Design and Development of Novel 1,3-Thiazin-4-one compounds derived from Pyrazine-2,3-Dicarboxylic Acid: Synthesis and Bioactivity Screening

 

Ahmed N. Ayyash¹*, Hadeel Q. Abdalrazzaq Habeeb², Entesar J. Fadel¹

¹Lecturer of Organic Chemistry, Ph.D. of Heterocyclic Chemistry, Department of Applied Chemistry,

College of Applied Sciences, University of Fallujah, Anbar, Iraq.                 

²Assist. Lecturer of Organic Chemistry, M.Sc.  of Organic Chemistry, Department of Nursing,

Alfarabi University College, Baghdad, Iraq.

 

ABSTRACT:

In this study, a variety of new 1,3-thiazin-4-one compounds bearing 1,3,4-thiadiazoles and /or 1,2,4-triazoles moieties have been prepared via their relating Schiff bases with good yields by intramolecular cyclocondensation reaction starting with pyrazine-2,3-dicarboxylic acid. The structures conformity of newly synthesized compounds were based on their physiochemical properties, elemental analysis, as well as FTIR,¹H NMR, and ¹³C NMR spectra. These newly compounds have been screened for their antimicrobial activities with excellent results.

 

 

 

INTRODUCTION:

1,3-Thiazin-4-ones are class of heterocyclic compounds and are constitute of six-membered ring with two hetero atoms; sulfur and nitrogen located at the positions first and third positions of the ring, respectively, beside the carbonyl group attached at the C-4 position. In the last five years, there is a remarkable attractive to synthesis new derivatives of six-heterocyclic systems.¹-⁴ Compounds with six-membered heterocycles are important and interesting for the wide spectrum of their biological activities. By the literature survey, 1,3-thiazin-4-one derivatives have exhibited different bioactivity in many fields, such as anticancer,5^,6,7 antimalarial,⁸ antibacterial,⁹ antifungal,⁹ Anti-depressant,¹⁰ antioxidant.¹¹ However, the cyclocondensation reaction of mercaptopropionic acid and some imino compounds afforded new 1,3-thiazin-4-ones.¹²

 

Whereas, 2,6-diamino-5-azo-1,3-thiazinones were produced by the reaction of some azo derivatives and thiourea.¹³ Also, 1,3-thiazin-4-ones with a piperidyl moiety were synthesized when a thioamide was cyclized with an acetylene diester.¹⁴ Another series of 1,3-thiazine-2-thione derivatives were yielded by the reaction of  substituted acrylaldehyde with some different amines and CS₂ in a solution of acetonitrile and (Et₃)N.¹⁵ Furthermore, by one-pot reaction, a series of 5,6-dihydro-1,3-thiazin-4-ones have been prepared from methacryloylisothiocyanate and an aminomorpholin compound.¹⁶ Moreover, bis ­(2-substituted-1,3-thia­zin-4-one) derivatives have been obtained from the reaction of variety phenyl­methanimines and 3-mercaptopropionic acid in precense of pyridine.¹⁷ Recently, an efficient method has been reported for 1,3-benzothiazines and 2-arylthiazin-4-ones from various substituted alcohols and amides as raw materials.¹⁸ Consequently, our present study focus on the design and synthesis of some new compounds of bis (1,3-thiazin-4-ones) containing 1,3,4-thiadiazole and 1,2,4-triazole moieties and screening for their antifungal and antibacterial activities.

 

MATERIAL AND METHODS:

Chemicals and reagents:

All the chemicals and reagents were used as purchased from BDH, Fluka, Merck and Sigma-Aldrich companies.

 

Instrumentation:

For the reactions progress monitoring, thin-layer chromatography (TLC) was performed on pre-coated aluminum plates. Uncorrected melting points were determined in Celsius degree on open-capillary Electro-thermal apparatus. For IR spectra, the FTIR Shimadzu (8400s) spectrophotometer was operated using KBr disc. Bruker spectrometer (400 and 100 MHz in DMSO-d₆) was utilized to predict ¹H NMR and ¹³C NMR spectra and are expressed as part per million (δ ppm) downfield from an internal reference (TMS). Elemental Analyzer Model (Fison EA1108) was turned-on for C. H. N analysis. As for structures illustrating, the software application of Chem Draw Ultra (6.0) was applied.

