AN EFFICIENT, GREENER MICROWAVE ASSISTED MULTI-COMPONENT ONE POT SYNTHESIS OF [1, 3, 4] THIADIAZIN-2-YL-THIAZOLIDIN-4-ONES

AN EFFICIENT, GREENER MICROWAVE ASSISTED MULTI-COMPONENT ONE POT SYNTHESIS OF [1, 3, 4] THIADIAZIN-2-YL-THIAZOLIDIN-4-ONES

Savita R. Dhongade^* and Sandeep A. Kenawade

Research Laboratory in Heterocyclic Chemistry, Devchand College, Arjunnagar Kolhapur - 416012, Maharashtra, India.

ABSTRACT: This work involves synthesis of [1, 3, 4] thiadiazin-2-ylamine 3(a-c) derivatives from various substituted acetophenone derivatives 1(a-c), and thiosemicarbazide 2 mixed in ethanol and irradiation with microwaves which were directly used for next step. [1, 3, 4]Thiadiazin-2-yl)-thiazolidin-4-one 6(a-f) were synthesized in the second step from substituted-6H-[1, 3, 4] thiadiazin-2-ylamine 3(a-c), substituted aromatic aldehyde 4(a-b), and thioglycolic acid mixed in ethanol. After completion of the reaction products obtained 6(a-f) was confirmed by spectroscopy. Library of such [1, 3, 4] thiadiazin-2-ylamine and [1, 3, 4] thiadiazin-2-yl)-thiazolidin-4-one derivatives has been generated and the structures were subjected to PASS for their probabilities of being biologically active. Biological prediction study of the library was done to find out most active molecules. Computer programme PASS predicted for three activities with top probability for compound 3(a-c) as- 1. Mucomembranous protector, 2. Arylacetonitrilase inhibitor, 3. Macrophage elastase inhibitor. Similarly Compounds 6(a-f) were predicted for two activities with top probability as- 1. CC chemokine-4-receptor antagonist, 2. Phosphatase inhibitor.

[1,3,4]thiadiazin-2-ylamine, [1,3,4]thiadiazin-2-yl)-thiazolidin-4-one, PASS, Biological prediction study

INTRODUCTION: 1, 3, 4-thiadiazine derivatives involve in many biological processes and serve as  medicinally interesting compounds ^{1, 2}. The wide range of therapeutic activities of 1, 3, 4-thiadiazine are antifungal ³, antibacterial ⁴, antimicrobial ⁵, anti-inflammatory ⁶ cardiovascular ⁷, anti-HIV ⁸, antidiabetic ⁹, antidepressant ¹⁰ etc. 4-Thiazolidi-none derivatives have also been known to exhibit diverse bio-activities such as anti-convulsant ¹¹, anti-diarrheal ¹², anti-platelet activating factor ¹³, antihistaminic ¹⁴, anti-diabetic ¹⁵,

Cyclooxygenase (COX) inhibitory ¹⁶, Ca²⁺-channel blocker ¹⁷, platelet activating factor (PAF) antagonist ¹⁸, cardioprotective ¹⁹, anti-ischemic ²⁰, anti-cancer ²¹, tumor necrosis factor-α antagonist ²² and nematicidal activities ²³. 2-Phenylimino-3-aryl-4- S- benzyl-6-tetra-O-acetyl-β-D-galactosylimino-2, 3-dihydro-1, 3, 5-thiadiazine (hydrochloride) derivatives ²⁴ show antimicrobial activity against various pathogenic bacteria and fungi.

These biologically active spiroheterocycle inspired us to integrate thiadiazine moiety in a triazole framework ²⁵. Some new 1, 3, 4-thiadiazines with coumarin moieties and their derivatives ²⁶ were shown to have antioxidant activity, employing different antioxidant assays (DPPH scavenging activity, iron chelating activity, power reducing activity).

Again some new series of novel 3-(5-methyl-1-phenyl- 1H-1,2,3-triazol-4-yl)- 6-aryl- 7H- [1, 2, 4] triazolo[3,4b] [1,3,4] thiadiazine derivatives ²⁷ shown antibacterial activity against four human pathogenic bacteria viz. Escherichia coli, Klebseilla pneumoniae, Shigella dysentriae and Shigella flexnei. Herein we report the synthesis of a new series of spiro-thiadiazines and their antimicrobial activity. The synthesis of heterocycles containing such multistructure in a molecule has received much attention in recent years ²⁸.

PASS: PASS is a software application that predicts 565 possible biological activities of a user selected (set of) compound(s). These activities include 5-hydroxytryptamine antagonists, neuromuscular blocking agents, antibiotics, antidepressants, antiviral agents (AIDS), contraceptives, tumor necrosis factor antagonists and many others. Using PASS predictions, novel pharmaceutical agents have been discovered with anxiolytic, anti-inflammatory, antihypertensive, anticancer and other activities. PASS is applicable to chemical libraries containing millions of compounds.

