Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2026 Sep 12;17(10):2251–2259. doi: 10.1021/acsmedchemlett.6c00407

Decoupling Neuroprotection from MAO Inhibition via Indane-to-Azaindane Bioisosteric Replacement of Rasagiline

Ivo E Sampaio-Dias †,*, Sara C Silva-Reis †,‡, Xavier C Correia †, Hugo F Costa-Almeida †, Maria B Igreja-Cardoso †, Gabriel M Azevedo †, Vera M Costa ‡,§, Damijan Knez ∥, Stanislav Gobec ∥, José E Rodríguez-Borges †
PMCID: PMC13656277  PMID: 42866009

Abstract

Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with neuroprotective effects, whose dependence on MAO-B inhibition remains unclear. Here, indane-to-azaindane rasagiline isosteres (rac-2a and rac-2b) were developed to investigate whether neuroprotection can be decoupled from MAO-B inhibition. Direct regioselective oxidation of 4-azaindane catalyzed by Mn­(OAc)2/ t BuOOH afforded the key 4-azaindan-1-one intermediate (6a). In paraquat-insulted dopaminergic differentiated SH-SY5Y cells, both analogs showed neuroprotection at 10 and 100 μM, with rac-2b outperforming rasagiline. The azaindane analogs displayed markedly reduced MAO-B inhibition and no time-dependent inhibition. These findings demonstrate that rasagiline neuroprotection can be dissociated from MAO-B inhibition, supporting azaindane bioisosterism for exploring MAO-independent neuroprotection.

Keywords: Azaindane, Parkinson’s Disease, Rasagiline, Regioselective Oxidation

graphic file with name ml6c00407_0010.webp

graphic file with name ml6c00407_0009.webp

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective and progressive loss of dopaminergic neurons in the substantia nigra and the consequent depletion of striatal dopamine levels. A central feature of PD pathogenesis is oxidative stress, arising from mitochondrial dysfunction, impaired redox homeostasis, and dopamine metabolism.

Monoamine oxidase B (MAO-B), predominantly expressed in glial cells, plays a central role in this process by catalyzing the oxidative deamination of monoamines, generating hydrogen peroxide and other reactive byproducts. , These species contribute to oxidative damage, lipid peroxidation, and neuronal death, and are further implicated in the bioactivation of neurotoxins such as MPTP to MPP+. Accordingly, MAO-B inhibition has long been considered a rational strategy to reduce oxidative stress and confer neuroprotection, as well as increase dopamine levels.

(R)-N-Propargyl-1-aminoindane, commonly known as rasagiline (1, Figure ), is the active pharmaceutical ingredient of Azilect, which is marketed as a mesylate salt. − It is widely used to treat PD, either as monotherapy or in combination with levodopa and carbidopa to control motor symptoms. − Chemically, rasagiline consists of a secondary cyclic benzylamine (1-aminoindane) scaffold bearing an N-propargyl substituent. Pharmacologically, it acts as a selective, irreversible MAO-B inhibitor by covalently modifying the flavin cofactor. Its activity is stereochemically dependent, with the (R)-enantiomer responsible for potent MAO-B inhibition, whereas the (S)-enantiomer (TVP 1022) displays markedly reduced inhibitory activity, with a 104-fold increase in the half-maximal inhibitory concentration (IC50 value). ,

1.

1

Open in a new tab

Structures of rasagiline (1) and its azaindane-based isosteres rac-2a and rac-2b.

Beyond its dopaminergic effects, rasagiline has consistently been reported to exert neuroprotective activity across multiple experimental models, including protection against oxidative stress, mitochondrial dysfunction, and apoptotic signaling pathways. − However, growing evidence suggests that these effects are not solely attributable to MAO-B inhibition. Notably, both enantiomers exhibit comparable neuroprotective effects, indicating that additional mechanisms may contribute to their activity, , consistent with studies on TVP 1022, which retains significant neuroprotective activity despite weak MAO-B inhibition. ,

These effects have been associated with the N-propargyl pharmacophore and have been implicated in mitochondrial stabilization and antiapoptotic signaling, including modulation of Bcl-2 family proteins and attenuation of mitochondrial permeability transition pore opening. ,, Moreover, the principal metabolite of rasagiline, (R)-1-aminoindane, displays antioxidant and neuroprotective effects, potentially reinforcing the overall protective profile attributed to rasagiline. These findings suggest that rasagiline neuroprotection may arise from MAO-independent mechanisms, although the relative contribution of each pathway remains unclear.

This mechanistic ambiguity complicates the interpretation of rasagiline pharmacology and raises a fundamental question: to what extent is its neuroprotective activity intrinsically dependent on MAO-B inhibition? Addressing this question requires molecular tools capable of uncoupling these pharmacological properties. In this context, bioisosteric molecular editing represents a particularly attractive medicinal chemistry strategy, as it enables the selective modulation of target engagement while preserving the broader physicochemical and pharmacological profile of the parent scaffold. Accordingly, the design of rasagiline analogs that selectively abolish MAO-B inhibition while retaining neuroprotective activity offers a unique opportunity to define the molecular determinants underlying each function. − ,− Beyond providing mechanistic insight into rasagiline pharmacology, such compounds could lay the foundation for a new generation of neuroprotective agents devoid of irreversible MAO inhibition and its associated mechanism-based liabilities, including tyramine-mediated dietary interactions and other MAO-related adverse effects.

Guided by this rationale, we focused on the 1-aminoindane bicyclic scaffold of rasagiline, which plays a critical role in MAO-B recognition by inducing the “open” conformation of the gating residue Ile199 (PDB: 1S2Q). We hypothesized that replacing this core with an azaindane bioisostere would perturb key enzyme-ligand interactions, as previously observed for rasagiline-related inhibitors, thereby attenuating or abrogating MAO-B inhibition while potentially preserving structural determinants responsible for MAO-independent neuroprotective activity.

Our research group has been exploring 4-azaindane (6,7-dihydro-5H-cyclopenta­[b]­pyridine, CPP) as an indane surrogate (Figure ). ,, The incorporation of a nitrogen atom within the aromatic framework is expected to alter the electronic properties of the scaffold and potentially modulate its interactions within the MAO-B active site. Despite the increased polarity introduced by the ring nitrogen, the resulting physicochemical profile remains compatible with blood-brain barrier permeation, as supported by in silico analysis (Supporting Information). Azaindane scaffolds are also found in diverse bioactive molecules, including cephalosporins such as cefpirome sulfate, a fourth-generation cephalosporin, or as endothelin receptor antagonists, which are used in renal disease, hypertension, and congestive heart failure. Other studies suggest that azaindanes might be used as antifungals and phosphatase CDC25 inhibitors. ,

In a previous study, we reported the synthesis of 1-(propargylamino)-7-azaindane (rac-2b, Figure ). , Building on that work, we investigate the effect of azaindane regioisomers (rac-2a vs rac-2b) on neuroprotective activity and MAO inhibition, compared with rasagiline. While protocols for the preparation of rac-2b are well established based on the key Boekelheide rearrangement, ,,, synthesis routes for the preparation of rac-2a are not.