 

General synthetic procedure of 5,5'-pyrazine-2,3-diylbis[N-(1,3,4-thiadiazol-2-amine), 2: To a solution of (0.168g, 0.001 mole) of pyrazine-2,3-dicarboxylic acid and (0.19 g, 0.002 mole) of thiosemicarbazide in (10mL) of absolute ethanol, (4 mL) of conc. H₂SO₄ was added with stirring and refluxed for 3h. After cooling at 25^oC, the mixture was poured onto ice-bath. The solid obtained was separated out, filtered, and recrystallized from ethanol.

 

General synthetic procedure of 5,5'-pyrazine-2,3-diylbis(4-amino-4H-1,2,4-triazole-3-thiol), 3: A mixture of (0.168g, 0.001 mole) of pyrazine-2,3-dicarboxylic acid and (0.213g, 0.002 mole) of thiocarbohydrazide was melted. The product was obtained on cooling and pushed into crushed-ice. The precipitated solid was separated by filtration and crystallized from DMF.¹⁹

 

General synthetic procedure of (Z,Z)-N,N'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[1-(4-substituted-pyridin-2-yl)methanimine], 4a-d : To a solution of (0.28g, 0.001 mole) of 2 and (0.002 mole) of appropriate pyridine-2-carbaldehyde in (20mL) of absolute ethanol, (3-4 drops) of glacial acetic acid (GAA) were added under stirring. The mixture was heated under reflux for 4h. and kept at room temperature to cool. The colored crystals were produced and filtered. After drying, the product was washed with water and purified by recrystallization from ethanol.

 

General synthetic procedure of 5,5'-pyrazine-2,3-diylbis{4-[(E)-(4-substitutedpyridin-2-ylmethylidene)amino]-4H-1,2,4-triazole-3-thiol}, 5a-d: The same procedure mentioned above for the preparation of compounds 4a-d, was applied for the synthesis of 5a-d except the  (0.3g, 0.001 mole) of 3 was used instead of 2.

 

General synthetic procedure of 3,3'-(pyrazine-2,3-diyl)bis[(1,3,4-thiadiazole-5,2-diyl)-2-(4-substitutedpyridine-2-carbaldehyde)-1,3-thiazin-4-one], 6a-d and/(or) 3,3'-(pyrazine-2,3-diyl) bis[(5-mercapto-4H-1,2,4-triazole-3,4-diyl)-2-(4-substitutedpyridine-2-carbaldehyde)-1,3-thiazin-4-one], 7a-d: To a solution of suitable of compound 4a-d and /(or 5a-d) (0.002 mole) in (20mL ) of dry benzene with a pinch of anhydrous ZnCl₂ , (0.7mL, 0.005 mole) of  3-mercaptopropionic acid was added. The mixture was heated gradually at 45^oC in a water-bath with stirring for 18-19h. (monitored by TLC). Then the reactants were kept to cool at 5^oC overnight. The crude product was separated-off by filtration and crystallized from DMF-H₂O solution (1:1).

 

Table 1: Physiochemical properties and elemental analysis of all the synthesized compounds.

