научная статья по теме SYNTHESIS OF SELENIUM-CONTAINING AMINO ACID ANALOGUES AND THEIR BIOLOGICAL STUDY Химия

Текст научной статьи на тему «SYNTHESIS OF SELENIUM-CONTAINING AMINO ACID ANALOGUES AND THEIR BIOLOGICAL STUDY»

H

EHOOPrAHH^ECKAa XHMH3, 2011, moM 37, № 3, c. 293-301

SYNTHESIS OF SELENIUM-CONTAINING AMINO ACID ANALOGUES AND THEIR BIOLOGICAL STUDY

© 2011 Sh. H. Abdel-Hafez*, **#, H. A. Saad*, ***, and M. R. E. Aly*, ****

*Chemistry Department, Faculty of Science, Taif University, 888, Alhawiya, Taif University, Taif, Kingdom of Saudi Arabia;

**Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt;

***Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt;

****Chemistry Department, Faculty of Applied Science, Port Said University, Egypt

Received November 29, 2010; in final form, December 29, 2010

Synthesis of selenium-containing amino acid analogues is described. These compounds were prepared in a concise and short synthetic route in good yields by nucleophilic substitution reaction of pyridineselenol and quinolineselenol derivatives with N-phthaloylglycyl chloride followed by hydrazinolysis. The newly synthesized compounds were screened against different strains of bacteria and fungi.

Keywords: pyridineselenol, quinolineselenol, amino acid, anti-bacterial activities, anti-fungal activities.

In recent years, the interest in organoselenium chemistry increased remarkably due to its pivotal role in the synthesis of a large number of biologically active compounds and important therapeutic products ranging from anticancer, antioxidant and antifungal to naturally occurring food supplements [1—7].

Moreover, selenium is an essential micronutrient for animals and humans: to date, its bio-availability seems to depend upon the naturally occurring selenium-containing amino acids selenocysteine, selenom-ethionine, other seleno amino acids, such as seleno-cystathionine, are also involved in seleno amino acid metabolic pathways [8, 9].

In our previous work, we described the synthesis of pyrimidoselenolo[2,3-b]quinoline [10], pyrimi-doselenolo[2,3-c]pyridazine [11] and demonstrated that certain compounds manifest significant anti-inflammatory and analgesic activities with strong fungicidal effects. Stimulated by our recent work on the synthesis of selenium-containing sulfa drugs [12], we decided to expand our interest to the introduction of

# Corresponding author; phone: 00966 552453944; e-mail: sabdel68@yahoo.co.uk; shams@aun.edu.eg.

an organoselenium compounds in the amino acid analogues framework. To accomplish this task, we sought to functionalize the pyridineselenol and quin-olineselenol derivatives with ^-phthaloylglycyl chloride followed by hydrazinolysis by hydrazine hydrate followed by treatment with HCl.

To accomplish and attend our plan, firstly we started with compound (I) and prepared 4-hydrazi-no-7,9- dimethylpyrido[3',2':4,5]selenolo[3,2-d]py-rimidine (II) as described previously [13].

Compound (II) reacted with chloroacetyl chloride to furnish 2-chloro-^"-(7,9-dimethylpyri-do[3',2':4,5]selenolo[3,2-d]pyrimidin-4-yl)aceto-hydrazide (III), which, when allowed to react with piperidine or morpholine, afforded compound (II) instead of (IVa), (IVb). This cleavage of the amide linkage in compound (III) by amines instead of nu-cleophilic substitution is due to enhancement of the sensitivity of the carbonyl group to nucleophiles induced by the electronegativity of the P-chlorine atom (Scheme 1).

b, X = O

Reagents and conditions: a, NH2NH2, reflux; b, ClCOCH2Cl, room temperature; c, piperidine/morpholine, reflux

Scheme 1.

In an attempt to introduce amino acid analogues into organoselenium compounds, we tested the quinoline derivative instead of that with the pyridine nucleus. The reaction of 4-hydrazino-11-me-thylpyrimido[4',5':4,5]selenolo[2,3-b] quinoline (VI) [11] with chloroacetyl chloride afforded 2-chloro-

^-(11-methylpyrimido[4',5':4,5]selenolo[2,3-è]quin-olin-4-yl)acetohydrazide (VII). Its reaction with pip-eridine or morpholine afforded compound (VI) rather than compounds (VlIIa), (VlIIb) and the reason for that seems to be the same as mentioned above (Scheme 2).

