Joshua J.
Bornstein
c,
Todd J.
Eckroat
ac,
Jacob L.
Houghton
ac,
Christopher K.
Jones
bc,
Keith D.
Green
c and
Sylvie
Garneau-Tsodikova
*abc
aDepartment of Medicinal Chemistry in the College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-2216, USA. E-mail: sylviegt@umich.edu; Fax: +734-615-5521; Tel: +734-615-2736
bChemical Biology Doctoral Program, University of Michigan, Ann Arbor, MI 48109-2216, USA
cLife Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216, USA
First published on 9th March 2011
Alzheimer's disease (AD) is a complex syndrome characterized by the degeneration of the brain and central nervous system that may be caused by an assortment of genetic and environmental factors. Consequently, a conjunctive approach targeting multiple affecters of AD could lead to improved drug candidates for the treatment of AD. A convergent chemical synthetic approach yielded a series of COMPOUND LINKS
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Download mol file of compoundtacrine-COMPOUND LINKS
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Download mol file of compoundmefenamic acid hybrids that were evaluated for their ability to inhibit acetylcholinesterase (AChE). A majority of the compounds tested showed low nanomolar IC50 values, an improvement over the parent compound, COMPOUND LINKS
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Download mol file of compoundtacrine, suggesting that they could be effective in increasing cholinergic function. Additionally, an assay to evaluate the compounds upon exposure to reactive oxygen species was performed, the results of which may suggest a role for the COMPOUND LINKS
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Download mol file of compoundmefenamic acid moiety in the inhibition of AChE. Molecular modeling studies were performed to rationalize the experimental results.
One of the primary pharmacological strategies employed in the treatment of AD has been inhibition of cholinesterases (ChEs). These therapies aim to decrease the rate of decomposition of COMPOUND LINKS
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Download mol file of compoundACh at synapses in the brain thereby raising the potential for increased levels of EAA transmission and improved cognitive function. This strategy has proved moderately successful, yielding potent reversible acetylcholinesterase inhibitors (AChEi) such as COMPOUND LINKS
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Download mol file of compoundtacrine (1) (Fig. 1), COMPOUND LINKS
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Download mol file of compounddonepezil, and COMPOUND LINKS
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Download mol file of compoundgalantamine, as well as substrate mimics such as COMPOUND LINKS
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Download mol file of compoundneostigmine and COMPOUND LINKS
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Download mol file of compoundpyridostigmine, all of which have shown benefit in the management of AD symptoms to varying degrees. However, despite the moderate clinical successes that have been observed, it has been suggested that these treatments, highlighted by clinical studies of COMPOUND LINKS
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Download mol file of compounddonepezil, are not cost-effective and that an alternative approach may provide better outcomes.4,5 Nonetheless, interest in developing improved ChE inhibitors for treatment of AD has increased recently, likely due to the body of empirical evidence showing the benefits of ChE inhibitors in AD patients as well as the lack of successful alternative approaches.
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Fig. 1 Structures of COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundtacrine (1) and COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundmefenamic acid (2). |
Other factors responsible for the onset and progression of AD have been identified, including inflammatory responses and the resultant increased oxidative stress in the form of free-radicals. The increase in oxidative stress related to the natural decline in an aging body's defense mechanisms often precedes the onset of the previously mentioned indications associated with AD. There is substantial epidemiological evidence linking the development of AD to inflammatory processes in the brain6 as well as evidence that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) may improve cognition and delay the progression of AD.7–10 Given this information, it is evident that treatment of only a single determinant of the pathology of AD is not an effective approach. Furthermore, the evidence implies that treatment of multiple determinants of the disease, especially those related to oxidative stress, may provide synergistic effects.