Herein, we report the design and synthesis of indane-to-azaindane rasagiline isosteres through regioselective functionalization of the 4-azaindane scaffold. We describe an effective and straightforward synthetic route enabling the regioselective preparation of rac-2a via direct functionalization at the 1-position of the 4-azaindane system, alongside its previously reported structural isomer (rac-2b). Their neuroprotective effects were evaluated in a dopaminergic SH-SY5Y cell model of paraquat (PQ)-induced oxidative stress, while MAO inhibitory activity was assessed using a cell-free enzymatic assay. This approach enabled direct assessment of structure–activity relationships and the disentanglement of neuroprotection from MAO inhibition for this chemotype.

Organic Chemistry

The synthesis of rac-2a started with the preparation of ketone 6a (Scheme ), a costly intermediate commonly employed in the synthesis of antipsychotic agents. , Our initial approach toward ketone 6a involved a superacid-promoted intramolecular cyclization of ester 5, under conditions typically used for indanone formation. Starting from aldehyde 3 (Scheme ), conjugated ester 4 was obtained via a Wittig reaction using the stabilized ylide (carbethoxymethylene)­triphenylphosphorane in 82% yield, with complete E-selectivity (1H NMR, J = 15.7 Hz). Subsequent hydrogenation of 4 over 10% Pd/C afforded saturated ester 5 in excellent yield (99%). However, attempted cyclization of 5 to azaindanone 6a using triflic acid proved unsuccessful, with complete recovery of starting material.

1. Attempted Synthesis of 4-Azaindan-1-one (6a) via Cyclization of Ester 5 .

1

Open in a new tab

a Reagents and conditions: (i) (carbethoxymethylene)­triphenylphosphorane, anhydrous CH2Cl2, 25 °C, 24 h; (ii) H2 (3.45 bar), Pd/C, EtOAc, 25 °C, 1 h; (iii) triflic acid (neat), 25 °C, 24 h.

To circumvent this limitation, we investigated the direct regioselective oxidation of CPP (Scheme ) to ketone 6a, which is known to be challenging. , Oxidation of CPP using CrO3 in a mixture of acetic and sulfuric acids afforded 6a in low yield (10%). More recently, electrochemical , and photochemical approaches have been reported, providing moderate yields (41–57%); − however, these methods require specialized equipment and setups. −

2. Synthesis of Ketone 6a Following the Protocol of Ren and Co-workers ,

2

Open in a new tab

a Reagents and conditions: (i) Mn­(OTf)2, H2O, t BuOOH (70% in H2O), 25 °C, 72 h.

Iron-catalyzed oxidative functionalization of CPP has also been described, delivering 6a in 40% yield using 30% H2O2 as the oxidant, polyoxometalate (NH4)3[FeMo6O18(OH)6] as the catalyst, and ethyl 2-bromoacetate as an additive. In addition, a greener manganese-catalyzed oxidation protocol in water, employing tert-butyl hydroperoxide ( t BuOOH) as the oxidant and manganese triflate (0.5 mol %) as the catalyst, was reported by Ren and co-workers (Scheme ).

Following this protocol (Scheme ), ketone 6a was successfully isolated, along with its positional regioisomer (ketone 6b, Scheme ) as a minor byproduct. The similar retention factors of 6a and 6b made their chromatographic separation particularly challenging, resulting in lower isolated yields of 6a than those previously reported (maximum yield of 16% vs 88% and 68% reported at 0.5 and 25 mmol scales, respectively). Importantly, the low yields obtained do not necessarily reflect the intrinsic efficiency of the oxidation process.

Considering the poor solubility of CPP in water, nonaqueous solutions of t BuOOH were evaluated for the regioselective oxidation of CPP. A 5.5 M solution of t BuOOH in nonane was selected as oxidant. In addition, several manganese­(II) salts, including MnCl2, Mn­(OAc)2, and Mn­(OTf)2, were screened for the oxidation of CPP to ketone 6a under controlled conditions. Among the catalysts tested, Mn­(OAc)2 provided the best results.

The optimal conditions employed 5 equiv of t BuOOH and 5 mol % Mn­(OAc)2, with a reaction time of 48 h (Table S2). Under these conditions, chromatographic purification was significantly simplified due to the reduced number of side products observed by TLC, affording ketone 6a in moderate yield (42%, Scheme ). Notably, regioisomer 6b was not detected by NMR analysis of the crude reaction mixture, indicating a highly regioselective oxidation. The observed regioselectivity may arise from the different coordinating properties of acetate and triflate, together with the low-temperature addition of the oxidant (−20 °C) and the improved solubility of CPP in the nonaqueous hexane/nonane medium.

3. Synthesis of Rasagiline Isosteres rac-2a and rac-2b .

3

Open in a new tab

a Reagents and conditions: (i) Mn­(OAc)2, dry hexane, t BuOOH (5.5 M in nonane, added over 20 min at −20 °C), then 20 °C, 48 h; (ii) propargylamine, NaBH­(OAc)3, CH2Cl2, 25 °C, 24 h; (iii) m-CPBA, CH2Cl2, 25 °C, 2 h; (iv) Ac2O, 100 °C, 2 h; (v) KOH, EtOH, 25 °C, 1 h; (vi) 1. (CO2)­Cl2, CH2Cl2, DMSO, −78 °C; 2. Et3N, 20 h, −78 °C to room temperature.

With ketone 6a in hand, rasagiline isostere rac-2a was readily obtained in good yield (76%, Scheme ) via reductive amination with propargylamine using sodium triacetoxyborohydride, NaBH­(OAc)3, as the reducing agent.

For the preparation of rasagiline isostere rac-2b, a regioselective synthetic route previously developed in our group was followed (Scheme ). , Briefly, CPP was oxidized using meta-chloroperbenzoic acid (m-CPBA) to the corresponding N-oxide (8) in near-quantitative yields (99%). Subsequent treatment with acetic anhydride (Ac2O) afforded ester rac-9 via Boekelheide rearrangement (75%). , Saponification of rac-9 with KOH in ethanol (EtOH) delivered alcohol rac-10 in 92% yield. Oxidation of alcohol rac-10 under Swern conditions, namely oxalyl chloride and dimethyl sulfoxide (DMSO), followed by triethylamine (Et3N), furnished ketone 6b in 71% yield. Finally, reductive amination with propargylamine afforded rac-2b in 74% yield (Scheme ).