CH

3 N=

N

-N- "Se Cl (V)

CH

3 №

N

Se NH

-NH

(VlIIa, b) O (VlIIa), X = H

b, X = O

N

-X

CH

3 N=N

N

Se NH'NH2

(VI)

b

N

N^Se NH

-NH

(VII)

Cl

Reagents and conditions: a, NH2NH2, reflux; b, ClCOCH2Cl, room temperature; c, piperidine/morpholine, reflux

Scheme 2.

a

Yet another putative precursor, 4,6-dimethylquin-oline-2-selenol (IXa), was prepared by the reaction of 2-chloro-4,6-dimethylquinoline with sodium hydro-genselenide in ethanol in low yield (10%); diquinoli-nyl diselenide derivative (IXb) formed in high yield (90%) due to self oxidation of (Ixa) in air accelerated by heating [14]. Compounds (IXa) and (IXb) were isolated by fractional crystallization.

The reaction of derivatives (IXa) and (IXb) with chloroacetamide in refluxing ethanol in the presence of sodium borohydride afforded 2-[(4,6-dimeth-ylquinolin-2-yl)selanyl]acetamide (X), which allowed to react with chloroacetyl chloride to yield (XI). Again, the reaction with piperidine or morpholine afforded compound (X) instead of (XIIa), (XIIb) (Scheme 3).

N ^Se^^^Cl (XI) O O

n n L v

(XlIa, b) (XlIa), X = H

b, X = O

Reagents and conditions: a, ClCH2CONH2, NaBH4, reflux; b, ClCOCH2Cl, room temperature; c, piperidine/morpholine, reflux

Scheme 3.

Secondly, to accomplish our target we started with another precursor, viz, N-phthaloylglycyl chloride (XIV), which has been prepared long ago [15], and allowed to react with organoselenium compound (XIII) to yield 3-cyano-4,6-dimethyl-S<?-[(N-phthalimido)glycyl]pyri-

dine-2-selenol (XV), which on hydrazinolysis with NH2NH2 followed by treatment with 2N HCl gave the corresponding 3-cyano-Se-glycyl-4,6-dimeth-ylpyridine-2-selenol hydrochloride (XVI) (Scheme 4).

CH3

CN

H3C N Se— (XIII)

+

O O

N

Cl

O (XIV)

CH3

XN O*

- - - . ^N^ H3C N Se ^ V

O

(XV)

CH3

CN O

A ^NH2HCl

a — -

H3C N Se

(XVI)

Reagents and conditions: a, NaBH4, EtOH, reflux; b, i) NH2NH2/reflux, ii) 2M HCl, 40°C, 5 min

Scheme 4.

Under similar conditions, compound (XVII) re- which on hydrazinolysis furnished the corresponding acted with (XIV) to form 3-cyano-4-methyl-Se- 3-cyano-Se-glycyl-4-methylquinoline-2-selenol hy-[(N-phthalimido)glycyl]quinoline-2-selenol (XVIII), drochloride (XIX) (Scheme 5).

a

b

N Se— (XVII)

CH3

Cl

CN CK rv O 4>—( >

O (XIV)

N Se

O

(XVIII)

5A^nh2HCI

Reagents and conditions: a, NaBH4, EtOH, reflux; b, i) NH2NH2/reflux, ii) 2M HCl, 40°C, 5 min

Scheme 5.

Finally, as the last example in our target plan, the phthalimido)glycyl]quinoline-2-selenol, which on reaction of compound (IXb) with compound (XIV) hydrazinolysis furnished Se-glycyl-4,6-dimethylquin-afforded derivative (XX), i.e., 4,6-dimethyl-Se-[(N- oline-2-selenol hydrochloride (XXI) (Scheme 6).

CH3

H3C

N Se-(IXb)

+

O O

N

O (XIV)

CH3

Cl H3C

O

O

N Se

(XX)

A^N.

O

CH

H3C

N Se (XXI)

Reagents: a, NaBH4, EtOH/ref.; b, i) NH2NH2/reflux, ii) 2N HCl/heat 5 min/40°C

Scheme 6.

NH2HCl

a

a

2

b

The structures of the synthesized compounds were confirmed by their physical, analytical and spectral data (Table 1).