Compd.	R	Yield (%)	mp. (oC)	M. wt. g/mol	Empirical Formula	Anal. found (calcd.) %
2		84	211-212	278.32	C8H6N8S2	C, 34.44 (34.52); H, 2.12 (2.17); N, 4.19 (40.26)
3		78	223-226	308.35	C8H8N10S2	C, 31.08 (31.16); H, 2.58 (2.62); N, 45.36 (45.43)
4a	H	83	242-243	456.51	C20H12N10S2	C, 52.56 (52.62); H, 2.62 (2.65); N, 30.61 (30.68)
4b	5-CH3	79	250-252	484.56	C22H16N10S2	C, 54.47 (54.53); H, 3.29 (3.33); N, 28.86 (28.91)
4c	5-OCH3	86	252-255	516.56	C22H16N10O2S2	C, 51.03 (51.15); H, 3.08 (3.12); N, 27.07 (27.12)
4d	3-Cl	72	231-233	525.40	C20H10Cl2N10S2	C, 45.65 (45.72); H, 1.93 (1.92); N, 26.61(26.66)
5a	H	87	238-241	486.54	C20H14N12S2	C, 49.32 (49.37); H, 2.87 (2.90); N, 34.50(34.55)
5b	5-CH3	86	244-245	514.59	C22H18N12S2	C, 51.28 (51.35); H, 3.49 (3.53); N, 32.61(32.66)
5c	5-OCH3	79	248-251	546.59	C22H18N12O2S2	C, 48.28 (48.34); H, 3.28 (3.32); N, 30.71(30.75)
5d	3-Cl	88	226-229	555.43	C20H12Cl2N12S2	C, 43.19 (43.25); H, 2.15 (2.18); N, 30.21 (30.26)
6a	H	68	261-262	632.77	C26H20N10O2S4	C, 49.30 (49.35); H, 3.16 (3.19); N, 22.11 (22.14)
6b	5-CH3	71	268-271	660.82	C28H24N10O2S4	C, 50.82 (50.89); H, 3.62 (3.66); N, 21.15 (21.20)
6c	5-OCH3	69	278-280	692.82	C28H24N10O4S4	C, 48.49 (48.54); H, 3.46 (3.49); N, 20.16 (20.22)
6d	3-Cl	63	255-257	701.66	C26H18Cl2N10O2S4	C, 44.43 (44.51); H, 2.54 (2.59); N,19.92 (19.96)
7a	H	66	269-270	662.80	C26H22N12O2S4	C, 47.07 (47.12); H, 3.31 (3.35); N, 25.29 (25.36)
7b	5-CH3	71	274-275	690.85	C28H26N12O2S4	C, 48.62 (48.68); H, 3.74 (3.79); N, 24.28 (24.33)
7c	5-OCH3	60	277-280	722.85	C28H26N12O4S4	C, 46.45 (46.52); H, 3.62 (3.63); N, 23.21 (23.25)
7d	3-Cl	63	251-254	731.69	C26H20Cl2N12O2S4	C, 42.63 (42.68); H, 2.73 (2.76); N, 22.91 (22.97)

RESULTS AND DISSCUSION:

A variety of new 1,3-thiazin-4-ones entitled 3,3'-(pyrazine-2,3-diyl) bis [(1,3,4-thiadiazole-5,2-diyl)-2-(4-substitutedpyridine-2-carbaldehyde)-1,3-thiazin-4-one], 6a-d and 3,3'-(pyrazine-2,3-diyl) bis[(5-mercapto-4H-1,2,4-triazole-3,4-diyl)-2-(4-substitutedpyridine-2-carbaldehyde)-1,3-thiazin-4-one], 7a-d have been synthesized in good yields from their Schiff bases as outlined in Scheme 1. Some of the physical properties of all prepared compounds are listed in Table 1, and the spectral data are given in Table 2.

 

Table 2: Most characteristic spectral data for the synthesized compounds.

 2)    5,5'-pyrazine-2,3-diylbis[N-(1,3,4-thiadiazol-2-amine) / IR (KBr), v (cm^-1): 3452-3362 (NH), 3080 (C-H), 1653 (C=N), 1575 (C=C), 1298 (C-N). ¹H NMR (DMSO-d6), δ (ppm):   9.69 (s, 2H, pyrazine), 3.99 (s, 4H, Ar. NH2)

 3)    5,5'-pyrazine-2,3-diylbis(4-amino-4H-1,2,4-triazole-3-thiol) / IR (KBr), v (cm^-1): 3466-3185 (NH), 3020 (C-H), 1606 (C=N), 1581 (C=C), 1226 (C-N) ¹H NMR (DMSO-d6), δ (ppm): 8.87 (s, 2H, pyrazine), 3.28 (s, 2H, Ar.SH) 2.59 (s, 4H, Ar. NH2)

4a)    (Z,Z)-N,N'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[1-(pyridin-2-yl)methanimine] / IR (KBr),

          v (cm^-1) :3310-3188 (NH), 3035 (C-H), 1646 (C=N), 1589 (C=C), 1321 (C-N). ¹H NMR (DMSO-d6), δ (ppm):    9.03 (s, 2H, pyrazine), 8.31 (s, 2H, HC=N), 7.99-7.15 (m, 8H, Ar-H).

4b)   (Z,Z)-N,N'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl) bis [1-(5-methylpyridin-2-yl)methanimine] / IR (KBr), v (cm^-1): 3410-3167 (NH), 3018-2899 (C-H), 1660 (C=N), 1599 (C=C), 1301 (C-N) ¹H NMR (DMSO-d6), δ (ppm): 8.87 (s, 2H, pyrazine), 8.20 (s, 2H, HC=N), 7.84-7.07 (m, 6H, Ar-H), 2.43 (s, 6H, Ar-CH₃).