Since isosteres rac-2a and rac-2b were prepared as racemic mixtures, racemic rasagiline (rac-1) was also synthesized for comparison purposes via reductive amination of indan-1-one (11) with propargylamine, affording rac-1 in 79% yield (Scheme ).

4. Synthesis of rac -1 .

4

Open in a new tab

a Reagents and conditions: (i) propargylamine, NaBH­(OAc)3, CH2Cl2.

With the target rasagiline isosteres rac-2a and rac-2b and reference analogs in hand, we next investigated their neurotoxicity and neuroprotective properties in a dopaminergic cell model relevant to PD.

Neurotoxicity Assays

Differentiated SH-SY5Y cells were employed as the neuronal model. Differentiation into a dopaminergic-like phenotype was achieved following a well-established protocol routinely used in our group, involving sequential treatment with retinoic acid and phorbol 12-myristate 13-acetate, yielding a more mature, neuron-like phenotype. The acquisition of a dopaminergic phenotype was confirmed in previous work of the group using suitable neuronal markers, , including increased expression of tyrosine hydroxylase and dopamine transporter. Oxidative stress was induced using PQ, a well-established neurotoxin, which was also used as a positive control for neurotoxicity. PQ is a widely used herbicide with well-documented neurotoxic properties that has been strongly associated with PD-like neurodegenerative alterations. Its toxicity in neuronal cells is primarily mediated by oxidative stress, mitochondrial dysfunction, and the selective vulnerability of dopaminergic neurons, key mechanisms implicated in PD pathogenesis. Accordingly, PQ-based in vitro models represent a relevant approach for evaluating the neuroprotective potential of candidate compounds against PD.

An initial screening was performed to assess the cytotoxicity of the rasagiline derivatives at 10 and 100 μM in differentiated SH-SY5Y cells using the MTT reduction assay (Figure A) and the neutral red (NR) uptake assay (Figure B). The selection of 10 μM was based on previous reports describing the biological activity of rasagiline in SH-SY5Y neuronal models under oxidative stress conditions.

2.

2

Open in a new tab

Cytotoxicity assays. MTT reduction (A) and NR uptake (B) assays performed in differentiated SH-SY5Y cells exposed to the selected rasagiline derivatives (10 and 100 μM, 48 h), PQ (300 μM), and the vehicle control for compound rac-2b (DMSO, 0.5% [v/v]). Data are expressed as a percentage of control (PBS) and presented as mean ± standard deviation. Results were obtained from at least three independent experiments performed in quadruplicate. Statistical analysis was performed using one-way ANOVA followed by Tukey post hoc test (*p < 0.05, **p < 0.01, and ****p < 0.0001 vs control; # p < 0.05, and #### p < 0.0001 vs DMSO 0.5% condition).

Although those studies were conducted in nondifferentiated SH-SY5Y cells, they provide a relevant reference range for compound activity. The higher concentration (100 μM) was included as an upper exploratory dose to evaluate potential cytotoxic effects and to establish a safety margin for subsequent neuroprotection studies.

DMSO (0.5% [v/v] final concentration) was used as the vehicle for compound rac-2b, while the remaining compounds were dissolved in phosphate-buffered saline (PBS).

In both assays, PBS-treated cells served as the control group and were defined as 100% of control. Exposure to PQ resulted in significant cytotoxicity relative to control, as evidenced by decreased MTT reduction (49.91 ± 7.21%, ****p < 0.0001, Figure A) and NR uptake (51.32 ± 4.52%, ****p < 0.0001, Figure B), confirming the expected neurotoxic effect of PQ and validating the assays.

No significant changes were observed in the 0.5% DMSO-treated group compared with the control in both assays (MTT reduction and NR uptake), indicating that this vehicle itself did not influence cellular metabolic activity or lysosomal integrity (Figures A and B, respectively).

Among the tested compounds, no significant differences were observed relative to the respective PBS or 0.5% DMSO vehicles, except for rac-2b. In the MTT reduction assay, rac-2b showed a statistically significant increase relative to the 0.5% DMSO vehicle at 10 μM (102.42 ± 3.16%, # p < 0.05) and at 100 μM (106.56 ± 3.17%, #### p < 0.0001), the latter being also significantly higher than the PBS vehicle (**p < 0.01). In the NR uptake assay, a significant increase was observed only at 100 μM relative to PBS (107.51 ± 11.20%, *p < 0.05). As the 0.5% DMSO caused no significant change, the observed increase cannot be attributed to the vehicle. Moreover, as the values only marginally exceeded 100%, the effect is unlikely to be biologically relevant.

Overall, these data demonstrate that compounds 1, rac-1, rac-2a, and rac-2b do not exhibit cytotoxicity at concentrations up to 100 μM, in clear contrast to the pronounced cytotoxic effects induced by the neurotoxicant PQ, indicating that their half-maximal cytotoxic concentration (CC50) values exceed 100 μM.

Neuroprotective Assays against PQ-Induced Toxicity

Following the initial cytotoxicity assessment, the selected compounds were evaluated for their potential neuroprotective effects against PQ-induced toxicity (300 μM) in differentiated SH-SY5Y neuroblastoma cells exhibiting a dopaminergic phenotype (Figure ). The absence of compound-induced cytotoxicity under basal conditions (Figure ) ensured that any effects observed in the presence of PQ could be attributed to neuroprotection rather than to intrinsic toxicity.

3.

3

Open in a new tab

Neuroprotection assays. MTT reduction (A) and NR uptake (B) assays performed in differentiated SH-SY5Y cells coincubated with the selected rasagiline derivatives (10 and 100 μM, 48 h), including the vehicle for compound rac-2b (DMSO 0.5%), and PQ (300 μM). Data are expressed as a percentage of control (PBS) and are presented as mean ± standard deviation. Results were obtained from at least three independent experiments performed in quadruplicate. Statistical analysis was performed using one-way ANOVA followed by Tukey post hoc test (****p < 0.0001 vs control; # p < 0.05, ## p < 0.01, and #### p < 0.0001 vs PQ; &&& p < 0.001, &&&& p < 0.0001 vs DMSO 0.5% + PQ).

