الفهرس 
Alzheimer’s Disease
SteroidsOnly 14 pages are availabe for public view
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Abstract
A number of novel hybrid steroid and curcumin derivatives were
synthesized with different substituent fused to the essential starting moiety.
The structures of all of the synthesized compounds were confirmed by their
spectral and analytical data; IR, 1H NMR, ¹³C NMR and Mass spectra
which all agreed with the assigned structures. The prepared compounds
were evaluated as anti-Alzheimer’s agents.
When curcumin was allowed to react with 3β-hydroxy -17-hydrazone -
5α-androstane derivative in boiling ethanol in presence of acetic acid as a
catalyst it yielded the hybrid Bis-(andorstanhydrazono)curcumin
derivative 4 (Scheme 1).
Scheme 1
When curcumin 1 was submitted to react with phenyl thiosemicarbazide
in boiling ethanol afford 5 (Scheme 2). Scheme 2
Interaction of curcumin 1 with diethyl malonate in the presence of
sodium methoxide in boiling ethanol yielded 6(Scheme 3).
Scheme 3
When curcumin 1 was allowed to react with chloroacetyl chloride in
pyridine with stirring 24 hours at room temperature yielded 7 Scheme 4.Scheme 4
When the diazonium salt of Z-aminotetrahydrobenzothiophene
carbonitrile derivative was coupled with Curcumin 1 in acetic acid and
sodium acetate yielded the coupling product 8. Similarly, when curcumin
1 was submitted to react with 2-aminobenzo]b[ thiophene(diazonium salt)
in acetic acid and sodium acetate it yielded 9 (Scheme 5).
Scheme 5
When compound 8 or 9 were allowed to react with hydrazines namely,
hydrazine hydrate, phenyl hydrazine, and or thiosemicarbazide or cyanoaceticacidhydrazide in boiling ethanol in presence of Et3N it
afforded the pyrazole derivatives 10a-d or 11a-d (Scheme 6).
Scheme 6
When a solution of compound 8 in boiling ethanol was allowed to react
with ethylcyanoacetate or malononitrile in presence of catalytic amount
of piperidine, 12 and 13 respectively (Scheme 7).When curcumin 1 was submitted to react with 2-(3-oxoandrost-4-en-17-
yl-amino)benzoic acid in boiling benzene (30mL) and H2SO4 (3mL) it
yielded 14 (Scheme 8).
Scheme 8
When compound 2 was submitted to react with sulpha drugs namely,
sulphathiazole (a), sulphamethoisooxazole (b) and sulphadiazine (c) in
least amount of glacial acetic acid in an oil bath at 120oC, it yielded
phenylpyrazolocurcminsulfa derivatives 15, 16 and 17 respectively
(Scheme 9).When curcumin 1 was submitted to react with 2-(3-oxoandrost-4-en-17-
yl-amino)benzoic acid in boiling benzene (30mL) and H2SO4 (3mL) it
yielded 14 (Scheme 8).
Scheme 8
When compound 2 was submitted to react with sulpha drugs namely,
sulphathiazole (a), sulphamethoisooxazole (b) and sulphadiazine (c) in
least amount of glacial acetic acid in an oil bath at 120oC, it yielded
phenylpyrazolocurcminsulfa derivatives 15, 16 and 17 respectively
(Scheme 9).Scheme 9
When compound 3 was submitted to react with sulpha drugs namely,
sulphathiazole (a), sulphamethoisooxazole (b) and sulphadiazine (c)
(suspension in glacial acetic acid in an oil bath at 120oc), it afforded
isoxazolocurcuminsulpha derivatives (18 a-c) (Scheme 10).Scheme 10
When α–bromoandrostanalone was submitted to react with
phenylisothiocyanate and malononitrile in the presence of catalytic
amount of potassium hydroxide in N,N-dimethylformamide, it yielded the
thiazoloandorstane derivative (19). When α-bromoandrostanalone was
submitted to react with phenyl isocyanate and ethylcyano acetate in
presence of KOH in DMF yielded (20) (Scheme 11).Scheme 11
When compound 19 was allowed to react with hydrazines namely,
hydrazine hydrate or phenyl hydrazine in boiling ethanol in presence of a
catalytic amount of triethylamine, it yielded 21 and 22 respectively
(Scheme 12).Scheme 11
When compound 19 was allowed to react with hydrazines namely,
hydrazine hydrate or phenyl hydrazine in boiling ethanol in presence of a
catalytic amount of triethylamine, it yielded 21 and 22 respectively
(Scheme 12).When thiazole derivatives 19 allowed to react with nitrogen nucleophiles
namely, urea, thiourea and guanidine hydrochloride in boiling ethanol
and in presence of tri ethyl amine as a catalyst it yielded
pyrimidinothaiazoloandorstane derivative s 23 a-c respectively (Scheme
13).Scheme 13
When the thiazole derivative 20 was allowed to react with guanidine
hydrochloride in boiling ethanol in the presence of tri ethyl amine as a
catalyst, it yielded pyrimidine derivative 24 (Scheme 14).Adult female albino rats (3 months old) weighing 200–220 g were
classified into 5 main groups.
