Synthesis of New Nicotinyl-4-Aminobenzoyl amino acids Derivatives

T. M.A. Ibrahim¹*, M El Deen Mohamed²

¹Chemistry Department, Faculty of Science, Al Zahra University, Nasr City, Egypt.

²Production Manager, In Kandil Steel, Cairo, Egypt

*Corresponding Author E-mail:

ABSTRACT:

The synthesis of (nicotinyl -4-aminobenzoyl) amino acids (4-10), dipeptide methyl ester (11-24), dipeptide(25-38) and their corresponding hydrazides (39-52) is described. All the synthesized compounds were found to be active against some of the tested micro organisms and fungi

KEYWORDS: nicotinyl -4-aminobenzoyl) amino acids derivatives, antimicrobial activity.

INTRODUCTION:

Recently the synthesis of many substituted nitro, amino acid and peptide Derivatives was reported^(1-4) . All these compounds were found to   possess specific antimicrobial activity^(1-4). This promoted me to synthesis some (nicotinyl -4-aminobenzoyl) amino acids, dipeptide methyl ester, dipeptide and hydrazides.

EXPERIMENTAL:

Melting points are uncorrected and determined using electrothermal melting point apparatus "SMPI". Purity of compounds was checked by  Thin layer chromatography "TLC" on plastic sheets silica gel-60- "Merek" and developed with benzene-ethyl acetate (3:1) using  iodine-KI (20%)solution as spraying  agent. Benzidine, ninhydrin, hydroxamate, and silver nitrate tests were used for detection reactions. The infrared "IR" Spectra were taken in KBr on   Berkin elmar IR 5300 spectrometer. UV and visible spectra were measured on Shimadzu UV160 spectrometer. The mass spectra were taken  on GC MS-QP 1000  mass spectrometer at 70 ev. Elemental analysis were carried out in microanalytical Research Center, Faculty of Science, Cairo University

Biological activities were measured in Botany and Microbiology department.

Scheme  1

(4-10) (nicotinyl -4-aminobenzoyl)aminoacids.

(11-24) (nicotinyl -4-aminobenzoyl)aminoaciddipeptide methyl esters.

(25-38)   (nicotinyl -4-aminobenzoyl)aminoaciddipeptides.

(39-52) (nicotinyl -4-aminobenzoyl)aminoacid dipeptidhydrazides.

General procedure for synthesis of (nicotinyl -4-aminobenzoyl)aminoacids derivatives  (4-10):

The amino acids (0.001 mole) were dissolved in 1N NaOH, and the solution cooled to (10 °C) (solution A). Nicotinyl -4-aminobenzoyl acid chloride (3) [0.01mole] was dissolved in benzene (solution B). Solution (A) was gradually added during 75 mins. with stirring to solution (B). The temperature of the reaction mixture was kept at (10 °C) until complete addition, and the reaction mixture stirred for further three hrs. at room temperature. The benzene layer was separated out, and the aqueous layer acidified with 2N-HCl to pH =5. The crude compound (4-10) was filtered, washed with cold water and recrystallized from –water.

The IR spectrum of compounds (4-10) in KBr showed the characteristic bands at: 3452 cm-1 (OH), 3353, 3235 cm-1 (NH), 2952 cm-1 (CH- aliph.), ,1657cm-1(C=O), and 1595 cm-1 (CONH),  which confirmed its structure.

1Hn.m.r spectrum of compounds (4-10) in dimethylsulfoxide-d6 exhibited the following signals at δ =2.0  (s, 3H, CH3-SCH3), 2.3 (s, 3H, CH3-CH3CO.), 2.4 (s, 4H, CH2CH2-met.), 3.3(b,2H, CH-H glycine ), 4.2 (s, 1H, CH-(CH2)2methionine),  5.8 (b, 1H, NH-CO-Met.),6.5-7.6  (m, aromatic protons), 12.2(b, 1H, NH), which confirmed its structure .