4c)   (Z,Z)-N,N'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl)bis[1-(5-methoxypyridin-2-yl)methanimine] / IR (KBr), v (cm^-1): 3410-3167 (NH), 3018-2885 (C-H), 1620 (C=N), 1592(C=C), 1331 (C-N). ¹H NMR (DMSO-d6), δ (ppm): 8.80 (s, 2H, pyrazine), 8.51 (s, 2H, HC=N), 7.94-7.36 (m, 6H, Ar-H), 2.98 (s, 6H, Ar-OCH₃).

4d)    (Z,Z)-N,N'-(pyrazine-2,3-diyldi-1,3,4-thiadiazole-5,2-diyl) bis [1-(3-chloropyridin-2-yl)methanimine] / IR (KBr), v (cm^-1): 3345-3195 (NH), 3045 (C-H), 1638 (C=N), 1583 (C=C), 1253 (C-N), 722 (C-Cl). ¹H NMR (DMSO-d6), δ (ppm): 8.84 (s, 2H, pyrazine), 8.29 (s, 2H, HC=N), 7.99-7.32 (m, 6H, Ar-H).

5a)    5,5'-pyrazine-2,3-diylbis{4-[(E)-(pyridin-2-ylmethylidene) amino]-4H-1,2,4-triazole-3-thiol} / IR(KBr),v

        (cm ^-1): 3396-3188 (NH), 3042 (C-H), 1648 (C=N), 1593 (C=C), 1267 (C-N). ¹H NMR (DMSO-d6), δ (ppm): 9.22      (s, 2H, pyrazine), 8.09-7.28 (m, 2H, HC=N and 8H, Ar-H), 6.08 (s, 2H, Het-SH).

5b)  5,5'-pyrazine-2,3-diylbis{4-[(E)-( 5-methylpyridin-2-ylmethylidene)amino]-4H-1,2,4-triazole-3-thiol} / IR (KBr), v (cm^-1): 3403-3183 (NH), 3029-2893 (C-H), 1619 (C=N), 1589 (C=C), 1308 (C-N). ¹H NMR (DMSO-d6), δ (ppm): 8.67 (s, 2H, pyrazine), 8.12-7.58 (m, 2H, HC=N and 6H, Ar-H), 6.89 (s, 2H, Het-SH), 1.85 (s, 6H, Ar-CH₃).

5c)   5,5'-pyrazine-2,3-diylbis{4-[(E)-(5-methoxypyridin-2-ylmethylidene)amino]-4H-1,2,4-triazole-3-thiol}/ IR (KBr), v (cm^-1): 3215-3157 (NH), 3063-2941 (C-H), 1635 (C=N), 1606 (C=C), 1238 (C-N). ¹H NMR (DMSO-d6), δ (ppm): 8.87 (s, 2H, pyrazine), 8.32-7.49 (m, 2H, HC=N and 6H, Ar-H), 6.21 (s, 2H, Het-SH), 2.65 (s, 6H, Ar-OCH₃).

5d)   5,5'-pyrazine-2,3-diylbis{4-[(E)-(3-chloropyridin-2-ylmethylidene) amino ]-4H-1,2,4-triazole-3-thiol} / IR (KBr), v (cm^-1): 3310-3210 (NH), 3037 (C-H), 1642 (C=N), 1592 (C=C), 1338 (C-N), 719 (C-Cl). ¹H NMR (DMSO-d6), δ (ppm): 8.92 (s, 2H, pyrazine), 8.47-7.54 (m, 2H, HC=N and 8H, Ar-H), 5.16 (s, 2H, Het-SH).

6a)   3,3'-(pyrazine-2,3-diyl)bis[(1,3,4-thiadiazole-5,2-diyl)-2-(pyridine-2-carbaldehyde)-1,3-thiazin-4-one] /

        IR (KBr), v (cm^-1): 3053-2974 (C-H), 1687 (C=O), 1627 (C=N), 1604(C=C), 1253 (C-N). ¹H NMR (DMSO-d6), δ (ppm): 8.68 (s, 2H, pyrazine), 7.88-7.38 (m, 8H, Ar-H), 6.06 (s, 2H, CH, Thiazinone), 5.68 (d, 8H, CH₂, Thiazinone). ¹³C NMR (DMSO-d6), δ (ppm): 26.7 (S-CH₂-C, thiazinone ring), 47.0 (C-CO-CH₂, thiazinone ring), 65.5 (C₃-CH, thiazinone ring), 118.5-150.5 (Het. Carbons), 162.0 (2-pyridine carbons), 170.5 (N-C=O, thiazinone ring).

