Design, Synthesis and Characterization of Some Novel Amino and Aldehyde Substituted Azaphenothiazines

 

Dhiraj Raghuvanshi¹*, Pramod Kumar Sharma¹, Nimita Manocha¹, Shikha Agrawal²,Prerna Chaturvedi¹

¹Department of Pharmaceutical Chemistry, Swami Vivekanand College of Pharmacy, Near Toll Naka, Khandwa Road, Indore, M.P. PIN-452020

²Department of Pharmaceutics, Swami Vivekanand College of Pharmacy, Near Toll Naka, Khandwa Road, Indore, M.P. PIN-452020

*Corresponding Author E-mail: dhirajraghuwanshi3@gmail.com

 

 

 

INTRODUCTION:

Phenothiazines (heterocyclic ring system consisting of two benzene rings ortho-fused to 1,4-thiazine ring) and their analogues constitutes an important class of bioactive heterocycles. Phenothiazine and related compounds have been reported to possess various diverse biological activities including neuroleptic^[1], tranquilizer^[1], antifungal^[1], antimicrobial^[1], antitumor^[1], antiparkinson^[1], antibacterial^[2], antimalarial^[2], CNS depressant^[2], analgesic^[2], antiviral^[2], antipyretic^[3], antiinflammatory^[3], antitubercular^[3] and antihistamine^[3] properties. Phenothiazine derivatives having amino alkyl side chain connected to the nitrogen atom of heterocyclic unit play a crucial role in medicinal chemistry are reported in the literature.

 

Phenothiazine nucleus containing drugs have been reported to possess anti-microbial and CNS effects. Replacement of one aromatic nucleus of phenothiazine by pyridine ring has been reported to possess more prominent biological activity. Chemical name of azaphenothiazine is pyrido[3,2-b][1,4]benzothiazine-1-azaphenothiazine. It is a tri-cyclic compound; its molecular weight is 200.66.^[3]

 

Nitrogen containing heterocyclic compound like azaphenothiazine have received considerable attention in recent years due to their biological activities like antihypertensive, anti-histaminic, anti-microbial, sedative and anti-allergic activities. Since aza-phenothiazine is bioisosteric isomer of phenothiazine, it is expected to have biological activities similar to phenothiazine.

 

Azaphenothiazine can be prepared by following process^[4]

1.      By direct sulfonation of 2-Anilinopyridene in presence of iodine.

2.      By sulfonation of 2-Aminopyridene with phenol in presence of iodine.

3.      By Smile rearrangement of 2-Acetamidophenyl-3-nitro-4-pyridylsulfide.

4.      By reaction between 2-Chloropyridene and 2-Aminothiophenol in presence of iodine and sulfur.

Keeping in view of these valid observations we are planned to synthesize 10-substituted azaphenothiazine derivatives and screened for antimicrobial and sedative activity.

 

EXPERIMENTAL:

The melting points were determined in open capillary tubes and are uncorrected. The IR spectra of the compounds were recorded on Perkin-Elmer FTIR spectrometer in KBr pellets. ¹HNMR spectra were recorded on Bruker 400 MHZ ADVANCE ¹HNMR spectrometer. The chemical shifts are reported in parts per million downfield from tetramethylsilane.

 

Scheme of work: (Scheme-1)

 

 

Mass spectra were recorded on LC-MS Schimadzu 2010A using dimethyl sulfoxide as solvent. All the compounds gave satisfactory chemical analysis, the homogencity of the compounds was checked by TLC on aluminum foil packed precoated silica gel plates using Chloroform: Methanol: Acetic acid (9.4:0.5:0.1 v/v) and Chloroform: Benzene (7.5:2.5 v/v) as mobile phase and visualized by iodine vapors.

 

Procedure for synthesis of azaphenothiazine (1)

2-Amino thiophenol (0.2 mol) and 2-chloropyridine (0.2 mol) was taken in round bottom flask and refluxed for 3 hours in presence of iodine at the temperature of 90°-120°C with continuous stirring. After this the reaction flask was cooled with ice and contents were dried at room temperature. The completion of reaction was monitored by TLC by using precoated silica gel plate [Chloroform: Methanol: Acetic acid (9.4:0.5:0.1) v/v] and iodine vapours used as a spot detecting reagent. The compound was confirmed by melting point and IR spectra.