General procedure for synthesis of (nicotinyl -4-aminobenzoyl) dipeptide methyl esters (11-24):

nicotinyl -4-aminobenzoyl) aminoacids (4-10); 0.001 mole) was dissolved in (15 ml.) tetrahydrofuran (THF) [Solution A]. Amino acid methyl ester hydrochloride (1-2; 0.001mole) was suspended in (THF; 20 ml.) containing triethylamine (0.5 ml.). The mixture was stirred for 30 min; then cooled to (0°C). The precipitated triethylamine hydrochloride was filtered off {the filtrate contains free amino acid methyl ester [Solution B]}.   Solution (A) was added to solution (B), and the mixture cooled to 0 °C, then N,N`-dicyclohexylcarbodiamide  [DCC; 0,206 g; 0.001 mole] was added. The reaction mixture was stirred for 4-6 hrs. at (0°C), and left over night. The precipitated dicyclohexylurea was filtered off. The filtrate evaporated in vacuo and the residual material was purified by recrystallization from ethanol-water to give compounds   (11-24).

The synthesized compounds (11-24) were chromato- graphically homogeneous when developed with benzidine, iodine solution, and gave positive hydroxamate reaction and negative ninhydrin test.

The IR spectrum of compounds (11-24) in KBr showed the characteristic bands at: 3460 cm-1 (OH), 3363, 3230 cm-1 (NH), 2922 cm-1 (CH- aliph.), ,1671cm-1(C=O), and 1602 cm-1 (CONH),  which confirmed its structure .

1Hn.m.r spectrum of compounds (11-24) in dimethyl sulfoxide-d6 exhibited the following signals at δ: 2.5 (t, 4H, CH2-CH2-Ala.), 2.8 (s, 3H, COOCH3), 5.8 (b, 1H, CO- NH-Phe..),7.2-8 (m, aromatic protons), 10.6(b, 1H, CO- NH-Nico.), which confirmed its structure 

General procedure for synthesis of (nicotinyl -4-aminobenzoyl) dipeptide (25-38) :

Nicotinyl -4-aminobenzoyldipeptide methyl esters  (11-24) : 0.001mole) was added to a solution of 0.5-N NaOH.  The mixture was refluxed with continuous stirring for 1 hour at (100 °C) on water bath. The reaction mixture was allowed to cool, then acidified   with 1N HCl to pH=5. The crude product       (25-38) was separated, filtered and purified by recrystallization from DMF.

All the synthesized compounds (25-38) were chromato-graphically homogeneous when developed with iodine solution, benzidine and gave negative ninhydrin test, and hydroxamate reaction.

The IR spectrum of compounds (25-38) in KBr showed the characteristic bands at: 3423 cm-1 (OH),  2924 cm-1 (CH- aliph.), ,1680cm-1(C=O), and 1583 cm-1 (CONH),  which confirmed its structure.

M.R spectrum of compounds (25-38) in dimethylsulfoxide-d6 exhibited the following signals at δ =2.0  (s, 3H, SCH3), 2.5 (m, 5H, CH-(CH2)2-met.), 3.2  (t,2H, CH2-Ala.), 4 (b, 1H, CO- NH-Ala.), 6.6 (b, 1H, CO- NH-Met.),7.4-8.4 (m, aromatic protons), which confirmed its structure

General procedure for synthesis of (nicotinyl -4-aminobenzoyl)amino acid dipeptidhydrazides (39-52):

nicotinyl -4-aminobenzoyldipeptide methyl esters (11-24); 0.001mole) was dissolved in (30 ml) of  1M  alcoholic hydrazine hydrate (prepared from 6.6 ml hydrazine hydrate in 93.4 ml of abs. ethanol). The reaction mixture was heated on water bath for ½ hr. and kept 24 hrs in the refrigerator. The hydrazide was separated out and recrystallized from ethanol-water.

All compounds (39-52) were chromatographically homogenous when developed with iodine solution, Benzedrine, and gave positive silver nitrate test and negative hydroxamate, and ninhydrin tests.