6b)   3,3'-(pyrazine-2,3-diyl)bis[(1,3,4-thiadiazole-5,2-diyl)-2-(5-methylpyridin-2-carbaldehyde)-1,3-thiazin-

        4-one] / IR (KBr), v (cm^-1): 3018-2910 (C-H), 1695 (C=O), 1616 (C=N), 1598 (C=C), 1264 (C-N). ¹H NMR (DMSO-d6), δ (ppm): 9.42 (s, 2H, pyrazine), 7.78-7.25 (m, 6H, Ar-H), 5.98 (s, 2H, CH, Thiazinone), 5.25 (d, 8H, CH₂, Thiazinone), 3.25 (s, 6H, Ar-OCH₃). ¹³C NMR (DMSO-d6), δ (ppm): 22.5 (Ar-CH₃), 29.7 (S-CH₂-C, thiazinone ring), 48.2 (C-CO-CH₂, thiazinone ring), 65.8 (C₃-CH, thiazinone ring), 120.5-152.8 (Het. Carbons), 161.5 (2-pyridine carbons), 171.4 (N-C=O, thiazinone ring).

6c)   3,3'-(pyrazine-2,3-diyl)bis [(1,3,4-thiadiazole-5,2-diyl)-2-(5-methoxypyridin-2-carbaldehyde)-1,3-thiazin-4-one]/IR (KBr), v (cm^-1): 3065-2994 (C-H), 1712 (C=O), 1649 (C=N), 1605(C=C), 1281 (C-N). ¹H NMR (DMSO-d6), δ (ppm): 8.88 (s, 2H, pyrazine), 7.69-7.20 (m, 6H, Ar-H), 5.48 (s, 2H, CH, Thiazinone), 4.19 (d, 8H, CH₂, Thiazinone), 3.59 (s, 6H, Ar-OCH₃). ¹³C NMR (DMSO-d6), δ (ppm): 30.5 (S-CH₂-C, thiazinone ring), 48.6 (C-CO-CH₂, thiazinone ring), 55.0 (Ar-OCH₃), 66.0 (C₃-CH, thiazinone ring), 119.8-150.0 (Het. Carbons), 161.7 (2-pyridine carbons), 172.2 (N-C=O, thiazinone ring).

6d)    3,3'-(pyrazine-2,3-diyl)bis[(1,3,4-thiadiazole-5,2-diyl)-2-(3-chloropyridine-2-carbaldehyde)-1,3-thiazin-

         4-one] / IR (KBr), v (cm^-1): 3062-2822 (C-H), 1708 (C=O), 1635(C=N), 1604(C=C), 1298 (C-N), 722 (C-Cl).

          ¹H NMR (DMSO-d6), δ (ppm): 8.69 (s, 2H, pyrazine), 7.86-7.22 (m, 6H, Ar-H), 5.42 (s, 2H, CH, Thiazinone), 4.87 (d, 8H, CH₂, Thiazinone). ¹³C NMR (DMSO-d6), δ (ppm): 29.5 (S-CH₂-C, thiazinone ring), 47.4 (C-CO-CH₂, thiazinone ring), 63.5 (C₃-CH, thiazinone ring), 118.5-152.2 (Het. Carbons), 160.6 (2-pyridine carbons),170.8 (N-C=O, thiazinone ring).

7a)   3,3'-(pyrazine-2,3-diyl) bis[(5-mercapto-4H-1,2,4-triazole-3,4-diyl)-2-(pyridine-2-carbaldehyde)-1,3-thiazin-4-one] / IR (KBr), v (cm^-1): 3084-2916 (C-H), 1705 (C=O), 1624 (C=N), 1593 (C=C), 1290 (C-N). ¹H NMR (DMSO-d6), δ (ppm): 8.84 (s, 2H, pyrazine), 8.28-7.14 (m, 8H, Ar-H), 6.64 (s, 2H, CH, Thiazinone), 6.21(d, 8H, CH₂, Thiazinone), 3.81 (s, 2H, Ar-SH). ¹³C NMR (DMSO-d6), δ (ppm): 29.5 (S-CH₂-C, thiazinone ring), 42.0 (C-CO-CH₂, thiazinone ring), 63.5 (C₃-CH, thiazinone ring), 118.2-151.5 (Het. Carbons), 161.8 (2-pyridine carbons), 171.5 (N-C=O, thiazinone ring).