In the presence of PQ, rac-2b significantly conferred protection compared with the corresponding 0.5% DMSO + PQ vehicle control in both the MTT reduction and NR uptake assays (Figure ). At 100 μM, rac-2b increased MTT reduction from 47.48 ± 5.64% to 63.34 ± 5.85% (&&&& p < 0.0001) and NR uptake from 53.60 ± 5.10% to 69.70 ± 13.41% (&&&& p < 0.0001), representing an approximately 16% improvement in both assays. Similar, although less pronounced, effects were observed at 10 μM, with values of 56.85 ± 5.82% (&&& p < 0.001) and 63.43 ± 6.15% (&&& p < 0.001) in the MTT reduction and NR uptake assays, respectively (Figure ). As 0.5% DMSO served as the vehicle for rac-2b, comparison with the corresponding vehicle control ensured that the observed biological effects were attributable to the compound rather than to vehicle-associated effects.

Overall, rac-2b attenuated PQ-induced cytotoxicity, as reflected by improved MTT reduction and NR uptake values, indicating preservation of cellular metabolic activity and lysosomal function.

Similarly, rac-2a also exhibited a significant neuroprotective effect, although this was only evident in the NR uptake assay (Figure B). Compared with PQ-treated cells (51.32 ± 4.52%, ****p < 0.0001), treatment with rac-2a increased NR uptake to 55.75 ± 4.62% (# p < 0.05) and 61.44 ± 7.49% (## p < 0.01) at 10 and 100 μM, respectively.

Compounds 1 and rac-1 also produced a partial neuroprotective effect, with statistically significant improvements observed exclusively in the NR uptake assay (Figure B). At 10 and 100 μM, compound 1 increased NR uptake to 57.05 ± 5.13% (## p < 0.01) and 61.31 ± 6.63% (#### p < 0.0001), respectively; the corresponding NR uptake values for rac-1 were 58.64 ± 6.32% (# p < 0.05) and 68.64 ± 10.18% (## p < 0.01). These findings suggest that both compounds preferentially help preserve lysosomal functionality, with limited effects on mitochondrial metabolic activity under PQ-induced stress. Notably, no significant differences were observed between enantiomerically pure rasagiline (1) and its racemic mixture (rac-1), supporting the use of the racemic derivatives rac-2a and rac-2b throughout this study.

Overall, rac-2a and particularly rac-2b displayed the most consistent neuroprotective profiles against PQ-induced toxicity. Whereas rac-2a exerted a significant protective effect only in the NR uptake assay, rac-2b significantly improved cell viability in both the MTT reduction and NR uptake assays, indicating protection of both mitochondrial metabolic activity and lysosomal integrity. Although all tested compounds significantly attenuated PQ-induced lysosomal damage in the NR uptake assay at both 10 and 100 μM, the magnitude and consistency of the response differed among compounds. Collectively, these findings identify rac-2b as the most promising derivative in this series, exhibiting greater neuroprotective activity than rasagiline under PQ-induced stress.

MAO Inhibition Assay

To determine whether the observed neuroprotective effects were related to MAO inhibition, enzymatic assays were performed to evaluate their inhibitory activity. In these experiments, 1, rac-1, and isosteres rac-2a and rac-2b were tested against human (h)­MAO-A and (h)­MAO-B using a time-dependent Amplex Red oxidation by horseradish peroxidase (AR/HRP) assay. For hMAO-B, inhibition was assessed after 5, 15, and 30 min preincubation, whereas for hMAO-A, a 15 min preincubation period was used, as previously described. ,

As expected, both 1 (commercially available enantiomerically pure rasagiline) and its racemate, rac-1, displayed potent and time-dependent inhibition of hMAO-B (Table and Figure ). Compound 1 exhibited submicromolar potency at short preincubation times (IC50 = 0.375 μM at 5 min), which further increased upon prolonged preincubation (IC50 = 0.098 μM at 30 min), consistent with a time-dependent inhibition mechanism (Table and Figure ). The racemate rac-1 showed a similar trend, albeit with approximately 2-fold lower potency across all time points (IC50 = 0.744 μM at 5 min; 0.184 μM at 30 min), reflecting the contribution of the inactive enantiomer.

1. Inhibitory Activity (IC50, μM) of Compounds 1, rac-1, rac-2a, and rac-2b against MAO Isoforms (hMAO-A and hMAO-B), Determined Using the AR/HRP Assay at Different Preincubation Times.

Compound hMAO-A IC50 (μM) hMAO-B IC50 (μM)
1 15 min: 50.35 ± 9.27 5 min: 0.375 ± 0.027
15 min: 0.186 ± 0.013
30 min: 0.098 ± 0.006
rac-1 15 min: 90.05 ± 19.29 5 min: 0.744 ± 0.063
15 min: 0.373 ± 0.020
30 min: 0.184 ± 0.011
rac-2a 15 min: 37.48 ± 13.81 5 min: 57.73 ± 10.94
15 min: 71.54 ± 16.09
30 min: 66.56 ± 12.63
rac-2b n.a. 5 min: 74.74 ± 15.19
15 min: 49.27 ± 6.18
30 min: 47.45 ± 13.96
Open in a new tab
a

n.a., not active (residual activity: RA at 100 μM > 50%)

4.

4

Open in a new tab

Concentration–response curves for inhibition of hMAO-B by compounds 1 (A), rac-1 (B), rac-2a (C), and rac-2b (D), determined using the AR/HRP assay at different preincubation times (5, 15, and 30 min).

In contrast, both reference compounds displayed weak inhibition of hMAO-A, with IC50 values in the tens of micromolar range (50.35 μM for 1 and 90.05 μM for rac-1, Table ), confirming their marked selectivity toward hMAO-B.

A markedly different profile was observed for the novel analogs rac-2a and rac-2b. For hMAO-B, both compounds exhibited only weak inhibition, with IC50 values in the high micromolar range (approximately 47–75 μM) and, importantly, no significant time-dependent increase in potency (Table , Figure ). When compared to the racemic reference rac-1, this corresponds to a loss of activity of approximately 2 orders of magnitude, shifting from submicromolar to tens of micromolar IC50 values. Relative to 1, the decrease reaches nearly 3 orders of magnitude at longer preincubation times.

A similar trend was observed for hMAO-A (Table ). While rac-1 already displays weak inhibition (IC50 = 90.05 μM), rac-2a shows only marginally improved activity (IC50 = 37.48 μM), remaining within the same order of magnitude, and rac-2b exhibited no detectable inhibition under the experimental conditions. Overall, no meaningful enhancement of hMAO-A inhibition is observed for the new analogs, and all compounds remain weak inhibitors of this isoform.