One solution to this type of problem that has recently emerged is a conjunctive approach in which two biologically active molecules with similar or dissimilar mechanisms of action are combined into a single molecule to improve potency and/or exhibit multiple modes of action, resulting in a synergistic effect. COMPOUND LINKS
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Download mol file of compoundTacrine-based dimers and hybrids with improved pharmacological properties have been the target of a number of discovery efforts in the past decade, leading in several cases to compounds with desirable synergy and improved potency.11–15
Based on the potential of reported COMPOUND LINKS
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Download mol file of compoundtacrine-based molecules, we decided to take a similar approach in identifying compounds with the potential to serve as multi-functioning therapeutics. The ability of NSAIDS such as COMPOUND LINKS
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Download mol file of compoundmefenamic acid (2) to inactivate enzymes, including AChE, in the presence of peroxidases and their potential for AD treatment has been well-characterized in the literature (Fig. 1).9,16–18 Studies have shown that COMPOUND LINKS
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Download mol file of compoundmefenamic acid is capable of decreasing the occurence of free-radicals and attenuating Aβ peptide-induced neurotoxicity while improving cognitive impairments.10 Additionally, it has been suggested that AChE may accelerate the formation of stable amyloid fibrils and stable Aβ complexes.19 This role is attributed to the peripheral anionic site (PAS) as COMPOUND LINKS
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Download mol file of compoundpropidium iodide, a PAS binding molecule, has proved effective in reducing Aβ aggregation while there are no similar reports implicating CAS inhibitors.20 The numerous desirable properties of COMPOUND LINKS
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Download mol file of compoundmefenamic acid led us to believe that it would be an ideal scaffold to incorporate into a series of COMPOUND LINKS
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Download mol file of compoundtacrine-based hybrid molecules aimed at both the CAS and PAS, taking advantage of tacrine's affinity for the CAS and using it to guide the COMPOUND LINKS
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Download mol file of compoundmefenamic acid portion of the molecules to the PAS. This type of strategy has been widely discussed in the literature and was recently reviewed.21
Herein, we report the synthesis and evaluation of a series of COMPOUND LINKS
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Download mol file of compoundtacrine- and 6-chlorotacrine-COMPOUND LINKS
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Download mol file of compoundmefenamic acid hybrid molecules aimed at combining the AChE inhibitor properties of COMPOUND LINKS
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Download mol file of compoundtacrine with the antioxidant and AChE modulating properties of COMPOUND LINKS
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Download mol file of compoundmefenamic acid into a single, dual-action molecule for the treatment of AD. This conjunctive medicinal chemistry approach led to the identification of nanomolar and sub-nanomolar inhibitors of AChE.
Compda | Series | R | n | n′ | IC50 (nM)b | ROS IC50 (nM) |
---|---|---|---|---|---|---|
a See Scheme 1 for chemical structures. b AChE from eel was used. | ||||||
1 | 52.4 ± 7.3 | 183 ± 21 | ||||
2 | > 1.25 mM | 6120 ± 680 | ||||
1 and 2 (1![]() ![]() |
