[311]</td></tr></tbody></table>

Additionally, it acted as a blocker of the MK-801 binding site, blocking NMDA receptors that contain NR2B subunits with an IC₅₀ of 27.4 µM. Moreover, this hybrid demonstrated microtubule-stabilizing properties (maximal rate of polymerization = 330 %) and the ability to protect nerve cells from death under calcium-overloaded conditions [310]. Similarly, Makhaeva et al. investigated the effect of structure on the ability of MTDLs, aminoadamantane-carbazole conjugates linked by five different spacers, to restrict AChE, BChE, carboxylesterase, radical scavenging, mitoprotective activity, and tubulin polymerization [311]. The presence of anti-BChE and radical scavenging activity was found to be determined by the nature of the spacer. A lead compound, **292** (Table 21), showed promising BChE inhibition with an IC₅₀ value of 5.43 µM and free radical scavenging potential of 48.4 % compared to Trolox's activity of 99.8 % in the ABTS assay. The SAR results indicated that the structure of the linker in the aminoadamantane adducts with carbazole derivatives is critical for the compounds' inhibitory activity against BChE. Notably, fluorine-containing tetrahydrocarbazole compounds were identified as potent BChE inhibitors [311].

## 6. Perspective analysis

Among the MTDLs surveyed, the compounds **2, 8, 9, 30, 66, 75, 105, 116, 134, 135, 136, 157, 158, 159, 189, 208, 209, 210, 212, 213, 221, 222,** and **238** exhibit significant efficacy as ChE inhibitors (Fig. 3), even better than the reference drugs used for comparison. Careful structural analysis reveals a commonality; most of these compounds feature at least two aryl rings, either conjugated via π bonding, fused, or linked through an amide functionality and/or other flexible linkers. Fused ring aromatic compounds having extended conjugation by a moiety like nitrone (compound **2**) or thiosemicarbazone (compound **9**), also demonstrate potent ChE inhibition. Additionally, they have a good number of hydrogen bond donor and acceptor sites.

Notably, the compounds which are conformationally flexible having an extended π electron conjugated system, such as in compound **238**, show better AChE inhibition compared to BChE inhibition. Similarly, the compounds having long linkers between two aryl systems and/or have ortho-substituted aryl rings, like in compound **221** demonstrate superior BChE inhibition. This can be attributed to the slightly different binding pocket characteristics of the two enzymes [312]. While both enzymes possess hydrophobic internal cavities capable of interacting with hydrophobic moieties such as aromatic rings or alkyl chains of inhibitors through π-π or CH-π interactions, differences in their binding pockets lead to selectivity. Specifically, the active site of AChE is characterized by a 20 Å-deep gorge featuring a deep down CAS and PAS, providing a relatively rigid bottleneck-like structure [313]. The PAS containing polar and charged residues, contributes to the binding affinity by facilitating the binding of inhibitors through hydrogen bonding and electrostatic interactions. Moreover, the hydrogen bonding interactions between polar groups on inhibitors and complementary residues on AChE stabilize the inhibitor-enzyme complex, enhancing inhibitory potency. Hydrogen bonding interactions between polar groups on inhibitors and complementary residues on AChE can stabilize the inhibitor-enzyme complex and enhance inhibitory potency [313]. The larger volume of BChE active-site gorge, approximately ~200 Å³ more than that of AChE, however has potential to accommodate larger and slightly bulkier molecules [312].

Similarly, compounds **1, 3, 4, 15, 30, 46, 92, 102, 103, 115, 145, 164, 165, 192, 226, 227, 228, 229, 275** and **282** exhibit notable activity against beta-sheet structures of beta-amyloid aggregates, while compounds **80, 105, 111, 112, 115, 124, 125, 142, 143, 156, 172, 206, 207, 211, 214,** and **215** demonstrate significant activity against Tau tangles (Fig. 3). These compounds share some common structural motifs such as robust aromatic scaffolds (for strong π-π stacking interactions), chelating sites (to bind metals), and various hydrogen bond

<footnote>a Not tested.</footnote>

<footnote>b µM.</footnote>

<footnote>c Percent inhibition.</footnote>
<figure><img src="image_24.png" /><figcaption>Fig. 3. MTDLs outperforming standard drugs in potency against one or more key targets involved in AD.</figcaption></figure>