The IR spectrum of compound (39-52) in KBr showed the characteristic bands at: 3426 cm-1 (OH), 3223 cm-1 (NH), 2950 cm-1 (CH- aliph.), ,1717cm-1(C=O), and 1633 cm-1 (CONH),  which confirmed its structure

1Hn.m.r spectrum of compound (39-52) in dimethylsulfoxide-d6 exhibited the following signals at δ =2.0  (s, 3H, CH3-SCH3), 2.3 (s, 3H, CH3-CH3CO.), 2.4 (s, 4H, CH2CH2-met.), 3.3(b,2H, CH-H glycine), 4.2 (s, 1H, CH-(CH2)2methionine),  5.8 (b, 1H, NH-CO-Met.),6.5-7.6  (m, aromatic protons), 12.2(b, 1H, NH), which confirmed its structure 

Table (1): Physical data of compounds [4-52].

compd. No.	X	Yield (%)	M.P.  ^oC	Rf	Molecular Formula	(M.Wt.)	Elemental Analysis calculated/Found
							C	H	N
4	Gly	80	186-88	0.74	C15 H13 N3 O4	(299)	60.20 60.23	4.34          4.38	14.04        14.01
5	β -Ala	83	179-81	0.76	C16 H15 N3 O4	(313)	61.34 61.36	4.79          4.83	13.41        13.39
6	DL-Ala	75	183-85	0.82	C16 H15 N3 O4	(313)	61.34 61.38	4.79          4.83	13.41        13.38
7	DL-Val	77	217-19	0.79	C18 H19 N3 O4	(341)	63.34 63.36	5.57          5.61	12.31        12.28
8	DL-Ser	75	175-77	0.77	C16 H15N3 O5	(329)	58.35 58.37	4.55          4.59	12.76        12.73
9	DL-Met	86	201-03	0.73	C18H19 N3 O4 S	(373)	57.90 57.92	5.09          5.13	11.26        11.22
10	DL-Phe	79	207-09	0.80	C22 H19 N3 O4	(389)	67.86 67.88	4.88          4.92	10.79        10.76

compd. No.	X	Yield (%)	M.P. ^oC	Rf	Molecular Formula	(M. Wt.)	Elemental Analysis calculated/Found
							C	H	N
11	Gly-β -Ala-OMe	82	185-87	0.84	C19 H20 N4 O5	(384)	59.37    59.40	5.20     5.24	14.58   14.56
12	β -Ala-β -Ala-OMe	70	179-81	0.80	C20 H22 N4 O5	(398)	60.30     60.32	5.52     5.57	14.07   14.06
13	DL-Ala-β -Ala-OMe	76	215-17	0.82	C20 H22 N4 O5	(398)	60.30     60.33	5.52     5.57	14.07   14.06
14	DL-Val-β -Ala-OMe	79	182-84	0.74	C22 H26N4 O5	(426)	61.97     61.99	6.10     6.15	13.14   13.11
15	DL-Ser-β -Ala-OMe	83	156-58	0.72	C20H22N4O6	(414)	57.97     57.98	5.31     5.35	13.52   13.50
16	DL-Met-β -Ala-OMe	85	200-02	0.67	C22H26 N4 O5S	(458)	57.64     57.66	5.67     5.72	12.22   12.19
17	DL-Phe-β -Ala-OMe	74	175-77	0.83	C26 H26N4 O5	(474)	65.82     65.85	5.48     5.52	11.81   11.78