68.7 ± 3.8 | 83.9 ± 0.4 | ||||
3 | > 25 μM | |||||
4 | > 50 μM | |||||
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundNeostigmine |
4.6 ± 1.0 | |||||
COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundPyridostigmine |
82.0 ± 1.5 | |||||
10a | A | H | 6 | 2.24 ± 0.11 | 0.129 ± 0.030 | |
10b | A | H | 7 | 1.39 ± 0.21 | 25.2 ± 4.5 | |
10c | A | H | 8 | 75.5 ± 19.2 | 0.045 ± 0.015 | |
10d | A | H | 9 | 1.54 ± 0.17 | 15.1 ± 0.2 | |
10e | A | H | 10 | 385 ± 48 | 0.908 ± 0.267 | |
10f | A | H | 12 | 50.9 ± 1.4 | 6.94 ± 1.42 | |
11a | A | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
6 | 7230 ± 187 | 1.02 ± 0.36 | |
11b | A | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
7 | 1380 ± 340 | 29.8 ± 4.0 | |
11c | A | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
8 | 0.495 ± 0.064 | 1.49 ± 0.30 | |
11d | A | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
9 | 6.94 ± 0.66 | 6.72 ± 0.78 | |
11e | A | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
10 | 0.776 ± 0.108 | 1.85 ± 0.11 | |
11f | A | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
12 | 2360 ± 830 | 16.2 ± 1.8 | |
12a | B | H | 3 | 1 | 87.3 ± 33.6 | 47.5 ± 11.5 |
12b | B | H | 3 | 2 | 3800 ± 280 | 7.92 ± 1.96 |
12c | B | H | 3 | 3 | 3730 ± 253 | 23.0 ± 9.0 |
12d | B | H | 3 | 5 | 811 ± 70 | 20.2 ± 6.5 |
12e | B | H | 4 | 1 | 262 ± 68 | 53.6 ± 3.8 |
12f | B | H | 4 | 2 | 426 ± 86 | 2.43 ± 0.36 |
12g | B | H | 4 | 3 | 89.7 ± 11.3 | 14.6 ± 2.4 |
12h | B | H | 4 | 5 | 1860 ± 290 | 34.0 ± 9.0 |
12i | B | H | 6 | 1 | 18.3 ± 4.0 | 54.8 ± 4.7 |
12j | B | H | 6 | 2 | 985 ± 95 | 40.2 ± 8.4 |
12k | B | H | 6 | 3 | 195 ± 27 | 29.9 ± 11.1 |
12l | B | H | 6 | 5 | 1440 ± 197 | 34.0 ± 2.4 |
12m | B | H | 7 | 1 | 5.55 ± 1.21 | 15.3 ± 6.6 |
12n | B | H | 7 | 2 | 13.9 ± 1.4 | 1.02 ± 0.36 |
12o | B | H | 7 | 3 | 8.09 ± 0.91 | 44.6 ± 1.2 |
12p | B | H | 7 | 5 | 3.60 ± 0.16 | 3.66 ± 0.24 |
12q | B | H | 8 | 1 | 3.30 ± 0.75 | 17.2 ± 4.3 |
12r | B | H | 8 | 2 | 8.58 ± 1.42 | 4.07 ± 0.56 |
12s | B | H | 8 | 3 | 17.4 ± 6.2 | 14.6 ± 5.2 |
12t | B | H | 8 | 5 | 18.7 ± 5.0 | 6.26 ± 1.79 |
13a | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
3 | 1 | 28.1 ± 5.2 | 3.10 ± 0.94 |
13b | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
3 | 2 | 20.3 ± 1.4 | 21.3 ± 3.3 |
13c | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
3 | 3 | 7.13 ± 0.41 | 1.03 ± 0.22 |
13d | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
3 | 5 | 1.65 ± 0.33 | 7.85 ± 2.45 |
13e | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
4 | 1 | 156 ± 34 | 89.4 ± 6.2 |
13f | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
4 | 2 | 2470 ± 98 | 33.0 ± 9.3 |
13g | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
4 | 3 | 13.6 ± 1.8 | 12.4 ± 1.8 |
13h | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
4 | 5 | 37.4 ± 9.4 | 0.299 ± 0.067 |
13i | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
6 | 1 | 7.65 ± 0.24 | 3.46 ± 0.49 |
13j | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
6 | 2 | 1.14 ± 0.31 | 2.96 ± 0.41 |
13k | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
6 | 3 | 41.7 ± 11.5 | 15.6 ± 1.5 |
13l | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
6 | 5 | 2.94 ± 0.45 | 7.39 ± 1.51 |
13m | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
7 | 1 | 0.418 ± 0.025 | 0.009 ± 0.003 |
13n | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
7 | 2 | 6.67 ± 1.82 | 10.0 ± 1.6 |
13o | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
7 | 3 | 7.91 ± 0.69 | 6.55 ± 1.66 |
13p | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
7 | 5 | 11.1 ± 1.1 | 13.4 ± 3.9 |
13q | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
8 | 1 | 39.8 ± 3.3 | 18.1 ± 3.7 |
13r | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
8 | 2 | 18.3 ± 5.5 | 4.97 ± 0.26 |