The antimicrobial screenings of the synthesized compounds were undertaken using agar well diffusion assay [16]. Table 2 lists the screening results of the tested compounds against Gram-negative and Gram-positive bacteria. Five bacterial test organisms such as Staphylococcus aureus (B-54) Bacillus cereus (B-52) Escherichia coli (B-53) Serratia marcescens (B-55), and Pseudomonas aeruginosa (B-73) and seven fungi test

organism such as Candida albicans (418), Geotrichum candidum (226), Trichophyton rubrum (1804), Fusarium oxysporum (5119), Scopulariopsis brevicaulis (729), Aspergillus flavus (1276) were obtained from Assiut University Mycological Center. Chloramphenicol was used as an antibacterial standard, while Clotrimazole was used as an antifungal standard. DMSO was used as a blank, which exhibited no activity against any of the used organisms. The obtained data revealed that most of the compounds selected ((II), (IXb), (X), (XV), (XVI), (XVIII)-(XXI)) showed no activity against all

Table 1. Physical and spectral data of compounds (III), (VII), (IXa), (IXb), (X), (XI), (XV), (XVI), (XVHI)-(XX) and (XXI)

Compd. no. Mp °C (yield %) Mol. formula (M/wt) IR (cm-1) 1H NMR (5, ppm)

(III) 150- -152 (60) C13H12ClN5OSe (368.68) 3250-3200 (NH), 1650 (CO amide), 1610 (C=N) CDCl3: 8.04 (s, 1H, CH-pyrimidine); 7.18 (s, 1H, CH-pyridine); 5.35 (br, 1H, NH, NHNHCO); 3.96 (s, 2H, CH2) 2.81, 2.89 (2s, 6H, 2CH3); 1.13 (s, 1H, NH, NHNHCO).

(VII) 160- -162 (72) C16H12ClN5OSe (404.71) 3400 (NH), 1660 (CO amide), 1610 (C=N) DMSO-d6: 8.72 (s, 1H, CH-pyrimidine); 7.30-8.31 (m, 4H, Ar-H); 4.45 (s, 2H, CH2); 4.30 (s, 1H, NH, NHNHCO); 3.52 (s, 1H, NH, NHNH CO); 3.10 (s, 3H, CH3)

(IXa)a 175- -177 (10) C11H11NSe (236.17) 1615 (C=N) DMSO-d6: 7.42-7.78 (m, 4H, Ar-H); 3.60 (br, 1H, NH); 2.40 (s, 6H, 2CH3)

(IXb)b 275- 277 (90) C22H20N2Se2 (470.33) 1615 (C=N) DMSO-d6: 7.01-7.90 (m, 8H, Ar-H); 2.43 (s, 12H, 4CH3).

(X)a 180- -182 (81) C13H14N2OSe (293.22) 3150-3370 (NH2); 1670 (CO-amide); 1620 (CN) DMSO-d6: 7.46-7.87 (m, 4H, Ar-H); 7.43 (s, 1H, NH2); 3.82 (s, 2H, CH2); 2.53 (s, 3H, CH3); 2.50 (s, 3H, CH3).

(XI)a 170- -172 (73) C15H15ClN2O2Se (369.70) 3400 (NH); 1679 (CO-amide); 1610 (C=N) DMSO-d6: 8.90 (br, 1H, NH); 7.38-7.95 (m, 4H, Ar-H); 4.19 (s, 2H, COCH2Cl); 3.95 (s, 2H, SeCH2CO); 2.64 (s, 3H, CH3); 2.60 (s, 3H, CH3).

(XV)a,b 100- -102 (90) C18H13N3O3Se (398.27) 2200 (CN); 1720, 1680,1660 (3 CO) DMSO-d6: 7.50-7.95 (m, 4H, Ar-H); 7.42 (s, 1H, CH-pyridine); 4.40 (s, 2H, CH2); 2.60 (s, 3H, CH3); 2.40 (s, 3H, CH3).

(XVI)a >300(76) C10H12ClN3OSe (304.63) 3310-3190 (NH2); 2200 (CN); 1690 (CO) TFA: 8.30 (s, 2H, NH2HCl); 8.21 (s, 1H, CH-pyri-dine); 4.70 (s, 2H, CH2); 3.45 (s, 3H, CH3); 3.20 (s, 3H, CH3).

(XVIII)a,b 110- -112 (75) C21H13N3O3Se (434.31) 2200 (CN); 1720,1670,1660 (3 CO) DMSO-d6: 7.20-8.10 (m, 8H, Ar-H); 4.50 (s, 2H, CH2); 2.81 (s, 3H, CH3).

(XIX)a >300 (76) C13H12ClN3OSe (340.67) 3330-3140 (

Для дальнейшего прочтения статьи необходимо приобрести полный текст. Статьи высылаются в формате PDF на указанную при оплате почту. Время доставки составляет менее 10 минут. Стоимость одной статьи — 150 рублей.

Показать целиком