Com-pd. No.	X	Yield (%)	M.P.  ^oC	Rf	Molecular Formula	(M. Wt.)	Elemental Analysis calculated/Found
							C	H	N
18	Gly- DL-Phe-OMe	77	199-201	0.73	C25 H24 N4 O5	(460)	65.21     65.23	5.21     5.25	12.17   12.14
19	β -Ala- DL-Phe-OMe	81	195-97	0.76	C26 H26 N4 O5	(474)	65.82     65.85	5.48     5.52	11.81   11.79
20	DL-Ala- DL-Phe-OMe	82	213-15	0.82	C26 H26 N4O5	(474)	65.82     65.84	5.48     5.52	11.81   11.78
21	DL-Val- DL-Phe-OMe	72	208-10	0.79	C28 H30 N4 O5	(502)	66.93     66.95	5.97     6.02	11.15   11.12
22	DL-Ser- DL-Phe-OMe	70	225-27	0.70	C26 H26N4 O6	(490)	63.67     63.70	5.30     5.34	11.42   11.40
23	DL-Met- DL-Phe-OMe	80	247-49	0.83	C28H30 N4 O5S	(534)	62.92     62.95	5.61     5.66	10.48   10.45
24	DL-Phe- DL-Phe-OMe	85	252-54	0.80	C32 H30 N4 O5	(550)	69.81     69.83	5.45     5.49	10.18 10.14

compd. No.	X	Yield    (%)	M.P.  ^oC	Rf	Molecular Formula	(M. Wt.)	Elemental Analysis calculated/Found
							C	H	N
25	Gly-β -Ala	72	184-86	0.75	C18 H18 N4 O5	(370)	58.37          58.39	4.86      4.90	15.13   15.10
26	β -Ala-β -Ala	80	168-70	0.77	C19 H20 N4 O5	(384)	59.37          59.40	5.20      5.24	14.58   14.54
27	DL-Ala-β -Ala	76	178-80	0.79	C19 H20 N4 O5	(384)	59.37          59.39	5.20      5.24	14.58   14.56
28	DL-Val-β -Ala	79	201-03	0.78	C21 H24 N4 O5	(412)	61.16          61.19	5.82      5.87	13.59   13.56
29	DL-Ser-β -Ala	83	205-07	0.76	C19 H20N4 O6	(400)	57.00          57.03	5.00      5.03	14.00   13.99
30	DL-Met-β -Ala	85	243-45	0.72	C21H24 N4 O5 S	(444)	56.75          56.72	5.40      5.44	12.61   12.58
31	DL-Phe-β -Ala	74	188-90	0.70	C25 H24 N4 O5	(460)	65.21          65.19	5.21      5.25	12.17   12.15

compd. No.	X	Yield    (%)	M.P.  ^oC	Rf	Molecular Formula	(M. Wt.)	Elemental Analysis calculated/Found
							C	H	N
32	Gly- DL-Phe	75	215-17	0.69	C24 H22 N4O5	(446)	64.57        64.60	4.93       4.97	12.55   12.52
33	β -Ala- DL-Phe	84	238-40	0.70	C25 H24 N4 O5	(460)	65.21        65.24	5.21       5.25	12.17   12.16
34	DL-Ala- DL-Phe	70	230-32	0.74	C25 H24 N4 O5	(460)	65.21        65.23	5.21       5.25	12.17   12.15
35	DL-Val- DL-Phe	75	241-43	0.85	C27 H28 N4 O5	(488)	66.39        66.41	5.73       5.78	11.47   11.45
36	DL-Ser- DL-Phe	72	210-12	0.73	C25 H24N4O6	(476)	63.02        63.05	5.04       5.08	11.76   11.73
37	DL-Met- DL-Phe	80	226-28	0.78	C27H28 N4 O5 S	(520)	62.30        62.33	5.38      5.42	10.76   10.72
38	DL-Phe- DL-Phe	80	251-53	0.79	C31 H28 N4 O5	(536)	69.40        69.43	5.22      5.26	10.44   10.41