13s | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
8 | 3 | 17.0 ± 3.0 | 6.59 ± 0.83 |
13t | B | COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundCl |
8 | 5 | 80.1 ± 16.6 | 8.67 ± 0.73 |
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Fig. 2 Representative examples of IC50 curves (A–C) and ROS IC50 curves (D–E) for selected compounds from Series A (compounds 10b and 10c) and B (compound 13l). |
An additional set of experiments were completed in which the assays were performed with a 1:
1 equimolar ratio of COMPOUND LINKS
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Download mol file of compoundmefenamic acid and COMPOUND LINKS
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Download mol file of compoundtacrine in order to confirm that linking these two molecules was indeed beneficial. The results reported in Table 1 show that the best inhibitors did in fact outperform a 1:
1 mixture, with compound 13m being over 150-fold and 9300-fold more potent in the TcAChE and ROS assays, respectively. These results confirm that linking the two molecules yields more potent inhibitors than concurrent exposure to the two parent compounds.
Series A showed an overall better performance in the assays, consistently yielding potent compounds, particularly in the ROS assay. All compounds tested were in the low nanomolar range with several molecules that were active at picomolar concentrations, showing drastic improvement over COMPOUND LINKS
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Download mol file of compoundtacrine (AChE IC50 = 52.4 ± 7.3 nM, ROS AChE IC50 = 183 ± 21 nM). The data for Series A indicate that compounds with a 6-chlorotacrine moiety are more potent than their non-chlorinated COMPOUND LINKS
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Download mol file of compoundtacrine counterparts, a trend observed in similar studies with COMPOUND LINKS
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Download mol file of compoundtacrine hybrids.12,15,25 A linker region comprised of 8 to 10 aliphatic carbons between the amine and amide nitrogen atoms of the respective parent molecules was found to be ideal for this series as several of these compounds showed sub-nanomolar IC50 values, the best being compounds 11c and 11e (Table 1).
Close examination of the data for Series B revealed several trends. The 6-chlorotacrine derivatives consistently outperformed their non-halogenated counterparts, similarly to Series A, a trend observed in a number of other studies.12,15,25 Previous studies have also shown that the 6-Cl moiety may cause an increase in selectivity for AChE over butyrylcholinesterase (BChE), thus decreasing the occurrence of unwanted side effects.11,12,15 An optimal length for the amide containing methylene linker between 1 and 2 was determined to be about ten atoms, which was determined by direct comparison after adding the total number of methylene units to the amide atoms (n + n′ + 2 = number of atoms in linker). An optimal length for the methylene linker between COMPOUND LINKS
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Download mol file of compoundtacrine and the amide nitrogen was determined to be n = 7 by a direct comparison of all molecules with a value of n = 3, 4, 5, 6, 7, and 8. Without exception, all compounds with n = 7 showed IC50 values below 50 nM. Following these two trends led to the most potent compound 13m (AChE IC50 = 0.418 ± 0.025 nM, ROS AChE IC50 = 0.009 ± 0.003 nM). This compound exhibits >100-fold increase in potency in the AChE assay and >20,000-fold increase in the AChE ROS assay compared to the parent compound, COMPOUND LINKS
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Download mol file of compoundtacrine (1).