Importantly, comparison of rac-2a and rac-2b with the racemic reference rac-1 indicates that the pronounced loss of hMAO-B inhibitory activity arises from the structural modifications introduced, rather than stereochemical effects (Table , Figure ). At the same time, hMAO-A inhibition remains weak across the series (Table ). Furthermore, the absence of time-dependent inhibition for both compounds, together with their markedly reduced hMAO-B inhibitory potency, indicates that they do not display the characteristic behavior of mechanism-based MAO-B inhibition observed for rasagiline under the experimental conditions employed.

The substantially attenuated inhibitory activity observed for the azaindane derivatives may be rationalized based on structural features of MAO-B. Crystallographic analysis (PDB: 1S2Q) reveals a predominantly hydrophobic active site composed of a substrate cavity and an entrance cavity, connected by the gating residue Ile199. Compared to rasagiline, the introduction of a nitrogen atom into the aromatic ring increases polarity and may perturb favorable interactions within the predominantly hydrophobic MAO-B active site. Given the compact nature of the binding pocket and its sensitivity to subtle structural changes, this modification may affect ligand recognition and/or subsequent steps required for irreversible inhibition, including enzyme-catalyzed oxidation of the propargylamine moiety followed by covalent modification of the FAD cofactor. Thus, while these considerations provide a plausible structural rationale for the experimentally observed reduction in MAO-B inhibition, the present data do not establish which step of this multistep process is primarily affected by the ring nitrogen. ,

Collectively, these results demonstrate that rac-2a and rac-2b lack the potent, time-dependent hMAO-B inhibition characteristic of rasagiline, while maintaining only weak or negligible activity toward hMAO-A across the series. This corresponds to a reduction of approximately 2 to 3 orders of magnitude in hMAO-B inhibitory potency relative to rasagiline. Overall, these findings indicate that the indane-to-azaindane isosteric modification effectively abolishes potent hMAO-B inhibition, suggesting that rac-2a and rac-2b are unlikely to exert their biological effects through MAO inhibition.

Overall, a straightforward and reliable synthetic route for the assembly of rasagiline isostere rac-2a was established based on the direct, regioselective oxidation of CPP to afford ketone 6a as a key intermediate, using t BuOOH (in nonane) catalyzed by Mn­(OAc)2. Despite the moderate chemical yield obtained for ketone 6a under this protocol (42%), this value is within the range reported for photochemical and electrochemical processes (41–57%). Importantly, the transformation is operationally simple, fully regioselective, facilitates chromatographic purification, and does not require any specialized setup or equipment.

From a medicinal chemistry perspective, this work expands previous studies on rasagiline (1) in PQ-induced neurotoxicity by showing preservation of lysosomal integrity, as assessed by the NR uptake assay, in dopaminergic-differentiated SH-SY5Y cells. Within this context, rac-2a displayed a neuroprotective profile comparable to rasagiline, whereas its regioisomer rac-2b exhibited superior neuroprotective activity in the PQ-insulted differentiated SH-SY5Y cellular model employed, indicating that the indane-to-azaindane strategy is highly dependent on the position of nitrogen substitution. In contrast, both regioisomers markedly reduced MAO-B inhibitory activity, regardless of substitution pattern. Collectively, these results highlight a clear divergence between neuroprotective efficacy and MAO inhibition governed by azaindane regiochemistry. Notably, the data support the conclusion that the neuroprotective effects observed for rac-2a and rac-2b are independent of MAO-B inhibition, highlighting a pharmacological dissociation between these activities and suggesting a potentially safer neuroprotective mechanism, free from MAO-related adverse effects associated with tyramine-mediated interactions.

Altogether, these findings support the progression of this project toward the enantioselective preparation of these rasagiline isosteres, paving the way for the development of new neuroprotective leads to halt the progression of neurodegenerative disorders such as PD.

Supplementary Material

ml6c00407_si_001.pdf (1.6MB, pdf)

Acknowledgments

The authors thank Mariana Andrade and Sílvia Maia from Centro de Materiais da Universidade do Porto (CEMUP) for their technical assistance with the NMR and HRMS experiments, respectively.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.6c00407.

  • In silico prediction of blood-brain barrier permeability, detailed synthetic procedures and copies of 1H, 13C­{1H}, DEPT-135 NMR spectra for compounds 4, 5, 6a, 6b, rac-1, rac-2a, and rac-2b, and HRMS data for rac-2a (PDF)

#.

Biomedicine Department, Faculty of Medicine, University of Porto, 4200–319 Porto, Portugal

I.E.S.-D. conceived and designed the experiments; I.E.S.-D., G.M.A., X.C.C., H.F.C.-A., and M.B.I.-C. performed the organic chemistry experiments; S.C.S.-R. and V.M.C. performed the toxicological experiments; D.K. and S.G. performed the enzymatic assays; I.E.S.-D., S.C.S.-R., V.M.C., D.K., S.G. and J.E.R.-B. analyzed the data; I.E.S.-D. wrote the paper. All authors approved the final version of the manuscript.

This work received financial support from PT national funds (FCT/MECI, Fundação para a Ciência e a Tecnologia and Ministério da Educação, Ciência e Inovação) through project 2023.14440.PEX (DOI: 10.54499/2023.14440.PEX). FCT/MECI is also acknowledged for supporting project UID/50006/2025 (DOI: 10.54499/UID/50006/2025) - Laboratório Associado para a Química Verde - Tecnologias e Processos Limpos, and projects UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences (UCIBIO) and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy – i4HB. I.E.S.-D. and J.E.R.-B. thank funding through FEDER funds (COMPETE 2030), operation no. 15152, under reference COMPETE2030-FEDER-00881500. I.E.S.-D. thanks FCT for funding through the Individual Call to Scientific Employment Stimulus with reference 2020.02311.CEECIND/CP1596/CT0004 (DOI: 10.54499/2020.02311.CEECIND/CP1596/CT0004) and for funding through the research grants 2022.01175.PTDC (DOI: 10.54499/2022.01175.PTDC) and 2023.14440.PEX (DOI: 10.54499/2023.14440.PEX). V.M.C. is supported by FCT/Agência de Investigação e Inovação – AI2, Portugal, through the FCT-Tenure Programme, under a permanent research position [2023.13694.TENURE.051] hosted by the Faculty of Medicine, University of Porto, and integrated into the RISE-Health Research Unit (UID/06397/2025). S.C.S.-R., X.C.C., and H.F.C.-A. thank FCT for the Ph.D. grants SFRH/BD/147463/2019 (DOI: 10.54499/SFRH/BD/147463/2019), 2024.02245.BD (DOI: 10.54499/2024.02245.BD), and UI/BD/154888/2023 (DOI: 10.54499/UI/BD/154888/2023), respectively. S.C.S.-R. and M.B.I.-C. also thank REQUIMTE for the postdoc contract (REQUIMTE 2025–43) and research grant (REQUIMTE 2025–42), respectively. D.K. and S.G. were supported by the Slovenian Research and Innovation Agency (ARIS) research core funding No. P1–0208.