compd. No.	X	Yield (%)	M.P.  ^oC	Rf	Molecular Formula      (M.Wt.)	Elemental Analysis calculated/Found
						C	H	N
39	Gly-β -Ala-NHNH2	74	240-42	0.72	C18 H20 N6 O4       (384)	56.25   56.28	5.20     5.24	21.87   21.86
40	β -Ala-β -Ala- NHNH2	79	178-80	0.81	C19 H22 N6 O4       (398)	57.28   57.30	5.52     5.57	21.10   21.09
41	DL-Ala-β -Ala- NHNH2	82	202-04	0.70	C19 H22 N6 O4       (398)	57.28   57.31	5.52     5.57	21.10   21.09
42	DL-Val-β -Ala- NHNH2	80	183-85	0.74	C21 H26 N6 O4       (426)	59.15   59.18	6.10     6.14	19.71   19.68
43	DL-Ser-β -Ala- NHNH2	71	198-200	0.79	C19 H22N6 O5        (414)	55.07   55.10	5.31     5.35	20.28   20.25
44	DL-Met-β -Ala- NHNH2	83	186-88	0.84	C21H26 N6 O4 S  (458)	55.02   55.04	5.67     5.72	18.34   18.30
45	DL-Phe-β -Ala- NHNH2	72	205-07	0.80	C25 H26 N6 O4       (474)	63.29   63.31	5.48     5.52	17.72   17.71

compd. No.	X	Yield (%)	M.P.  ^oC	Rf	Molecular Formula      (M.Wt.)	Elemental Analysis calculated/Found
						C	H	N
46	Gly-DL-Phe - NHNH2	78	170-72	0.67	C24 H24N6 O4        (460)	62.60   62.63	5.21     5.25	18.26    8.25
47	β -Ala-DL-Phe - NHNH2	77	202-04	0.69	C25 H26 N6 O4       (474)	63.29   63.32	5.48     5.52	17.72   17.71
48	DL-Ala-DL-Phe - NHNH2	73	210-12	0.79	C25 H26 N6 O4       (474)	63.29   63.31	5.48     5.52	17.72   17.71
49	DL-Val-DL-Phe - NHNH2	82	180-82	0.74	C27 H30 N6 O4       (502)	64.54   64.56	5.97     6.02	16.73   16.72
50	DL-Ser-DL-Phe - NHNH2	77	174-76	0.75	C25 H26N6 O5        (490)	61.22   61.25	5.30     5.34	17.14   17.13
51	DL-Met-DL-Phe - NHNH2	80	193-95	0.71	C27H30 N6 O4 S (534)	60.67   60.68	5.61     5.66	15.73   15.72
52	DL-Phe-DL-Phe - NHNH2	79	215-17	0.72	C31 H30 N6 O4      (550)	67.63   67.66	5.45     5.49	15.27   15.26

RESULT AND DISCUSSION:

Chemistry

(nicotinyl -4-aminobenzoyl) amino acids  (4-10): were easily synthesized by coupling of nicotinyl -4-aminobenzoyl acid chloride (3) with amino acids in sodium hydroxide-benzene medium. First, amino acids were dissolved in 1N-NaOH solution and cooled to 10 °C solution (A), nicotinyl -4-aminobenzoyl acid chloride (3)  was dissolved in benzene (solution B). Solution (A) added gradually with stirring to solution (B)  during 75 mins. After complete addition, the stirring was continued for 3 additional hrs. at room temperature. The aqueous layer was separated, and acidified with 2N-HCl to pH=5 to give the desired compounds (4-10). The crude products (12-13) were purified by recrystallization from ethanol–water and obtained in yields (77-86 %).nicotinyl -4-aminobenzoyl aminoaciddipeptide methyl esters (11-24): were prepared by carbodiimide method(5) which considered the most suitable method for the preparation of these compounds and no side reactions observed. Many scientists confirmed that in peptide synthesis (6-10).

nicotinyl -4-aminobenzoyl aminoacids (4-10) was coupled with amino acid methyl ester hydrochlorides [1-2; 1:1 molar ratio] by carbodiimide technique⁽⁵⁾.  First, nicotinyl -4-aminobenzoyl aminoacids (4-10) was dissolved in tetrahydrofuran and cooled to 0 °C (Solution A). The amino acid methyl ester    hydrochlorides (1-2) were suspended in THF and triethylamine, and then the mixture stirred for 30 min. at  (0°C), the triethylamine hydrochloride was filtered off (Solution B). (Solution A) was added to (solution B) and N,N^\-dicyclohexyl carbodiimide (DCC) was added (as the same ratio of amino acid methyl ester hydrochlorides) at     (0 °C). The mixture was stirred at (0 °C) for  4-6 hrs., and left over night and the time of the reaction was controlled by TLC. The precipitated dicyclohexylurea was filtered off, and the filtrate evaporated in vacuo. The residual material was purified from ethanol-water. The compounds   (11-24) were obtained in yields (70-85%).

Nicotinyl -4-aminobenzoyl aminoaciddipeptides. (25-38)

were prepared by adding nicotinyl -4-aminobenzoyl aminoaciddipeptide methyl esters (11-24):  0.001mole) to   a  solution of 0.5-N NaOH. and refluxed the mixture with continuous stirring for 1 hour ON water bath. The reaction mixture was allowed to cool, then acidified with 1N-HCl to pH=5. The crude    compounds (11-24) were separated, filtered, recrystallized from ethanol-water, and obtained in (70-85%) yields.

Nicotinyl -4-aminobenzoyl aminoacid dipeptidhydrazides (39-52)

The titled compounds (39-52) were synthesized by the action of hydrazine hydrate in presence of ethyl alcohol on the corresponding nicotinyl -4-aminobenzoyl aminoacid dipeptide methyl esters (11-24):  The reaction mixture was heated on water bath for ½ hr. and left 24 hrs at °C. The crude hydrazides (39-52) were separated out, recrystallized from ethanol-water, and obtained in good yields (71-83%).

The biological activities of the synthesized compounds :-

The biological activities of the synthesized compounds  (4-52) were tested using the hole plate and filter paper disk methods ^(11-14). All the compounds (4-52) were tested against different types of Bactria (Gram-positive and Gram-negative bacteria) as follow:

A.    Pseudomonas aeruginosa.

B.    E.Coli.

C.    Bacillus Subtilis.

D.    Staphyococus.

And, Ampicillin was used as a reference compound (c.f. Table 2).

Also, all the synthesized compounds (4-52) were tested against different types of fungi as follow :

A.    Asprigillus flavus.

B.    Asprigillus niger.

And, Claforan was used as a reference compound (c.f.Table 2).

From table (2), we found the following:-

1.     The compounds (4-52) were found to possess a inactivities against fungi . (c.f. Table 2).

2.     The compounds (2-52) were found to be Moderate active or have a very weak activity against all tested microorganisms, at MIC  >500 μg/ml (c.f.Table2).

Table (2): Antimicrobial  activities of the synthesized

Comp	pseudo		E-coli		B-sutilis		staph		Aspero.n		Aspero.fl
No.	A	M.I.C	A	M.I.C	A	M.I.C	A	M.I.C	A	M.I.C	A	M.I.C
4	-	-	2	250	-	-	1	500	-	-	-	-
5	-	-	2	250	-	-	1	500	-	-	-	-
6	-	-	2	250	-	-	1	500	-	-	-	-
7	-	-	2	250	-	-	1	500	-	-	-	-
8	-	-	2	250	-	-	1	500	-	-	-	-
9	-	-	2	250	-	-	1	500	-	-	-	-
10	-	-	2	250	-	-	1	500	-	-	-	-
11	-	-	2	250	-	-	1	500	-	-	-	-
12	-	-	2	250	-	-	2	250	-	-	-	-
13	-	-	1	500	-	-	1	500	-	-	-	-
14	-	-	1	500	-	-	2	250	-	-	-	-
15	-	-	2	250	-	-	-	-	-	-	-	-
16	-	-	2	250	-	-	1	500	-	-	-	-
28	-	-	1	500	-	-	1	500	-	-	-	-
29	-	-	1	500	-	-	1	500	-	-	-	-
30	-	-	1	500	-	-	1	500	-	-	-	-
31	-	-	1	500	-	-	1	500	-	-	-	-
32	-	-	1	500	-	-	-	-	-	-	-	-
33	-	-	1	500	-	-	-	-	-	-	-	-
34	-	-	1	500	-	-	-	-	-	-	-	-
35	-	-	1	500	-	-	-	-	-	-	-	-
36	-	-	1	500	-	-	-	-	-	-	-	-
37	-	-	1	500	-	-	-	-	-	-	-	-
38	-	-	1	500	-	-	-	-	-	-	-	-
39	-	-	1	500	-	-	2	250	-	-	-	-
40	-	-	2	250	-	-	2	250	-	-	-	-
41	-	-	2	250	-	-	-	-	-	-	-	-
42	-	-	2	250	-	-	-	-	-	-	-	-
43	-	-	2	250	-	-	-	-	-	-	-	-
44	-	-	1	500	-	-	-	-	-	-	-	-
45	-	-	1	500	-	-	-	-	-	-	-	-
46	-	-	1	500	-	-	-	-	-	-	-	-
47	-	-	1	500	-	-	-	-	-	-	-	-
48	-	-	1	500	-	-	-	-	-	-	-	-
49	-	-	1	500	-	-	-	-	-	-	-	-
50	-	-	1	500	-	-	-	-	-	-	-	-
51	1	500	-	-	-	-	-	-	-	-	-	-
52	-	-	-	-	-	-	-	-	-	-	-	-
MIC     Minimal inhibtory concentration
A	Antimicrobial activities.
^_	Inactive compound or its MIC>500 μ/ml
+	Weak activity
++	Moderate activity
+++	High activity

From the above results, we concluded  that the combination of nicotinyl -4-aminobenzoyl with different  amino acids or peptides residues gave Moderate active compounds against all tested.

REFERENCE:

1. T. M. Ibrahim, M. F. Badie, S. A. Shedid, and A. M. El-Naggar, Int. J. Chem., 2 (4), 141 (1991).

2. T. M. Ibrahim, Al-Azhar Bull. Sci., 241, 65 (1991).

3. T. M. Ibrahim, A. A. Shabana and H. A. Hammad, Arch. Pharm. Sci., 15 (2), 130 (1992).

4. A. A. Magdel-din,H. M.Abou-Yossef and T. M.                Ibrahim, Phosph. Sulpher and Silicon J., 68,297 (1992).

5. J. C. Sheehan, M. Goodman, and G. P. Hess, J. Am. Chem. Soc., 78, 1367 (1956).

6. H. Asyagi, T. Kats, M. Ohno, M. Kondo and N. J. Izumiya, J. Am. Chem. Soc. 86, 5700(1964).

7. M. Bondanseky, M. A. Ondetti, C. A. Brickhimer, and P. L. Thomas, J. Am. Chem. Soc., 86,4452(1964).

8. P. A. Cruickshank and J. C. Sheehan, J. Am. Chem. Soc., 86, 2070(1964).

9. M. Goodman, B. Bery, and A. E. Lanzillotti, J. Am. Chem. Soc., 86,1880(1964).

10. K. Hofman, W. Hass, G. Zanetti, J. Am. Chem. Soc., 77,3419(1957).

11. T.Curtius, and F.Goebel, J.Prakt. Chem. 37(2),150(1888).

12. A.L.Banker, and G.S.Skinner, J.Am.Chem. Soc., 46,403(1925).

13. E.Fischer, and W.A.Jacobs, Ber,39,2943(1906).

14. J.I.Harris, and W. H. Hartung, J.Biol.Chem. 191,143(1951).

Received on 04.06.2014         Modified on 25.06.2014

Accepted on 03.07.2014         © AJRC All right reserved

Asian J. Research Chem. 7(7): July 2014; Page 634-639