 

Procedure for synthesis of 2-Chloro-1-(10H-azaphenothiazine-10-yl-)ethanone (2)

To a solution of ethanol (25 ml) and chloroacetylchloride (0.2 mol), azaphenothiazine (0.2mol) was added drop wise and the solution was refluxed for 1 hour on a water bath. After this the reaction mixture was poured on to cold water and the precipitate solid was collected by filtration and recrystallized from ethanol. The completion of reaction was monitored by TLC by using precoated silica gel plate [Chloroform: Methanol: Acetic acid (9.4:0.5:0.1) v/v] and iodine vapours used as a spot detecting reagent. The compound was confirmed by melting point and IR spectra.

 

Procedure for synthesis of 2-(amino substitute)-1-(10H-azaphenothiazine-10-yl-)ethanone (3a-e)

To the compound 2 [2-Chloro-1-(10H-azaphenothiazine-10-yl-)ethanone] (0.01 mol) various amines (3a-3e) were added and mixture was dissolved in acetone. This mixture was kept on reflux for 2 hours on a water bath. After this the reaction mixture was poured on cold water in hot condition. Solid was precipitate out. Then precipitate was collected and recrystallized with methanol. Finally the compound was dried at room temperature. The completion of reaction was monitored by TLC by using precoated silica gel plate [Chloroform: Methanol: Acetic acid (9.4:0.5:0.1) v/v] and iodine vapours used as a spot detecting reagent. The compound was confirmed by melting point and IR spectra.

Table 1: List of amine and aldehyde substituents

S. No.	Compound Code	Compound Name	R
1	3a	Diphenyl amine
2	3b	o-Phenylene diamine
3	3c	Isopropyl amine
4	3d	Hydroxyl amine
5	3e	Dimethyl amine
6	4a	p-Methoxy benzaldehyde
7	4b	o-Hydroxy benzaldehyde
8	4c	p-Amino dimethyl benzaldehyde
9	4d	Benzaldehyde
10	4e	o-Nitro benzaldehyde

 

Procedure for synthesis of 2-hydrazinyl-1-(10H-azaphenothiazine-10-yl)ethanone (4)

To the compound 2 (0.1 mol) hydrazine hydrate (0.1 mol) was added. This mixture was dissolved in benzene and kept for reflux for 3 hours on a water bath. After this the reaction mixture was poured on to cold water and the precipitate solid was collected by filtration and recrystallized from benzene. Finally the compound was dried at room temperature. The completion of reaction was monitored by TLC by using precoated silica gel plate [Chloroform: Benzene (7.5:2.5) v/v] and iodine vapours used as a spot detecting reagent. The compound was confirmed by melting point and IR spectra.

 

Procedure for synthesis of 2-hydrazinyl-2(aldehyde substitute)-1-(10H-azaphenothiazine-10-yl) ethanone (4a-e)

A mixture of equimolar quantities of compound 4 (0.01 mol) and appropriate aryl aldehydes (4a-4e) (0.01 mol) were dissolved in ethanol (95%). Then the reaction mixture was kept on reflux for 3 hours on a water bath. After this the reaction mixture was poured on to cold water and the precipitate solid was collected by filtration and recrystallized from ethanol. Finally the compound was dried at room temperature. The completion of reaction was monitored by TLC by using precoated silica gel plate [Chloroform: Benzene (7.5:2.5) v/v] and iodine vapours used as a spot detecting reagent. The compound was confirmed by melting point and IR spectra.

 

 

Table 2: Lipinski rule values of compound 3a-4e

S. No.	Compound	M.W.	M.R.	LogP	No. of H bond Acceptor	No. of H bond Donor	No. of violation
1	3a	411.00	119.783	4.86	4	0	0
2	3b	350.00	102.238	4.31	5	3	0
3	3c	301.00	86.054	3.62	4	1	0
4	3d	275.00	72.694	2.67	5	2	0
5	3e	287.00	81.447	3.19	4	0	0
6	4a	392.00	111.484	4.25	5	1	0
7	4b	378.00	106.596	3.95	5	2	0
8	4c	405.00	119.259	4.32	5	1	0
9	4d	362.00	104.932	4.24	4	1	0
10	4e	407.00	111.073	4.52	6	1	0

 

Table 3: Physical and analytical data of newly synthesized compounds (3a-4e)

S. No.	Compound code	Molecular formula	Yield (%)	Melting point (°C)	Rf Value
1	3a	C26H20N2OS	55	189-191	0.55
2	3b	C20H17N3OS	68	178-180	0.73
3	3c	C17H18N2OS	49	167-169	0.52
4	3d	C14H12N2O2S	64	156-158	0.67
5	3e	C16H16N2OS	50	160-162	0.58
6	4a	C23H21N3O2S	62	198-200	0.64
7	4b	C22H19N3O2S	54	195-197	0.69
8	4c	C24H24N4OS	48	165-167	0.59
9	4d	C22H19N3OS	65	216-218	0.76
10	4e	C22H18N4O3S	58	209-211	0.56

Mobile phase (3a-3e) - Chloroform: Methanol: Acetic acid (9.4:0.5:0.1) v/v/v

Mobile phase (4a-4e) - Chloroform: Benzene (7.5:2.5) v/v/v

 

Bioavailability^[5]:

Prediction of bioavailability was done by a customized software using Lipinski rule of five. The data have been show in Table 2.