Safety statement: No unexpected or unusually high safety hazards were encountered.

The authors declare no competing financial interest.

References

  1. Zhou Z. D., Yi L. X., Wang D. Q., Lim T. M., Tan E. K.. Role of dopamine in the pathophysiology of Parkinson’s disease. Transl. Neurodegener. 2023;12:44. doi: 10.1186/s40035-023-00378-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Dias V., Junn E., Mouradian M. M.. The role of oxidative stress in Parkinson’s disease. J. Parkinsons Dis. 2013;3:461–491. doi: 10.3233/JPD-130230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Youdim M. B., Edmondson D., Tipton K. F.. The therapeutic potential of monoamine oxidase inhibitors. Nat. Rev. Neurosci. 2006;7:295–309. doi: 10.1038/nrn1883. [DOI] [PubMed] [Google Scholar]
  4. Bortolato M., Chen K., Shih J. C.. Monoamine oxidase inactivation: From pathophysiology to therapeutics. Adv. Drug Delivery Rev. 2008;60:1527–1533. doi: 10.1016/j.addr.2008.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Heikkila R. E., Terleckyj I., Sieber B. A.. Monoamine oxidase and the bioactivation of MPTP and related neurotoxins: Relevance to DATATOP. J. Neural Transm. Suppl. 1990;32:217–227. doi: 10.1007/978-3-7091-9113-2_32. [DOI] [PubMed] [Google Scholar]
  6. Youdim M. B., Gross A., Finberg J. P.. Rasagiline [N-propargyl-1R­(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br. J. Pharmacol. 2001;132:500–506. doi: 10.1038/sj.bjp.0703826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Sterling J., Veinberg A., Lerner D., Goldenberg W., Levy R., Youdim M., Finberg J.. (R)­(+)-N-propargyl-1-aminoindan (rasagiline) and derivatives: Highly selective and potent inhibitors of monoamine oxidase B. J. Neural Transm. Suppl. 1998;52:301–305. doi: 10.1007/978-3-7091-6499-0_30. [DOI] [PubMed] [Google Scholar]
  8. Mínguez-Mínguez S., Solís-García del Pozo J., Jordán J.. Rasagiline in Parkinson’s disease: A review based on meta-analysis of clinical data. Pharmacol. Res. 2013;74:78–86. doi: 10.1016/j.phrs.2013.05.005. [DOI] [PubMed] [Google Scholar]
  9. Youdim M. B. H., Fridkin M., Zheng H.. Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. Mech. Ageing Dev. 2005;126:317–326. doi: 10.1016/j.mad.2004.08.023. [DOI] [PubMed] [Google Scholar]
  10. Rascol O., Brooks D. J., Melamed E., Oertel W., Poewe W., Stocchi F., Tolosa E.. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): A randomised, double-blind, parallel-group trial. Lancet. 2005;365:947–954. doi: 10.1016/S0140-6736(05)71083-7. [DOI] [PubMed] [Google Scholar]
  11. Guay D. R.. Rasagiline (TVP-1012): A new selective monoamine oxidase inhibitor for Parkinson’s disease. Am. J. Geriatr. Pharmacother. 2006;4:330–346. doi: 10.1016/j.amjopharm.2006.12.001. [DOI] [PubMed] [Google Scholar]
  12. Oldfield V., Keating G. M., Perry C. M.. Rasagiline: A review of its use in the management of Parkinson’s disease. Drugs. 2007;67:1725–1747. doi: 10.2165/00003495-200767120-00006. [DOI] [PubMed] [Google Scholar]
  13. Gallagher D. A., Schrag A.. Impact of newer pharmacological treatments on quality of life in patients with Parkinson’s disease. CNS Drugs. 2008;22:563–586. doi: 10.2165/00023210-200822070-00003. [DOI] [PubMed] [Google Scholar]
  14. Bar-Am O., Weinreb O., Amit T., Youdim M. B.. The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline. J. Neurochem. 2010;112:1131–1137. doi: 10.1111/j.1471-4159.2009.06542.x. [DOI] [PubMed] [Google Scholar]
  15. Youdim M. B.. Multi target neuroprotective and neurorestorative anti-Parkinson and anti-Alzheimer drugs ladostigil and m30 derived from rasagiline. Exp. Neurobiol. 2013;22:1–10. doi: 10.5607/en.2013.22.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sousa C. A. D., Sampaio-Dias I. E., Rizzo-Aguiar F., García-Mera X., Rodríguez-Borges J. E.. Enantiopure synthesis of 7-(1-pyrindanyl)­propargyl ethers as rasagiline analogues via chemical or enzymatic resolution of 1-pyrindan-7-ol. RSC Adv. 2015;5:104509–104515. doi: 10.1039/C5RA24868J. [DOI] [Google Scholar]
  17. Binda C., Hubálek F., Li M., Herzig Y., Sterling J., Edmondson D. E., Mattevi A.. Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class. J. Med. Chem. 2004;47:1767–1774. doi: 10.1021/jm031087c. [DOI] [PubMed] [Google Scholar]
  18. Maruyama W., Akao Y., Carrillo M. C., Kitani K.-i., Youdium M. B. H., Naoi M.. Neuroprotection by propargylamines in Parkinson’s disease: Suppression of apoptosis and induction of prosurvival genes. Neurotoxicol. Teratol. 2002;24:675–682. doi: 10.1016/S0892-0362(02)00221-0. [DOI] [PubMed] [Google Scholar]
  19. Youdim M. B. H., Bar Am O., Yogev-Falach M., Weinreb O., Maruyama W., Naoi M., Amit T.. Rasagiline: Neurodegeneration, neuroprotection, and mitochondrial permeability transition. J. Neurosci. Res. 2005;79:172–179. doi: 10.1002/jnr.20350. [DOI] [PubMed] [Google Scholar]
  20. Cronin A., Grealy M.. Neuroprotective and neuro-restorative effects of minocycline and rasagiline in a zebrafish 6-hydroxydopamine model of Parkinson’s disease. Neuroscience. 2017;367:34–46. doi: 10.1016/j.neuroscience.2017.10.018. [DOI] [PubMed] [Google Scholar]