In order to investigate the mode of inhibition of the COMPOUND LINKS
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Download mol file of compoundmefenamic acid hybrids, representative compounds from each series A and B were selected and evaluated at constant inhibitor concentration and varying substrate concentrations. Surprisingly, Lineweaver–Burk analysis of the most potent compounds suggested that those inhibitors are non-competitive (Fig. 3). This is an interesting result considering what is known about tacrine's competitive mode of inhibition with regards to the natural COMPOUND LINKS
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Download mol file of compoundacetylcholine substrate. A more likely scenario than the observed non-competitive inhibition, given what is known of COMPOUND LINKS
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Download mol file of compoundtacrine, is that mixed inhibition is observed to some degree but the non-competitive aspect dominates under the given reaction conditions. The inhibition assay indicated that COMPOUND LINKS
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Download mol file of compoundtacrine acted as a competitive inhibitor. It may not be ruled out as a possibility that COMPOUND LINKS
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Download mol file of compoundtacrine is interacting with the CAS, disrupting the enzyme function, and in fact, analysis of a selection of weaker inhibitors (data not shown) indicated mixed inhibition patterns in a Lineweaver–Burk analysis. Studies of similar compounds, in which a class of hydrocarbon-linked COMPOUND LINKS
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Download mol file of compoundtacrine dimers were co-crystallized with TcAChE, suggested that the COMPOUND LINKS
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Download mol file of compoundtacrine moieties may also interact via π–π stacking interactions with the heterocyclic residues of the PAS.26 Given this crystallographic evidence, another plausible scenario in which the reported compounds interact with the PAS but do not form additional contacts with the CAS could explain this non-competitive pattern of inhibition. Interestingly, a recent study of COMPOUND LINKS
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Download mol file of compoundferulic acid hybrids showed a similar non-competitive inhibition profile while many other hybrids' mode of inhibition was not reported, but rather assigned based on docking studies.27 However, the exact mode of interaction may not be strictly defined based on the current study, and will be the target of future research efforts with this interesting set of compounds.
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Fig. 3 Representative plot showing the non-competitive inhibition with respect to COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundacetylthiocholine (COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundATC) with compound 10e using four concentrations of inhibitor 10e and four concentrations of COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundATC. |
Our goal was to visualize the interactions of the three sections of our inhibitors with their suspected regions of interaction in the TcAChE active site: the COMPOUND LINKS
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Download mol file of compoundtacrine moiety, the linker region, and the COMPOUND LINKS
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Download mol file of compoundmefenamic acid moiety with the catalytic active site (CAS), the mid-gorge region, and the PAS, respectively. Modeling was performed using Autodock. The best scoring conformations in terms of energetics were selected after 100 docking iterations focused around the active site (see experimental section for further details). Models of several COMPOUND LINKS
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Download mol file of compoundmefenamic acid hybrids were constructed, all of which suggested strong interactions between the energy minimized hybrids and the enzyme complex. A selection of these results are depicted in Fig. 4.
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Fig. 4 A selection of hybrid molecules docked in TcAChE showing A the interaction of the 6-chlorotacrine moiety of compounds 11c (yellow) and 13m (orange) with Trp84, Phe330, and His440 in the CAS, B the proximity of the COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundmefenamic acid moiety in compounds 10c (yellow), 11e (blue), and 13j (magenta) to Tyr70 and Trp279 of the PAS, and C the proximity of the COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundmefenamic acid moiety of compounds 11c (yellow) and 13m (orange) to Trp279 and Tyr residues (70, 121, and 334) near the PAS. COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundOxygen, nitrogen, and COMPOUND LINKS Read more about this on ChemSpider Download mol file of compoundhydrogen atoms are shown in red, blue, and white, respectively. |
The energy-minimized complexes of all molecules modeled predicted that the COMPOUND LINKS
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Download mol file of compoundtacrine portion would be situated in the CAS. In accordance with similar docking studies of COMPOUND LINKS
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Download mol file of compoundtacrine containing molecules, the COMPOUND LINKS
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Download mol file of compoundquinoline ring system is stacked between Trp84 and Phe330 while the nitrogen atom of the ring is positioned such that it indicates the formation of a COMPOUND LINKS
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Download mol file of compoundhydrogen bond with the backbone COMPOUND LINKS
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Download mol file of compoundcarbonyl of His440 (Fig. 4A). This is consistent with previous docking studies that used COMPOUND LINKS
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Download mol file of compoundtacrine-based molecules with TcAChE25,29 and suggests that these COMPOUND LINKS
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Download mol file of compoundtacrine-COMPOUND LINKS
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Download mol file of compoundmefenamic acid hybrids could be capable of acting as substrate competitive inhibitors like COMPOUND LINKS
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Download mol file of compoundtacrine (Fig. 4A–C). We suspect that the non-competitive or mixed-mode of inhibition may arise from additional beneficial interactions that are not predicted by these modeling experiments.