 

Spectral analysis of compounds (3a-4e):

2-(10H-azaphenothiazin-10-yl)-N,N-diphenylacetamide (3a): IR (KBr) cm^-1: 1597 (C=O), 1428 (C=C), 1370 (C-N), 741 (C-S), 3033 (Ar C-H), 2890 (Ali C-H); ¹HNMR (TMS): δ 2.53 (s, 2H, CH₂), 7.82-8.01 (m, 7H, Ar-H); LCMS (DMSO): m/z 406.

 

N-(2-aminophenyl)-2-(10H-azaphenothiazin-10-yl)acetamide (3b): IR (KBr) cm^-1: 1586 (C=O), 1456 (C=C), 1379 (C-N), 778 (C-S), 3058 (Ar C-H), 2884 (Ali C-H); ¹HNMR (TMS): δ 2.58 (s, 2H, CH₂), 7064-8.07 (m, 7H, Ar-H); LCMS (DMSO): m/z 358.

 

N-isopropyl-2-(10H-azaphenothiazin-10-yl)acetamide (3c): IR (KBr) cm^-1: 1610 (C=O), 1445 (C=C), 1365 (C-N), 728 (C-S), 3079 (Ar C-H), 2871 (Ali C-H); ¹HNMR (TMS): δ 2.89 (s, 2H, CH₂), 6.98-7.89 (m, 7H, Ar-H); LCMS (DMSO): m/z 309.

 

N-hydroxy-2-(10H-azaphenothiazin-10-yl)acetamide (3d): IR (KBr) cm^-1: 1581 (C=O), 1486 (C=C), 1376 (C-N), 738 (C-S), 3029 (Ar C-H), 2852 (Ali C-H); ¹HNMR (TMS): δ 2.59 (s, 2H, CH₂), 7.45-8.76 (m, 7H, Ar-H); LCMS (DMSO): m/z 282.

 

N,N-dimethyl-2-(10H-azaphenothiazin-10-yl)acetamide (3e): IR (KBr) cm^-1: 1645 (C=O), 1467 (C=C), 1398 (C-N), 732 (C-S), 3090 (Ar C-H), 2860 (Ali C-H); ¹HNMR (TMS): δ 2.66 (s, 2H, CH₂), 7.88-8.91 (m, 7H, Ar-H); LCMS (DMSO): m/z 279.

 

N'-(2-(4-methoxyphenyl)ethylidene)-2-(10H-azaphenthiazin-10-yl)acetohydrazide (4a): IR (KBr) cm^-1: 3480 (N-H), 1599 (C=O), 1489 (C=C), 1380 (C-N), 784 (C-S), 3010 (Ar C-H), 2832 (Ali C-H); ¹HNMR (TMS): δ 2.96 (s, 2H, CH₂), 7.42-8.95 (m, 7H, Ar-H); LCMS (DMSO): m/z 399.

 

N'-(2-(2-hydroxyphenyl)ethylidene)-2-(10H-azaphenothiazin-10-yl)acetohydrazide (4b): IR (KBr) cm^-1: 3455 (N-H), 1625 (C=O), 1468 (C=C), 1381 (C-N), 755 (C-S), 3057 (Ar C-H), 2869 (Ali C-H); ¹HNMR (TMS): δ 2.78 (s, 2H, CH₂), 7.40-8.70 (m, 7H, Ar-H); LCMS (DMSO): m/z 396.

 

N'-(2-(4(dimethylamino)phenyl)ethylidene)-2-(10H-azaphenothiazin-10-yl)acetohydrazide (4c): IR (KBr) cm^-1: 3468 (N-H), 1584 (C=O), 1455 (C=C), 1362 (C-N), 790 (C-S), 3030 (Ar C-H), 2821 (Ali C-H); ¹HNMR (TMS): δ 2.90 (s, 2H, CH₂), 7.55-8.60 (m, 7H, Ar-H); LCMS (DMSO): m/z 411.