7b)   3,3'-(pyrazine-2,3-diyl) bis[(5-mercapto-4H-1,2,4-triazole-3,4-diyl)-2-(5-methylpyridin-2-carbaldehyde)-1,3-  thiazin-4-one] / IR (KBr), v (cm^-1): 3080-2922 (C-H), 1715 (C=O), 1658 (C=N), 1608 (C=C), 1310 (C-N). ¹H NMR (DMSO-d6), δ (ppm): 9.30 (s, 2H, pyrazine), 8.45-7.18 (m, 6H, Ar-H), 6.08 (s, 2H, CH, Thiazinone), 5.73(d, 8H, CH₂, Thiazinone), 4.51 (s, 2H, Ar-SH), 1.86 (s, 6H, Ar-CH₃). ¹³C NMR (DMSO-d6), δ (ppm): 20.5 (Ar-CH₃), 29.8 (S-CH₂-C, thiazinone ring), 41.2 (C-CO-CH₂, thiazinone ring), 63.0 (C₃-CH, thiazinone ring), 120.5-150.7 (Het. Carbons), 161.0 (2-pyridine carbons), 173.2 (N-C=O, thiazinone ring).

7c)  3,3'-(pyrazine-2,3-diyl) bis[(5-mercapto-4H-1,2,4-triazole-3,4-diyl)-2-(5-methoxypyridin-2-carbaldehyde) 1, 3-thiazin-4-one] / IR (KBr), v (cm^-1): 3029-2895 (C-H), 1704 (C=O), 1636 (C=N), 1598 (C=C), 1292 (C-N). ¹H NMR (DMSO-d6), δ (ppm): 9.15 (s, 2H, pyrazine), 8.24-7.16 (m, 6H, Ar-H), 5.88 (s, 2H, CH, Thiazinone), 5.27(d, 8H, CH₂, Thiazinone), 4.28 (s, 2H, Ar-SH), 3.66 (s, 6H, Ar-CH₃). ¹³C NMR (DMSO-d6), δ (ppm): 31.2 (S-CH₂-C, thiazinone ring), 42.4 (C-CO-CH₂, thiazinone ring), 55.4 (Ar-OCH₃), 63.0 (C₃-CH, thiazinone ring), 121.5-153.0 (Het. Carbons), 161.4 (2-pyridine carbons), 172.6 (N-C=O, thiazinone ring).

 

However, the first step of the general synthetic pathway was the direct cyclization reaction of pyrazine-2,3-dicarboxylic acid 1, and thiosemicarbazide in solution of concentrated sulfuric acid of absolute ethanol under reflux conditions afforded 2-amino-1,3,4-thiadiazoles 2. Whereas the next step included the fusion of 1 and thiocarbohydrzide to give 4-amino-5-mercapto-1,2,4-triazole derivatives 3. A coincidence for the designed structures of synthesized compounds has been deduced from their physiochemical properties, microanalysis, FTIR, and ¹H NMR spectra. Whatever, the FTIR spectra of 2 and 3 showed the absorption bands in the region 3466-3185 cm^-1 due to the stretching vibrations of the amino group, Fig. 1. In addition, the most significant new peaks at 3.99-2.56 ppm caused by amino protons were observed in their ¹H NMR spectra as depicted in the Fig. 2.

 

 

Scheme 1: Synthetic route for the target compounds, 6a-d and 7a-d.

 

 

 

Fig. 1: FT-IR Spectrum of compound 2.    

                  

 

Fig. 2: ¹H NMR Spectrum of compound 2.