The methylene linker portion of both series spans the active-site gorge, allowing the COMPOUND LINKS
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Download mol file of compoundtacrine and COMPOUND LINKS
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Download mol file of compoundmefenamic acid to interact with the CAS and PAS, repsectively. There are approximately 16 Å between the two binding sites from the COMPOUND LINKS
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Download mol file of compoundquinoline ring nitrogen atom30 and a similar distance is observed in the TcAChE structure used in this study. As mentioned, a linker length of approximately 10 atoms showed the strongest inhibition in the biochemical assays. This trend is not perfectly defined across the two series of inhibitors with regards to inhibition data and the same is true of the modeling studies, which fail to further elucidate specific beneficial interactions. Yet, it is quite clear that a linker length of approximately 8–10 atoms, with or without an amide bond, would allow for the COMPOUND LINKS
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Download mol file of compoundmefenamic acid portion to interact with the PAS if the COMPOUND LINKS
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Download mol file of compoundtacrine moiety bound in the CAS.
A great deal of variability in the orientation of the COMPOUND LINKS
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Download mol file of compoundmefenamic acid moiety was observed in the molecules docked. Variations in the interactions of the linker section may explain the inconsistencies observed with the COMPOUND LINKS
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Download mol file of compoundmefenamic acid moiety. One trend that is immediately apparent is the ability of the COMPOUND LINKS
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Download mol file of compoundtacrine moiety, if bound in the CAS, to direct the COMPOUND LINKS
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Download mol file of compoundmefenamic acid to the vicinity of the PAS (Fig. 4B). COMPOUND LINKS
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Download mol file of compoundMefenamic acid is thought to deactivate AChE through a free-radical mechanism, not through specific interaction or modification of the CAS.16 Our modeling studies showed that the COMPOUND LINKS
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Download mol file of compoundmefenamic acid moiety would be in close proximity to Trp279 as well as tyrosines (Tyr70, 121, and 334) near the PAS (Fig. 4C), which may have two implications.
Since IC50 values were dependent on the enzyme concentration, it was hypothesized that the low IC50 values observed in the ROS assay may be due to the inactivation of some amount of the enzyme by radicals through interaction with COMPOUND LINKS
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Download mol file of compoundtyrosine or tryptophan residues proximal to the PAS, which provides another possible explanation for the non-competitive or mixed-mode of inhibition (Fig. 4B,C). It is known that AChE has an adhesion function, located at the PAS, that governs AChE's interactions with Aβ and is believed to induce Aβ fibril formation.19,31,32 Perturbation of the PAS by a number of small molecules and antibodies has been shown to inhibit Aβ fibril formation, presumably by blocking the interaction at the PAS.19,33 Consequently, we believe that the COMPOUND LINKS
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Download mol file of compoundtacrine-COMPOUND LINKS
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Download mol file of compoundmefenamic acid hybrids reported herein may be capable of disrupting Aβ fibril formation and further experiments will be carried out to determine whether or not this is the case.
Footnote |
† Electronic supplementary information (ESI) available: Synthetic, biochemical, and computational procedures as well as characterization of all novel compounds. See DOI: 10.1039/c0md00256a |
This journal is © The Royal Society of Chemistry 2011 |