  21. Wu Y., Kazumura K., Maruyama W., Osawa T., Naoi M.. Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: A novel anti-apoptotic function for neuroprotection. J. Neural Transm. 2015;122:1399–1407. doi: 10.1007/s00702-015-1398-0. [DOI] [PubMed] [Google Scholar]
  22. Akao Y., Maruyama W., Shimizu S., Yi H., Nakagawa Y., Shamoto-Nagai M., Youdim M. B. H., Tsujimoto Y., Naoi M.. Mitochondrial permeability transition mediates apoptosis induced by N-methyl­(R)­salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1­(R)-aminoindan. J. Neurochem. 2002;82:913–923. doi: 10.1046/j.1471-4159.2002.01047.x. [DOI] [PubMed] [Google Scholar]
  23. Weinreb O., Badinter F., Amit T., Bar-Am O., Youdim M. B. H.. Effect of long-term treatment with rasagiline on cognitive deficits and related molecular cascades in aged mice. Neurobiol. Aging. 2015;36:2628–2636. doi: 10.1016/j.neurobiolaging.2015.05.009. [DOI] [PubMed] [Google Scholar]
  24. Weinreb O., Amit T., Bar-Am O., Youdim M. B. H.. Rasagiline: A novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog. Neurobiol. 2010;92:330–344. doi: 10.1016/j.pneurobio.2010.06.008. [DOI] [PubMed] [Google Scholar]
  25. Maruyama W., Akao Y., Youdim M. B., Naoi M.. Neurotoxins induce apoptosis in dopamine neurons: protection by N-propargylamine-1­(R)- and (S)-aminoindan, rasagiline and TV1022. J. Neural Transm. Suppl. 2000:171–186. doi: 10.1007/978-3-7091-6301-6_11. [DOI] [PubMed] [Google Scholar]
  26. Maruyama W., Youdim M. B. H., Naoi M.. Antiapoptotic properties of rasagiline, N-propargylamine-1­(R)-aminoindan, and its optical (S)-isomer, TV1022. Ann. N.Y. Acad. Sci. 2001;939:320–329. doi: 10.1111/j.1749-6632.2001.tb03641.x. [DOI] [PubMed] [Google Scholar]
  27. Jiang D. Q., Wang H. K., Wang Y., Li M. X., Jiang L. L., Wang Y.. Rasagiline combined with levodopa therapy versus levodopa monotherapy for patients with Parkinson’s disease: A systematic review. Neurol. Sci. 2020;41:101–109. doi: 10.1007/s10072-019-04050-8. [DOI] [PubMed] [Google Scholar]
  28. Yogev-Falach M., Amit T., Bar-Am O., Youdim M. B.. The importance of propargylamine moiety in the anti-Parkinson drug rasagiline and its derivatives in MAPK-dependent amyloid precursor protein processing. FASEB J. 2003;17:2325–2327. doi: 10.1096/fj.03-0078fje. [DOI] [PubMed] [Google Scholar]
  29. Siddiqui M. A., Plosker G. L.. Rasagiline. Drugs Aging. 2005;22:83–91. doi: 10.2165/00002512-200522010-00006. [DOI] [PubMed] [Google Scholar]
  30. Youdim M. B., Weinstock M.. Novel neuroprotective anti-Alzheimer drugs with anti-depressant activity derived from the anti-Parkinson drug, rasagiline. Mech. Ageing Dev. 2002;123:1081–1086. doi: 10.1016/S0047-6374(01)00391-8. [DOI] [PubMed] [Google Scholar]
  31. Naoi M., Maruyama W., Youdim M. B., Yu P., Boulton A. A.. Anti-apoptotic function of propargylamine inhibitors of type-B monoamine oxidase. Inflammopharmacology. 2003;11:175–181. doi: 10.1163/156856003765764344. [DOI] [PubMed] [Google Scholar]
  32. Bar-Am O., Weinreb O., Amit T., Youdim M. B.. Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. FASEB J. 2005;19:1899–1901. doi: 10.1096/fj.05-3794fje. [DOI] [PubMed] [Google Scholar]
  33. Binda C., Hubálek F., Li M., Herzig Y., Sterling J., Edmondson D. E., Mattevi A.. Binding of rasagiline-related inhibitors to human monoamine oxidases: A kinetic and crystallographic analysis. J. Med. Chem. 2005;48:8148–8154. doi: 10.1021/jm0506266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Finberg J. P., Rabey J. M.. Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology. Front. Pharmacol. 2016;7:340. doi: 10.3389/fphar.2016.00340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pereira C. S., Salgado S., Rizzo-Aguiar F., Garcia-Mera X., Rodríguez-Borges J. E.. Synthesis of new propargylated 1-pyrindane derivatives as rasagiline analogues. Synlett. 2013;24:837–838. doi: 10.1055/s-0032-1318492. [DOI] [Google Scholar]
  36. Rizzo-Aguiar F., Sousa C. A. D., García-Mera X., Rodríguez-Borges J. E.. Synthesis and characterization of 1-pyrindane derivatives as rasagiline analogues. Chem. Data Collect. 2016;5–6:21–27. doi: 10.1016/j.cdc.2016.10.001. [DOI] [Google Scholar]
  37. Wiseman L. R., Lamb H. M.. Cefpirome. A review of its antibacterial activity, pharmacokinetic properties and clinical efficacy in the treatment of severe nosocomial infections and febrile neutropenia. Drugs. 1997;54:117–140. doi: 10.2165/00003495-199754010-00013. [DOI] [PubMed] [Google Scholar]
  38. Song Z. J., Zhao M., Frey L., Li J., Tan L., Chen C. Y., Tschaen D. M., Tillyer R., Grabowski E. J. J., Volante R., Reider P. J., Kato Y., Okada S., Nemoto T., Sato H., Akao A., Mase T.. Practical asymmetric synthesis of a selective endothelin a receptor (ETA) antagonist. Org. Lett. 2001;3:3357–3360. doi: 10.1021/ol016601s. [DOI] [PubMed] [Google Scholar]
  39. Altundas A., Ayvaz S., Logoglu E.. Synthesis and evaluation of a series of aminocyanopyridines as antimicrobial agents. Med. Chem. Res. 2011;20:1–8. doi: 10.1007/s00044-009-9273-x. [DOI] [Google Scholar]
  40. Kolb S., Goddard M.-L., Loukaci A., Mondésert O., Ducommun B., Braud E., Garbay C.. 5-Substituted [1]­pyrindine derivatives with antiproliferative activity. Eur. J. Med. Chem. 2010;45:896–901. doi: 10.1016/j.ejmech.2009.11.028. [DOI] [PubMed] [Google Scholar]
