Design of structures against neurodegeneration of Alzheimers type

Neurodegenerative diseases like senile dementia of Alzheimer's type (SDAT) are among the greatest challenges in pharmacochemistry It is estimated that there will be about 4 x 107 sufferers from this disorder by 2020.18 SDAT, cardiovascular disorders, and cancer are the first three causes of morbidity worldwide At present, there is no effective treatment for SDAT. The applied pharmacotherapy is based on the cholinergic hypothesis . 19 These drugs are of limited benefit, quite toxic, and fail to inhibit the progress of the disease . Furthermore, there is a challenge because the pathogenesis of SDAT is essentially not known . However, there is a series of patho-biochemical changes in the demented brain that could be used as a base for a rational design of drug molecules for SDAT. In addition to the cholinergic deficit, the patho-biochemical changes related to the present work are: inflammation, oxidative stress, hypercholesterolemia,20 and reduced presence of the nerve growth factor (NGF) . 21 Thus, there are several targets for a pharmacochemical approach against SDAT.

We have designed and synthesized structures II (figure I . 2) that are constructed from a nonsteroidal anti-inflammatory drug (NSAID), which offers anti-inflammatory properties and suppresses the amyloid pathologic process; a substituted proline connected to the NSAID via an amide bond, offering nootropic properties;22 23 and a cysteamine or L-cysteine ethyl ester moiety, which amidates the carboxylic group of proline, conferring antioxidant activity. Furthermore, the carboxylic group of proline was esterified with 4-methyl-2-methoxyphenol or 3-(3-pyridyl)propanol These are two neuroprotective agents, the former acting via induction of NGF,21 the latter by another, yet unknown mechanism .2425

The novel compounds are expected to have anti-hyperlipidemic properties, since we have found that closely related compounds reduce blood cholesterol levels Furthermore, they should have reduced gastrointestinal (GI) toxicity because the carboxylic group of the parent NSAID has been masked and also through their anti-oxidant properties, since the ulcerative GI tissue caused by NSAIDs suffers from oxidative stress . 26, 27

Almost all compounds possessed the expected properties:

• They demonstrated very satisfactory in vivo anti-inflammatory activity (car-rageenin or Freund's Complete Adjuvant [FCA]-induced paw edema model or FCA-induced arthritis). The best two compounds, 6 and 8, presented 69% and 61% inhibition in the carrageenin test, respectively, whereas compound 4 inhibited completely (100%) the FCA-induced arthritis . 28, 29

Comp.

NSAID

Q

W

R

1

Indomethacin

CH2

NH

CH2CH2SH

2

Indomethacin

CH2

NH

CH(COOC2H5)CH2SH

3

Naproxen

CH2

NH

CH2CH2SH

4

Naproxen

CH2

NH

CH(COOC2H5)CH2SH

5

Naproxen

CHOH

NH

CH2CH2SH

6

Naproxen

CHOH

NH

CH(COOC2H5)CH2SH

7

Naproxen

(CH2)2

NH

CH(COOC2H5)CH2SH

8

Ibuprofen

CH2

NH

CH2CH2SH

9

Ibuprofen

CH2

NH

CH(COOC2H5)CH2SH

10

Ibuprofen

CH2

O

^>CH3 CH3O

11

Ibuprofen

CH2

O

FIGURE I.2 Structures of the studied prospective nootropic molecules .

FIGURE I.2 Structures of the studied prospective nootropic molecules .

• They inhibited in vitro lipoxygenase activity, with IC50 values of 35 pM and 48 pM, for compounds 3 and 4, respectively. 28

• Compound 11 inhibited the production of cyclooxygenase-2 (COX-2) from spleenocytes from arthritic rats by 88% . 29

• Some of the compounds inhibited lipid peroxidation very efficiently. Compounds 7, 8, and 9 demonstrated IC50 values of 122 pM, 19 pM, and 75 pM, respectively, after 45 min of incubation . 28, 29

• They interacted with DPPH quite well . The best three compounds were 4, 3, and 7, interacting with DPPH by 86%, 79%, and 77%, at equimolar concentration . 28, 29

• Most of the compounds reduced tyloxapol-induced rat dyslipidemia. They decreased TC, LDL, and TG levels by about 70%, 55%, and 70%, respectively, at doses of 56 to 300 pmol/kg . 28, 29

• Compounds 10 and 11 demonstrated moderate acetylcholinesterase inhibitory activity 29

• Compound 9 protected the brain from oxidative injury caused by ischemia/ reperfusion . An increase in malondialdehyde (MDA) and a depletion of glu-tathione (GSH) indicated brain oxidative damage, whereas administration of 9 reduced MDA toward normal values and increased GSH concentration completely back to normal values . [MDA: 0 . 80±0. 13 (control); 1 .73±0. 31 (ischemia/reperfusion); 1 .35±0.17 (ischemia/reperfusion plus 9) nmol/ mg protein. GSH: 97.8±6. 8 (control); 54.1±8 .1 (ischemia/reperfusion); 90. 3±10 .0 (ischemia/reperfusion plus 9) ^mol/g brain] . 29

• We examined the effect of these compounds on the gastrointestinal tract, reporting mortality, gastrointestinal ulceration, and body weight loss and melena incidence The administered dose was equimolar to that of the parent NSAID, which produced 50% mortality, given subcutaneously to rats for four days 26,27 All tested compounds were almost free of gastrointestinal toxicity, a common, dangerous side effect of the NSAIDs We attribute this mainly to two reasons: The carboxylic group of the parent drug has been masked in the designed compounds Thus, the local irritation is prevented Furthermore, the ulceration due to NSAIDs causes oxidative stress to the injured tissue . The antioxidant activity of the synthesized compounds protects the gastrointestinal tract from oxidative insult 28,29

In conclusion, we designed and synthesized compounds 1-11 aiming for agents that would acquire a series of biological properties able to prevent or restore a number of pathological changes implicated in SDAT and appearing in the demented brain . Most of them possess anti-inflammatory, antioxidant, and antidyslipidemic actions . Two of them moderately inhibit acetylcholinesterase They were almost free of gastrointestinal toxicity, a property required for long-term application 29 Thus, it is indicated that the synthesized compounds could be considered satisfactory lead structures for agents against pathological conditions involving inflammation, oxidative stress, and dyslipidemia, such as SDAT. The fact that compound 9 protected the brain from oxidative injury produced by ischemia/reperfusion justifies this molecular design We believe that a multicausal disease such as SDAT can be better treated with multifunctional agents, acting at different causes and stages of the disease pathogenesis

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