Group 1: Normal healthy animals served as negative control.
Group 2: Induction of AD in aged rats were done via administration of
aluminum chloride in dose of 17 mg/kg b.wt. (Krasovskii et al., 1979)
for one month.
Group 3: This group included healthy animals and divided into five
subgroups according to the number of the tested compounds. Each
subgroup was given one of the tested compounds daily for two months, in
equimolar doses of 50mg/kg b.wt, so as to confirm the safety of these
compounds. These groups served as positive control group.
Subgroup (A): Group of healthy rats administrated compound 4.
Subgroup (B): Group of healthy rats administrated compound 13.
Subgroup(C): Group of healthy rats administrated compound 14.
Subgroup (D): Group of healthy rats administrated compound 17.
Subgroup (E): Group of healthy rats administrated compound 23c.
Group 4: This group was induced AD and divided also into five
subgroups. Each subgroup was treated with one of the tested
compounds daily for two months.
Subgroup (A): Group of rats expermintally inducted and treated with
compound 4.
Subgroup (B): Group of rats expermintally inducted and treated with
compound 13.
Subgroup(C): Group of rats expermintally inducted and treated with
compound 14.
Subgroup (D): Group of rats expermintally inducted and treated withcompound 17.Subgroup (E): Group of rats expermintally inducted and treated with
compound 23c.
Group 5: Animals were induced with AD and treated orally with
rivastigmine in (0.3 mg/kg) (Carageorgious et al., 2008) daily for two
months as a reference drug.
At the end of the expermintal period, rats were scarified after 3
months. At the end of the experimental period, the rats were fasted
overnight and subjected to diethylether anesthesia and were killed by
sudden decapitation. The whole brain of each rat was rapidly and
carefully removed, thoroughly washed with isotonic saline. Then each
brain was sagitally divided into two portions. The first portion was fixed
in formalin buffer (10%) for histopathological investigation. The second
portion of each brain was weighed and homogenized immediately to
give 10% (w/v) homogenate in ice-cold medium containing 50 mM TrisHcl and 300 mM sucrose, pH: 7.4. The homogenate was centrifuged at
3000 rpm for 10 min. in cooling centrifuge at 4 °C. The supernatant
(10%) was used for the biochemical analysis including AChE, choline
acetyl transferase, ACh level , paroxinase activity , 8-hydroxyguanosine
, glutathione levels., P53, BCL2 brain. And capase-3 activity .Also, total
protein concentration was measured to express the concentration of
different homogenate parameters per mg protein.
The results revealed that treatment of AD groups with compounds
4, 13, 14, 17 and 23c or rivastigmin experienced significant increase
in brain Ach, GSH, paraoxenase and BCL2 levels with respect to
untreated group associated with significant decrease in brain AchE
activity, urinary 8- OHG level, serum Caspase-3 level and brain P53
level relative to the untreated group. Immunohistochemical
investigation revealed that the selected treatments caused marked
increase in ChAT positive cells. These findings were documented by the histological investigation of the brain tissue. The activity of tested
compounds showed gradual increase from compound 13 followed by
compound 23c, 4 and 17 then compound 14. The anti-cholinesterase
potential, anti-oxidant properties and anti-apoptotic activity are
responsible for the anti- Alzheimer’s disease potential of these
compounds