 

Likewise, these newly heterocyclic amines 2 and 3 were condensed with various pyridine-2-carbaldehydes in refluxing ethanol and few drops of glacial acetic acid as a catalyst to produce some new derivatives of Schiff bases 4a-d and 5a-d, respectively. Their IR spectra displayed a strong absorption bands between 1648-1620 cm^-1 belonging to the significant imino C=N stretching vibrations ^20-22  beside the absence of the absorption bands of the primary amino groups stretching.  Further, the disappearance of the NH₂ proton peak in the ¹H NMR spectra of 4 and 5, and another new signals were recorded in the aromatic region 6.89-7.75 ppm which may be attributed to the azomethine proton HN=C  is considerable another directory for the proposed structure, ²³ Fig. 3.

 

 

Fig. 3: ¹H NMR Spectrum of compound 4c.

The target compounds of 1,3-thiain-4-ones, 6a-d and 7a-d have been synthesized on cyclocondensation reaction of the newly prepared Schiff bases and betamercapto propionic acid   in dry benzene according to the proposed mechanistic steps, Scheme 2. So, the reaction proceeds by a nucleophilic attack of the sulfur atom to the carbon atom of azomethine group, then the intramolecular cyclization led to the elimination of water molecule. The products yield is depending on the removal of water molecule. Thus, good yields were achieved wherein anhydrous ZnCl₂ was used as a dehydrating agent, as well as to accelerate the latest step of the cyclization reaction.

 

Scheme 2: Proposed mechanistic steps for the title compounds synthesis.

 

The structural confirmation of 6a-d and 7a-d has been achieved with an agreement by the spectroscopic analysis. The infrared spectrum of compound 6a revealed strong absorption bands at 1687-1728 cm^-1 corresponding to the lactam carbonyl group stretching. While some new peaks were noted in the region 5.48-4.19 ppm and 6.64-6.21ppm in proton NMR spectra of compounds 6c and 7a due to the chemical shifts of the methine CH and methylene CH₂ protons of the thiazine ring, respectively.²¹ beside the others data which are given in Table 2. Moreover, ¹³C NMR spectra of compounds 6 and 7 exhibited several peaks with a consequence results, Figs. 4 and 5.

 

 

Fig. 4: ¹³C NMR Spectrum of compound 6a

 

Fig. 5: ¹³C NMR Spectrum of compound 7a.

 

Bioactivity Screening:

The title compounds 6a-d, 7a-d and the newly corresponding Schiff bases 5a-d, 5a-d have been screened for their antibacterial activity against Staphylococcus Sciuri as gram-positive and Escherichia coli as gram-negative strains. As well as, they were investigated as antifungal agents versus two fungal strains; Aspergillus flavus and Candida albicans by diffusion method.²⁴ The dimethylsulfoxide (DMSO) solvent has been used to dissolve and preparing (100 µg/mL) concentration of the examined compounds. So, the plates of the bacterial culture were incubated at 37 °C for 24h. Whereas, for fungal culture, the plates were incubated at 25 °C and examined after 72h. The growth inhibition ability for the tested compounds was estimated as inhibition zone diameter, and expressed in millimeters. The results are given in Table 3, were measured relative to the cefuroxime and ketoconazole as antibacterial and antifungal standard references, respectively. A good to excellent activities of the investigated compounds have been recorded. In addition, some of the newly compounds, such as; 4c, 4d, 5d, 6a, 6d, and 7c were found more effective than the standard drugs.   

 

Table 3: Bioactivity interaction of 1,3-thiazin-4-ones 6,7 and relating Schiff bases 4,5.

Zone of inhibition (mm)                           Bacterial Strains               Fungal Strains
Compd.	Staph.   sciuri	Escherichia  coli	Aspergillus  flavus	Candida  albicans
4a	17	10	08	12
4b	16	08	13	17
4c	19	16	11	11
4d	20	21	18	19
5a	12	17	07	09
5b	18	14	11	14
5c	11	19	15	16
5d	19	24	19	21
6a	10	11	22	18
6b	16	18	16	16
6c	17	15	19	23
6d	20	17	20	22
7a	15	18	18	14
7b	12	18	18	21
7c	17	23	23	17
7d	15	18	19	22
Cefuroxime	18	28
Ketoconazole			20	24

 *Concentration (100 µg/mL), diameter (mm); milliliter.

 

CONCLUSION:

In concluded, a series of new bis (1,3-thiazin-4-ones) compounds bearing 1,3,4-thiadiazoles or 1,2,4-triazoles moieties and their relating Schiff bases have been obtained with good yields by intramolecular cyclo-condensation reaction starting with pyrazine-2,3-dicarboxylic acid. The chemical structures of newly heterocyclic compounds were in conformity based on their physiochemical properties, elemental and spectroscopic analysis. These newly compounds have been screened and investigated for their antimicrobial activities. Most of them exhibited a satisfactory scores as antibacterial and antifungal agents. In addition, the compounds 4c, 4d, 5d, 6a, 6d, and 7c   showed more effective properties rather than the standard references drugs.   

 

ACKNOWLEDGEMENT:

The author is thankful to the Dept. of Chemistry, College of Sci. at Al-Mustansiriayah University and to the Ministry of Science and Technology, Baghdad, Iraq for operating some of this work.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

REFERENCES: 

1.        Carey JS et al. Analysis of the reactions used for the preparation of drug candidate molecules. Organic & Biomolecular Chemistry. 2006: 4(12); 2337-2347.

2.        Rück-Braun K. et al. 1, 3-Dipolar cycloaddition on solid supports: nitrone approach towards isoxazolidines and isoxazolines and subsequent transformations. Chemical Society Reviews. 2005: 34(6); 507-516.

3.        Mehta PD et al. 2-Azetidinone- A new profile of various pharmacological activities. European Journal of Medicinal Chemistry. 2010: 45(12); 5541-5560.

4.        Solomon, VR et al. Design and synthesis of novel quinacrine-[1, 3]-thiazinan-4-one hybrids for their anti-breast cancer activity. European Journal of Medicinal Chemistry. 2018:143;1028-1038.

5.        Wang S et al. Scaffold diversity inspired by the natural product evodiamine: discovery of highly potent and multitargeting antitumor agents. Journal of Medicinal Chemistry. 2015: 58(16); 6678-6696.

6.        Arya K et al. Design, synthesis and biological evaluation of novel spiro [indole-pyridothiazine] analogs as antiproliferative agents. RSC Advances. 2014: 4(6); 3060-3064.

7.        Umamatheswari S and Sankar C. Synthesis, identification and in vitro biological evaluation of some novel quinoline incorporated 1, 3-thiazinan-4-one derivatives. Bioorganic & Medicinal Chemistry Letters. 2017: 27(3); 695-699.

8.        Popiołek Ł et al. Design, synthesis, and in vitro antimicrobial activity of new furan/thiophene‐1, 3‐benzothiazin‐4‐one hybrids. Journal of Heterocyclic Chemistry. 2016: 53(2); 479-486.

9.        Nachiket SD et al.  Synthesis and Evaluation of Phenothiazine derivative for Anti-depressant activity. Asian J. Research Chem.  2015: 8(12); 745-750.

10.      Bosenbecker J et al. Synthesis and antioxidant activity of 3‐(pyridin‐2‐ylmethyl)‐1, 3‐thiazinan (thiazolidin)‐4‐ones. Journal of Biochemical and Molecular Toxicology. 2014: 28(9); 425-432.

11.      Gadre JN et al. Synthesis of some new 4-thiazolidinones and thiazin-4-ones as biologically potent agents. Indian Journal of Chemistry - Section B. 2007: 46(4); 653-659.

12.      Azab M et al. Synthesis and antibacterial evaluation of novel heterocyclic compounds containing a sulfonamido moiety. Molecules. 2013: 18(1); 832-844.

13.      Anand SA et al. Synthesis of novel 1,3-thiazin-4-ones by acetylene diester cyclization and their anticancer activities. Phosphorus, Sulfur and Silicon and the Related Elements. 2016: 191(10);1396-401.

14.      Sharma A et al. Synthesis, anticancer evaluation, and molecular docking studies of novel (4-hydroxy-2-thioxo-3,4-dihydro-2h-[1,3]thiazin-6-yl)-chromen-2-ones via a multicomponent approach. Journal of the Chinese Chemical Society. 2018: 65(7); 810-821.

15.      Kulakov IV et al. Synthesis, steric structure, and biological activity of 5-methyl-2-(morpholin-4-ylamino)-5,6-dihydro-4h-1,3-thiazin-4-one. Russian Journal of General Chemistry. 2015: 85(2); 467-471.

16.      Putta VPRK et al. A metal-and base-free domino protocol for the synthesis of 1,3-benzoselenazines, 1,3-benzothiazines and related scaffolds. Organic and Biomolecular Chemistry. 2019: 17(9); 2516-2528.

 

Accepted on 01.12.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(5): 2221-2227.