donor or acceptor functionalities. These structural features are thought to play a key role in promoting the disaggregation of both beta-amyloid and Tau proteins [314–316]. Specifically, the aromatic moieties that intercalate the insoluble beta-sheet structures of beta-amyloid peptides and Tau tangles by means of π interactions, contributes to the observed potent disaggregation activity of these compounds [314–316]. The compounds 58, 59, 130, 131, 132, 133, 216, 217, and 243 demonstrate potent BACE-1 inhibition (Fig. 3). Notably, inhibiting BACE-1 offers a strategy to hinder the formation of insoluble beta-amyloid based senile plaques [316]. Similarly, compounds 29, 48, 142, 143, 194, and 200 exhibit significant GSK-3β inhibition (Fig. 3). Targeting GSK-3β inhibition is crucial due to its role in activating Tau hyperphosphorylation [317]. These compounds exhibit a diverse array of hydrophobic and hydrophilic moieties, allowing for effective interactions with critical catalytic residues within the active sites of both enzymes, notably aspartic acid residues in BACE-1 and serine/threonine residues in GSK-3β [316,317]. It is worth highlighting that compound 21 has been reported to exhibit dual potent activity i.e. ChE inhibition as well as beta-amyloid disaggregation activity. Similarly, compounds 115 demonstrates high capability of disaggregating both beta-amyloid and Tau tangles, while compounds 142 and 143 serve as potent Tau disaggregators and inhibitors of GSK-3β (Fig. 3). The compounds 169, 170, 173, 195, 200, 212, 215, 216, 217, 218, 223, 224, 225, 286, and 287, however, are reported to show multiple activities including AChE, BChE, beta-amyloid, Tau, BACE-1, GSK-3β, and LOX inhibition with good to moderate efficacy.

To highlight the importance of heterocycles within the structures of reported MTDLs and their powerful π-π stacking ability with aromatic amino acids in biological systems [318], various heterocyclic motifs have been identified (vide supra). Particularly, the quinoline, benzimidazole, pyridine, pyazole and benzoxazole, oxadiazole, thiazole, triazole, isatin, and coumarin are prominent examples of heterocycles incorporated into the compounds that led to potent AChE and BChE inhibitory properties. Derivatives of quinoline, carbazole and coumarin exhibit efficacy in β-amyloid disaggregation, whereas thiazolidine-2, 4-dione, quinoline and indole derivatives demonstrate potent Tau tangles disaggregation. Quinoline and oxadiazole derivatives are recognized for BACE-1 inhibition. Pyridine, indole and quinoline scaffolds have exhibited good GSK-3β inhibitory activity. Moreover, coumarin

derivatives bearing a propargyl moiety have been found to possess good MAO inhibitory effects.

In summary, as most of the biomolecular targets are interconnected [319], many of these compounds have shared structural characteristics. Predominantly, these include aromatic moieties capable of forming π-π stacking interactions with the hydrophobic cores of targeted proteins or enzymes. Additionally, the presence of functional groups such as amino, hydroxyl, carbonyl or amide/thioamide groups serve as hydrogen bond donors or acceptors, facilitating interactions with specific binding residues within the active sites of the respective enzymes or proteins. Furthermore, the presence of flexible linkers or motifs provides conformational adaptability to best fit into the diverse binding pockets, improving binding affinity and selectivity. The results of various studies also indicate that compounds having a ligating site are more advantageous to cope with the metal induced processes.

## 7. Conclusions and future outlook

MTDLs offers a holistic approach to tackle the intricate and multifaceted nature of AD. Unlike conventional therapies targeting single pathways, MTDLs have the unique ability to simultaneously modulate multiple disease targets (vide supra). In this review, we have comprehensively summarized the skeletal diversity of recently reported MTDLs for AD and highlighted the key scaffolds. This drug development strategy holds great promise for more effective and disease-modifying treatments for AD that could substantially improve the quality of life of millions of people worldwide. Compounds containing heteroaromatic rings (quinoline, pyrazolopyridines, isatin, and coumarin etc.) capable of forming robust π-π interactions demonstrate significant promise as ChE inhibitors, β-amyloid and Tau tangles disaggregators, BACE-1 and GSK-3β inhibitors. We have also highlighted and analyzed the structures of several promising MTDL molecules which demonstrated superior activity compared to standard drugs against at least one of the tested targets, in order to attract the attention of researchers, and facilitate future drug development.

Although MTDLs hold great promise for addressing the multifactorial nature of AD, several challenges exist in their development and clinical translation. One main hurdle is optimizing the pharmacokinetic and pharmacodynamic profiles of potent MTDLs to ensure efficacy, safety
and tolerability in patients. Achieving selectivity for specific targets while minimizing off-target effects represents another significant challenge. Additionally, the design and synthesis of MTDLs often require complex chemistry and innovative synthetic approaches, necessitating interdisciplinary collaboration and expertise. Furthermore, rigorous preclinical and clinical assessments to validate the therapeutic potential of MTDLs and ensure their efficacy in treating AD, is also a big challenge. Overcoming these challenges will require consistent research efforts, innovative approaches, and collaboration across academia, industry and regulatory authorities. Despite all these challenges, the future prospects of MTDLs for AD are promising, offering hope for the development of disease modifying treatments that could significantly impact the lives of individuals affected by this devastating neurodegenerative disorder.

### CRediT authorship contribution statement

**Uzma Azam:** Writing – original draft. **Muhammad Moazzam Naseer:** Writing – review & editing. **Christophe Rochais:** Writing – review & editing.

### Declaration of competing interest

There is no conflict of interest to declare.

### Acknowledgments

We are highly grateful to the Higher Education Commission (HEC) of Pakistan for the indigenous Ph.D. Scholarship to UA; Funding from the European Union's Horizon 2020 under the WINNINGnormandy COFUND program (Marie Skłodowska - Curie grant agreement N° 101034329) to MMN is gratefully acknowledged.

### Data availability

No data was used for the research described in the article.

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