 

2-(10H-azaphenothiazin-10-yl)-N'-(2-phenylethylidene)acetohydrazide (4d): IR (KBr) cm^-1: 3490 (N-H), 1589 (C=O), 1439 (C=C), 1390 (C-N), 768 (C-S), 3050 (Ar C-H), 2870 (Ali C-H); ¹HNMR (TMS): δ 2.89 (s, 2H, CH₂), 7.91-8.79 (m, 7H, Ar-H); LCMS (DMSO): m/z 356.

 

 

N'-(2-(2-nitrophenyl)ethylidene)-2-(10H-azaphenothiazin-10-yl)acetohydrazide (4e): IR (KBr) cm^-1: 3420 (N-H), 1600 (C=O), 1478 (C=C), 1339 (C-N), 748 (C-S), 3059 (Ar C-H), 2878 (Ali C-H); ¹HNMR (TMS): δ 2.70 (s, 2H, CH₂), 7.20-8.89 (m, 7H, Ar-H); LCMS (DMSO): m/z 416.

 

RESULTS AND DISCUSSION:

The present study reports the synthesis of some novel substituted azaphenothiazine derivatives and their biological screening.

 

The target compounds were synthesized in five steps. The starting compound azaphenothiazine (1) was synthesized from 2-Aminothiophenol and 2- Chloropyridine in presence of iodine as per the procedure given in literature. In the next step azaphenothiazine was treated with chloroacetyl chloride to give compound 2 [2-chloro-1-(10H-azaphenothiazine-10yl)-ethanone]. From here the scheme had been divided into two branches one goes for the amine substitution and the other goes for the aldehyde substitution. In the third step compound 2 was treated with different amine to give proposed five compounds (3a-e) [2-(amino)-1-1-(10H-azaphenothiazine-10yl)-ethanone]. In the fourth step compound 2 was reacted with hydrazine hydrate in presence of benzene to give compound 4 [2-hydrazinyl-1-(10H-azaphenothiazine-10yl)-ethanone]. In the final step compound 4 was treated with different aryl aldehydes to give proposed five compounds (4a-e) [2-hydrazinyl-(2-aldehyde)-1-(10H-azaphenothiazine-10yl)-ethanone)]

 

Melting points of all the synthesized compounds were done by open capillary tube method and were uncorrected and found to be in the range of 156-216^oC.

 

The purity of compound was confirmed by thin layer chromatography using precoated silica gel plates (thickness 0.25 mm) with the help of suitable mobile phase and the R_f values were calculated and tabulated in table no. 3.

All the synthesized compounds were found to be freely soluble in DMF, chloroform and DMSO.

 

CONCLUSION:

This can be concluded that the scheme proposed was feasible as it successfully lead to the synthesis of azaphenothiazine derivatives. Azaphenothiazine nucleus is very well known to posses various biological activities.

 

The chemistry of these systems involves considerable biological interest as azaphenothiazine nucleus coupled with substituted aromatic aldehyde and aliphatic/aromatic amine. As it is known that substituted aldehyde and amine when attached with some alkyl chain or heterocyclic moiety can lead to potentially biological active compound. The structure modification for their better biological activity includes substitution on nitrogen at 10^th position coupled with aliphatic/aromatic amine and aromatic aldehydes. The above result established the fact that azaphenothiazine can be a rich source of biologically active compounds.

It can be concluded that the scheme proposed would lead to the new congeners of azaphenothiazine which might have lesser side effects and enhanced duration of action as well as faster onset of action.

 

REFERENCES:

1.       Valentina P et al. Synthesis and biological screening of novel amino alkyl substituted azaphenothiazine. Asian J. Res. Chem. 02; 2009: 411-413.

2.       Rajasekaran A, Periasamy M and Venkatesan S. Synthesis, characterization and biological activity of some novel azetidinones. J. Developmental Bio. Tissue Eng. 02; 2010: 5-13.

3.       Swati et al. Synthesis of some novel 1-azaphenothiaiznes and their mesoionics as analogues of potent CNS-depressants. Phosphorus, sulphur and silicon and the related elements. 117; 1996: 111-120.

4.       Clark FH et al. Anti-depressant 10-(3-dimethylaminopropyl)-3-azaphenothiazine. J. Org. Chem. 26; 1960: 1126.

URL: http://www.scfbio-iitd.res.in/utility/LipinskiFilters.jsp

 

 

 

Received on 05.03.2012         Modified on 18.03.2012

Accepted on 25.03.2012         © AJRC All right reserved