  41. Montes M., Brand E., Miteva M. A., Goddard M. L., Mondésert O., Kolb S., Brun M. P., Ducommun B., Garbay C., Villoutreix B. O.. Receptor-based virtual ligand screening for the identification of novel CDC25 phosphatase inhibitors. J. Chem. Inf. Model. 2008;48:157–165. doi: 10.1021/ci700313e. [DOI] [PubMed] [Google Scholar]
  42. Neves P., Nogueira L. S., Valente A. A., Pillinger M., Gonçalves I. S., Sampaio-Dias I. E., Sousa C. A. D., Rizzo-Aguiar F., Rodríguez-Borges J. E.. Performance of chiral tetracarbonylmolybdenum pyrindanyl amine complexes in catalytic olefin epoxidation. J. Organomet. Chem. 2018;858:29–36. doi: 10.1016/j.jorganchem.2018.01.003. [DOI] [Google Scholar]
  43. Caprathe B. W., Jaen J. C., Wise L. D., Heffner T. G., Pugsley T. A., Meltzer L. T., Parvez M.. Dopamine autoreceptor agonists as potential antipsychotics. 3. 6-Propyl-4,5,5a,6,7,8-hexahydrothiazolo­[4,5-f]­quinolin-2-amine. J. Med. Chem. 1991;34:2736–2746. doi: 10.1021/jm00113a010. [DOI] [PubMed] [Google Scholar]
  44. Ren L., Wang L., Lv Y., Shang S., Chen B., Gao S.. Synthesis of 6,7-dihydro-5H-cyclopenta­[b]­pyridin-5-one analogues through manganese-catalyzed oxidation of the CH2 adjacent to pyridine moiety in water. Green Chem. 2015;17:2369–2372. doi: 10.1039/C4GC02471K. [DOI] [Google Scholar]
  45. Nakamura S., Sugimoto H., Ohwada T.. Superacid-catalyzed intramolecular cyclization reaction of arylcyanopropionate: Geminal substitution effect on superelectrophilicity. J. Org. Chem. 2008;73:4219–4224. doi: 10.1021/jo800674h. [DOI] [PubMed] [Google Scholar]
  46. Li X., Bai F., Liu C., Ma X., Gu C., Dai B.. Selective electrochemical oxygenation of alkylarenes to carbonyls. Org. Lett. 2021;23:7445–7449. doi: 10.1021/acs.orglett.1c02651. [DOI] [PubMed] [Google Scholar]
  47. Marko J. A., Durgham A., Bretz S. L., Liu W.. Electrochemical benzylic oxidation of C–H bonds. Chem. Commun. 2019;55:937–940. doi: 10.1039/C8CC08768G. [DOI] [PubMed] [Google Scholar]
  48. Lesieur M., Genicot C., Pasau P.. Development of a flow photochemical aerobic oxidation of benzylic C–H bonds. Org. Lett. 2018;20:1987–1990. doi: 10.1021/acs.orglett.8b00540. [DOI] [PubMed] [Google Scholar]
  49. Yu H., Zhao Q., Wei Z., Wu Z., Li Q., Han S., Wei Y.. Iron-catalyzed oxidative functionalization of C­(sp3)–H bonds under bromide-synergized mild conditions. Chem. Commun. 2019;55:7840–7843. doi: 10.1039/C9CC03939B. [DOI] [PubMed] [Google Scholar]
  50. Boekelheide V., Lehn W. L.. The rearrangement of substituted pyridine N-oxides with acetic anhydride1.2 . J. Org. Chem. 1961;26:428–430. doi: 10.1021/jo01061a037. [DOI] [Google Scholar]
  51. Boekelheide V., Linn W. J.. Rearrangements of N-oxides. A novel synthesis of pyridyl carbinols and aldehydes. J. Am. Chem. Soc. 1954;76:1286–1291. doi: 10.1021/ja01634a026. [DOI] [Google Scholar]
  52. Barbosa D. J., Capela J. P., Silva R., Vilas-Boas V., Ferreira L. M., Branco P. S., Fernandes E., Bastos Mde L., Carvalho F.. The mixture of ″ecstasy″ and its metabolites is toxic to human SH-SY5Y differentiated cells at in vivo relevant concentrations. Arch. Toxicol. 2014;88:455–473. doi: 10.1007/s00204-013-1120-7. [DOI] [PubMed] [Google Scholar]
  53. Ferreira P. S., Nogueira T. B., Costa V. M., Branco P. S., Ferreira L. M., Fernandes E., Bastos M. L., Meisel A., Carvalho F., Capela J. P.. Neurotoxicity of ″ecstasy″ and its metabolites in human dopaminergic differentiated SH-SY5Y cells. Toxicol. Lett. 2013;216:159–170. doi: 10.1016/j.toxlet.2012.11.015. [DOI] [PubMed] [Google Scholar]
  54. Di Monte, D. A. Chapter 15 - Paraquat-induced Neurodegeneration: a Model of Parkinson’s Disease Risk Factors. In Parkinson’s Disease; Nass, R. , Przedborski, S. , Eds.; Academic Press: 2008; pp 207–217. [Google Scholar]
  55. Tanner C. M., Kamel F., Ross G. W., Hoppin J. A., Goldman S. M., Korell M., Marras C., Bhudhikanok G. S., Kasten M., Chade A. R., Comyns K., Richards M. B., Meng C., Priestley B., Fernandez H. H., Cambi F., Umbach D. M., Blair A., Sandler D. P., Langston J. W.. Rotenone, Paraquat, and Parkinson’s Disease. Environ. Health Perspect. 2011;119:866–872. doi: 10.1289/ehp.1002839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Chau K. Y., Cooper J. M., Schapira A. H.. Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells. Neurochem. Int. 2010;57:525–529. doi: 10.1016/j.neuint.2010.06.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Knez D., Colettis N., Iacovino L. G., Sova M., Pišlar A., Konc J., Lešnik S., Higgs J., Kamecki F., Mangialavori I., Dolšak A., Žakelj S., Trontelj J., Kos J., Binda C., Marder M., Gobec S.. Stereoselective activity of 1-propargyl-4-styrylpiperidine-like analogues that can discriminate between monoamine oxidase isoforms A and B. J. Med. Chem. 2020;63:1361–1387. doi: 10.1021/acs.jmedchem.9b01886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Košak U., Knez D., Coquelle N., Brus B., Pišlar A., Nachon F., Brazzolotto X., Kos J., Colletier J.-P., Gobec S.. N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer’s agents. Bioorg. Med. Chem. 2017;25:633–645. doi: 10.1016/j.bmc.2016.11.032. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml6c00407_si_001.pdf (1.6MB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES