Preparation, Characterization and Study of Biological Activity for some new derivatives Mannich's bases derived from Shiff's bases

 

Nadia Sadiq Majeed1, Nada Ali Saleh2, Radhiyah Abd AL-Baqi Aldujaili3

1Chemistry Department,Faculty of Education for girl, University of Kufa, Najaf.

2Pharmaceutical Department, Faculty of pharmacy,University of Kufa, Najaf.

3Chemistry Department,Faculty of Education for girl, University of Kufa, Najaf.

*Corresponding Author E-mail: nadia.albobaid@uokufa.edu.iq

 

ABSTRACT:  

This paper involves synthesis new Mannich bases derived from Shiff' bases which prepared from isatin by the reaction  of isatin  with different aromatic amines to prepare Shiff bases derivatives (M, G, B, R, X, S), then Shiff's bases derivatives reacted with formaldehyde and piperazine to produce Mannich bases derivatives (M1, G1, B1, R1, X1, S1). The third step included the assay of biological activity of all compounds against four types of pathogens bacteria (Staphylococcus aureus, Granutice tella adiacens) gram positive and (E. coli, Proteus mirabilis) gram negative the results exhibited excellent biological activity for all derivatives compared to antibiotics (Ampicillin and Ciprofloxacin) these structures were identified by FT-IR,1HNMRand 13CNMR.

 

KEYWORDS: Isatine, Shiff's bases, Mannich's bases.

 

 

 

INTRODUCTION:

Isatine or (1H-indole -2,3-dione) 1,is an Indole derivative containing two ketone group at position 2 and 3 in the ring1. Isatine was first synthesized by Erdman and Laurent in 18412 . Isatine a multilateral bioactive has been found to exhibit tyrosine kinase inhibition3. Isatin is an important group of heterocyclic compound which is biologically active and of significant important in medicinal chemistry4. Schiff bases are the compounds including azomethine group(HC=N)5. They are a goodtype of organic compounds capable of binding to disparate metal ions with engaging medicals an non-medical properties6. Mannich base are beta –amino ketones formed by Mannich reaction 7. Mannich reaction is one of the most fundamental and important C-C bond pointing reactions in organic synthesis.Mannich base reaction are known to rise.The biological activity8 have also found numerous applications in the treatment of natural macromolecular materials such as leather, paper and textilesand as additives used by the petroleum industry 9.

 

Mannich bases derivatives have attracted much interest in the development of pharmacologically active compounds 10.

 

MATERIALS AND METHODS:

The chemicals compounds have high purity as supplied by sigma and GCC company, Melting point of the compounds recorded by electro thermal 9300, melting point engineering LTD, all measurements synthesis compounds were recorded by : FTIR spectra,Fourier transform infrared Shimadzu (8400), 1HNMR and 13CNMR –spectra in (ppm) in DMSO solvent by Bruker-300MHZ, Iran, Thin layer chromatography used silica gel in (Benzene :methanol) solvents.

 

Experimental:

Synthesis of Schiff bases derivatives

Schiff bases derivatives were prepared by reaction between isatin (0.002 mol) and (0.002 mol) from   aromatic amine derivatives as catalyst in the glacial acetic acid 2-3 drops 11. The mixture was heated under refluxed to 73C0 for 10 hours to produce Shiff bases derivatives (M, G, B, R, X, S), the compounds which recrystallized from absolute ethanol as in scheme (1)

 

Synthesis of Mannich derivatives:

Mannich bases derivatives were synthesized by the reaction between (0.01 mol) formaldehyde and shiff bases derivatives (M, G, B, R, X, S) and piperazine were taken in round bottom flask after that were dissolved in 30 ml ethanol 12. The solution was stirred for (12)h, then reaction mixture kept  in refrigerator  for 48h  after that  recrystallized from absolute ethanol to produce Mannich base derivatives (M1, G1, B1, R1, X1, S1). Scheme(3).

 

RESULT AND DISCUSSION:

Schiff bases derivatives (M, G, B, R, X, S) were prepared by condansation reaction between Isatine with (4-amino-3-hydroxybenzenesulfonamide, Sulphadiazine, 4-methoxy-2-nitroaniline, 2-amino-7-Mercapto benzo thiazol, 2-amino-5-methylphenol and 4-methoxyaniline) respectively. These reactions were done by using absolute Ethanol as solvent and glacial acetic acid (2-3) drops as catalyst and the reflux at (78ºC).

 

The proposed mechanism, which involved the nucleophilic attack of the amine nitrogen on the carbon atom of the carbonyl followed by water elimination has been illustrated by the following scheme 2.

 

 

Scheme. 1 Prepared Shiff,s bases derivatives

 

Scheme 2. Mechanism13 of Schiff base formation

 

 

Identification of Shiff base derivatives:

(M) :(Z)-4-((2-oxoindolin-3-ylidene) amino) benzenesulfonamide,

FT-IR(KBr)cm-1, ѵ 3444(OH)Hydroxyl group, ѵ3421-3400(NH2)14 Amine group, ѵ3290((NH)Isatine ring, ѵ1716(C=O) Carbonyl group, ѵ1670-1591(C=C) aromatic, ѵ1618(C=N) Imine group, ѵ1336(SO2), ѵ3064(C-H) aromatic, ѵ2981(C-H)Aliphatic .

 

(G) : (Z)-4-((2-oxoindolin-3-ylidene)amino)-N-(pyrimidin-2-yl)benzenesulfonamide,FT-IR(KBr)cm-1,3360 (NH)Isatine ring,ѵ3192(NH)Sulfon amide,ѵ1558(C=C) Aromatic,ѵ2931(CH)Aromatic, ѵ1730(C=O)Carbonyl group,ѵ1683(C=N)Pyrimidine ring,ѵ1618(C=N)imine,  ѵ1883(C=H)Aliphatic, ѵ1330(SO2) 1H-NMR(DMSO), : δ 10.7 (s,NH,1H)Isatine group,: δ 10.2(s,NH,1H)Sulfonic amide δ7.03-7.9(m, phenyl group, ,13 CNMR(DMSO) :δ 170(C, C=O)Isatine ring,δ 165 (C,  C=N)Imine group,δ 159- 157 (C,  N=C)Pyrimidine ring, δ 106-130(C of phenyl group).

 

(B) : (Z)-3-((4-methoxy-2-nitrophenyl)imino)indolin-2-one,,FT-IR(KBr)cm-1,3373 (NH)Isatine ring,ѵ3111(C-H)Aromatic, ѵ1732(C=O)Carbonyl group,ѵ1618(C=N)imine group,ѵ1573(C=C)Aromatic  ѵ1512-1334 (NO2) 15 Nitro group, ѵ1155(C-O,OCH3), 1H-NMR(DMSO), : δ 10 (s,NH,1H)Isatine group,δ3.1(s,CH,3H), δ6.9-7.3(m, phenyl group, 13CNMR(DMSO) :δ 170.136(C, C=O)Isatine ring,δ 161.988 (C,  C=N)Imine group,109.828-129.309 (C of phenyl group) 16,δ144(C,C-NO2),δ57.581(C,OCH3)

 

(R) : (Z)-3-((5-mercaptothiophen-2-yl)imino)indolin-2-one,FT-IR(KBr)cm-1, 3415 (NH)Isatine ring,ѵ3315(SH)Thiazolering, ѵ3103(C-H)Aromatic,ѵ2927-2900(CH)Aliphatic group ѵ1732(C=O)Carbonyl group,ѵ1556(C=C)Aromatic,ѵ1678(C=N) Thiazole ring, ѵ1618(C=N)Imine group,v 1201 (C-S-C), 1H-NMR(DMSO), : δ 10.3(s,NH,1H) 17 Isatine group, δ7.3-7.9(m, phenyl group) 18, δ 4.6(s,SH,1H) Thiazolering 13CNMR(DMSO) :δ169.585(C, C=O)Isatine ring,δ 160.486 19 (C,  C=N)Imine group,δ158.(C,  C=N)Thizole ring,,115.518-130.309(C of phenyl group).

 

(X) :(Z)-3-((5-hydroxy-2-methylphenyl)imino) indolin-2-one,FT-IR(KBr)cm-1,ѵ 3442(OH)Hydroxyl group,ѵ3240((NH)Isatine ring,ѵ3075(C-H)Aromatic,ѵ2908(CH)Aliphatic,ѵ1732(C=O)Carbonyl group, ѵ1558(C=C)aromatic,ѵ1616(C=N)Imine group.

 

(S): (Z)-3-((4-methoxyphenyl)imino)indolin-2-one, FT-IR(KBr)cm-1,ѵ 3228(NH)Isatine group,ѵ3068(C-H)Aromatic, ѵ2918(CH)Aliphatic,ѵ1737(C=O)Carbonyl group, ѵ1554(C=C)aromatic,ѵ1612(C=N)Imine group,ѵ1244(C-O,OCH3)Ether group,1H-NMR(DMSO), : δ 10.3 (s,NH,1H)Isatine group, δ7.3-7.9(m, phenyl group,δ 3.1 (s,OCH3,3H),13CNMR(DMSO) :δ171.263(C, C=O)Isatine ring,δ 160.964 (C,  C=N)Imine group,,116.782-138.420(C of phenyl group),59.963(C,OCH3).

 

The Mannich bases derivatives  (M1, G1, B1, R1, X1, S1) Scheme (3) were prepared by the proposed mechanism 20 which involved the nucleophilic attack of the Secondary amine nitrogen on the carbon atom of the formyl carbonyl in Formaldehyde  followed by elimination of water. This in turn was reacted with Isatin Schiff’s bases as illustrated in Scheme (4) to give the desired product.

 

Scheme (3) The prepared Mannich bases derivatives 

 

Scheme (4) The proposed mechanism for prepared Mannich bases derivatives

 

Identification of Mannich bases derivatives:

(M1):(Z)-3-hydroxy-4-((2-oxoindolin-3-ylidene)amino)benzenesulfonamide,FT-IR(KBr)cm-1, ѵ3432Symmitric,3404 Assymmitric(NH2)Amine group,ѵ3490(OH)Hydroxyl group,ѵ3191 (NH) Piperazine,ѵ3052(CH)Aromatic group,ѵ2941 (CH)Aliphatic group,ѵ1336 (SO2)Sulfoxide group,ѵ1734(C=O)Carbonyl group, ѵ1608(C=N)(21,22)Imine group,  ѵ1558(C=C)aromatic

 

(G1) :(Z)-4-((2-oxoindolin-3-ylidene)amino)-N-(pyrimidin-2-yl)benzenesulfonamide,FT-IR(KBr)cm-1,ѵ 3336(NH)Sulfon amide,ѵ3091(CH)Aromatic group ѵ2939-2877(CHaliphatic),ѵ1348 (S=O)Sulfoxide group, ѵ1735(C=O)Carbonyl group, ѵ1608(C=N)Imine group,  1668(C=N)Pyrimidine,13CNMR(DMSO):δ 169.525(C,C=O),δ161.989(C=N)Imine group, δ157.486(N=C1)Pyrimidine ring,δ153.515(N=C2)Pyrimidine ring,δ111.047(C, Phenyl ),δ76.385(N-CH2-N),δ56.895(C3,CH2)Piperidines ring,δ24.605(C2,CH2)Piperidines ring,δ 21.895(C3,CH2)

 

(B1) :(Z)-3-((4-methoxy-2-nitrophenyl)imino)indolin-2-one,FT-IR(KBr)cm-1,ѵ 3404(NH)Piperazine, ѵ2941 (CHaliphatic), ѵ1734(C=O)Carbonyl group, ѵ1608(C=N)Imine group,  ѵ1573(C=C)aromatic,ѵ 1348(NO2),ѵ1157 (C-O,OCH3),13CNMR(DMSO) :δ 170.662(C,C=O),δ162.397(C=N)Imine group,,δ110.351-130.253(C, Phenyl ),δ76.385(N-CH2-N),δ55.918 (C3,CH2)Piperidines ring,δ25.605(C2,CH2)Piperidines ring,δ 21.895(C3,CH2)

 

(R1): (Z)-3-((2-mercaptothiazol-5-yl)imino)indolin-2-one,FT-IR(KBr)cm-1 ѵ 3250(NH)Piperazine,ѵ2947 (CH) aliphatic, ѵ1739(C=O)Carbonyl group, ѵ1612(C=N)Imine group,  ѵ 1642(C=N)Thiazole ring,ѵ1562(C=C)Aromatic, 13CNMR(DMSO) : 170.411(C, C=O)Carbonyl group,δ160.917(C=N)Imine group,δ157.501(N=C)Thiazole group,116-130(C of phenyl group),80 (N-CH2-N),δ54.513 (C3,CH2)Piperidines ring,δ29.608(C2,CH2)Piperidines ring,δ 27.808(C3,CH2)

 

(X1) :(Z)-3-((2-hydroxy-5-methylphenyl)imino) indolin-2-one,FT-IR(KBr)cm-1,ѵ 3433(OH)Hydroxyl group, ѵ 3412(NH)Piperazine ѵ2922-2883(CHaliphatic), ѵ1737(C=O)Carbonyl group,ѵ 1612(C=N)Imine group,

 

(S1):(Z)-3-((4-methoxyphenyl)imino)indolin-2-one,FT-IR(KBr)cm-1, ѵ 3414(NH)Piperazine,ѵ2937- (CHaliphatic), ѵ1737(C=O)Carbonyl group,ѵ 1612(C=N)Imine group, ѵ1580 (C=C)aromatic, ѵ1140 (C-O,OCH3),13CNMR(DMSO) : 170.683(C, C=O)Carbonyl group,δ162.253(C=N)Imine group,δ157.501(N=C)Thiazole group,116-130(C of phenyl group),81 (N-CH2-N),δ59.958(C3,CH2)Piperidines ring,δ 55.918(C,OCH3)Ether group,δ27.518(C2,CH2)Piperidines ring,δ 23.883(C3,CH2)

 

 

Table 1 FT-IR spectrum for each compound

Detail

Scheme

RT-IR spectrum of compound (M)

 

 

RT-IR spectrum of compound (G)

 

 

RT-IR spectrum of compound (B)

 

 

RT-IR spectrum of compound (R)

 

 

RT-IR spectrum of compound (X)

 

 

RT-IR spectrum of compound (S)

 

 

FT-IR spectrum compound (M1)

 

 

FT-IR spectrum compound (G1)

 

 

FT-IR spectrum compound (B1)

 

 

FT-IR spectrum compound (R1)

 

 

FT-IR spectrum compound (X1)

 

 

FT-IR spectrum of compound (S1)

 

 

 

 

Table 2. HNMR spectrum of each  compound

Detail

Scheme

1HNMR spectrum of compound (G)

 

 

1HNMR spectrum of compound (B)

 

 

1HNMR spectrum of compound (R)

 

 

1HNMR spectrum of compound (S)

 

 

13C NMR spectrum of compound (G)

 

 

13C NMR spectrum of compound (B)

 

 

13C NMR spectrum of compound (R)

 

 

13C NMR spectrum of compound (S)

 

 

13C NMR spectrum of compound (G1)

 

 

13C NMR spectrum of compound (B1)

 

 

13C NMR spectrum of compound (R1)

 

 

13C NMR spectrum of compound (S1)

 

 

 

Table 3.  Physical properties of shiff bases derivatives

Solvent

%yield

color

RF

M.P

M.WT gm.\mol

M.F

NO

Ethanol

88

yellow

0.76

198-200

317

C14H11N3O4S

M

Ethanol

85

yellow

0.66

201-203

379

C18H13N5O3S

G

Ethanol

83

Red

0.9

188-190

297

C15H11N3O4

B

Ethanol

77

yellow

0.88

193-195

260

C12H18N2OS2

R

Ethanol

76

orange

0.74

186-189

250

C15H12N2O2

X

Ethanol

81

orange

0.55

207-209

251

C15H13N2O2

S

 

Table 4. Physical properties of Mannich bases derivatives

solvent

%yield

color

RF

M.P C0

M.WT gm.\mol

M.F

NO

Ethanol

85

yellow

0.7

218-220

398

C20H22N4O3S

M1

Ethanol

82

yellow

0.8

222-224

471

C24H13N6O3S

G1

Ethanol

79

Red

0.6

230-232

394

C21H22N4O4

B1

Ethanol

67

yellow

0.63

244-246

358

C17H18N2OS2

R1

Ethanol

80

orange

0.76

241-239

349

C21H23N3O2

X1

Ethanol

87

orange

0.85

236-238

350

C21H24N3O2

S1

 

Table 5: Zone inhibition (mm) of all derivatives against various microorganisms and compression the biological activity of these  compounds with biological activity of Ampicillin and Ciprofloxacin.

Inhibition zone (mm)

Concentrations

µg/L

NO

Proteus mirabilis

Escherichia Coli

Granutice tella adiacens

Staphylococcus Aureus

17

20

22

16

22

25

21

22

24

20

23

26

1        0.5       0.1

 M 

20

23

26

19

20

23

22

23

25

21

24

28

1        0.5       0.1

G

14

19

25

14

18

22

12

14

24

`15

18

16

1        0.5       0.1

B

19

23

28

23

25

27

20

23

26

20

22

24

1        0.5       0.1

R

18

22

23

20

20

22

19

18

24

21

20

25

1        0.5       0.1

X

21

24

30

20

25

28

22

26

32

12

15

17

1        0.5       0.1

S

22

25

28

22

24

26

20

22

26

22

24

27

1        0.5       0.1

M1

10

13

24

10

14

16

12

14

26

20

22

24

1        0.5       0.1

G1

10

12

16

10

14

25

12

 14

26

12

14

18

1        0.5       0.1

B1

11

13

26

10

12

28

18

20

26

18

22

30

1        0.5       0.1

R1

 

 

 

 

 

 

 

 

 

 

 

 

 

X1

 

 

 

 

 

 

 

 

 

 

 

 

 

S1

13

11

10

10

13

12

10

11

12

13

11

12

1        0.5       0.1

Amp.*

11

13

17

8

11

14

9

10

12

8

10

13

1        0.5       0.1

Cip.*

*Ampicillin antibiotics

*Ciprofloxacin antibiotics

 

 

Biological Activity:

The development of antibiotics for bacterial pathogenesis has a special importance in the treatment of infection diseases 23. The important conclusion is that the biological effectiveness of the best in the compound (G, M, R, G1, M1, R1) because their constituents including organic derivatives which containing sulphuer atoms.  All of these compounds showed high effective even at low concentrations. The results also showed that all compounds are effectively much higher than the effectiveness of Ciprofloxacin 24 and Ampicillin 25. some compounds like (G, M, R, G1, M1, R1) are a promising agent for further structural modification and pharmacological evaluation as target treatment of infections caused by these types of bacteria Table.3.

 

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Received on 17.11.2020            Modified on 19.01.2021

Accepted on 20.03.2021           © RJPT All right reserved

Research J. Pharm.and Tech 2021; 14(11):6025-6032.

DOI: 10.52711/0974-360X.2021.01047