The "the biological activity spectrum" is defined as the "intrinsic" property of a compound depending only on its structure and physico-chemical characteristics. Prediction of this spectrum by PASS is based on SAR analysis of the training set containing thousands of compounds which have many kinds of biological activities. In PASS biological activities are described qualitatively (“active” or “inactive”).

Importance of PASS:

1. Experimental determination of biological activity of a drug is time and cost consuming procedure, so making the use of PASS is generally important.
2. PASS can be effectively used for finding of compounds with required properties and without undesirable side effects.
3. It used for selecting the most prospective compounds from the set of available samples for specific screening.
4. For determining of more relevant screens for particular compound.

Due to this significance of PASS, it is used in the present study as a tool to design the drug with highest probable activity.

MATERIALS AND METHODS: All chemicals and solvents were reagent grade and used as purchased without any further purification. Analytical thin layer chromatography was performed on percolated silica gel 60-F 254 plates. IR spectra on KBr disks were recorded on a Schimazdu IR - 470 FT-IR spectrophotometer. The routine nuclear magnetic resonance spectra were taken in DMSO/CDCl₃ using a Bruker 300 MHz spectrophotometer with TMS as an internal standard. Chemical shift δ was given in ppm relative to TMS. The data found were in consistent with the proposed structure. Elemental analysis was done using EURO Vector Elemental Analyzer. Melting points are determined in an open capillary tube and are uncorrected.

Synthetic Procedure for the 5-phenyl-6H-[1, 3, 4] thiadiazin-2-ylamine 3(a): In 100 mL round bottom flask, acetophenone 1.20 g,(0.01 mole), and thiosemicarbazide 0.91 g, (0.01 mole) were mixed in ethanol (20 mL) and the reaction mixture was irradiated with microwaves at 20% microwave power (140 W) for 5 min. The completion of the reaction was confirmed by TLC (Ethyl acetate: Hexane 1:9). The reaction mixture was allowed to cool at room temperature, poured into crushed ice. The solid separated was filtered, washed with little ethanol and purified by recrystallization from ethanol to get pure products.

5-Phenyl-6H-[1, 3, 4] thiadiazin-2-ylamine 3(a):

Molecular Formula: C₉H₉N₃S_,

Melting Point: 222 °C,

IR (KBr) ν_max: 1200 (C=S), 3318 (>NH) 3552 (-NH₂) cm^–1. H¹ NMR (CDCl₃, 300 MHz): δ 2.60 (s, 2H, CH₂), 6.94-7.36 (m, 5H, Ar-H), 9.45 (s, 2H, NH₂) ppm. ¹³C NMR(CDCl₃, 100 MHz): δ 21.09, 127.91, 129.90, 133.30, 140.00, 150.01, 154.91 ppm. Similarly derivatives 3b and 3c are synthesized.

5- (3-Nitro-phenyl)- 6H- [1, 3, 4] thiadiazin-2-ylamine 3(b):

Molecular Formula: C₉H₈N₄O₂S_,

Melting Point: 206 °C,

IR (KBr) ν_max: 1330(C=S), 3010 (>NH), 3345 (-NH₂) cm^–1. H¹ NMR (CDCl₃, 300 MHz): δ 2.71 (s, 2H, CH₂), 7.66-8.99 (m, 4H, Ar-H), 9.78 (s, 2H, NH₂) ppm. ¹³C NMR(CDCl₃, 100 MHz): δ 21.18, 120.51, 126.41, 128.58, 132.28, 140.61, 142.27, 146.26, 150.55 ppm.

5-(4-Methoxy-phenyl)-6H- [1, 3, 4] thiadiazin-2-ylamine 3(c):

Molecular Formula: C₁₀H₁₁N₃OS_,

Melting Point: 202 °C,

IR (KBr) ν_max: 1120 (C=S), 2965 (>NH), 3317 (-NH₂) cm^–1. H¹ NMR (CDCl₃, 300 MHz): δ 2.56 (s, 2H, CH₂), 3.87 (s, 3H, OCH₃), 6.90-7.98 (m, 4H, Ar-H), 9.67 (s, 2H, NH₂) ppm. ¹³C NMR(CDCl₃, 100 MHz): δ 18.09, 67.42, 121.97, 124.51, 127.55, 128.93, 124.12, 156.67 ppm. The products thus obtained 3(a-c) were directly used for next step.

Synthetic procedure for the 2-(2,4dichloro-phenyl)-3- (5-phenyl-6H- [1,3,4] thiadiazin-2-yl)-thiazolidin-4-one6(a-f): In a 100 mL round bottom flask, the product of step I i.e. 5-phenyl-6H-[1,3,4]thiadiazin-2-ylamine(3a) (0.001 mole), 2,4-dichlorob-enzaldehyde (0.001 mole), and thio glycolic acid (2-mercapto acetic acid) (0.001 mole) were mixed in ethanol (15 mL). The reaction mixture was irradiated with microwaves at 20% microwave power (140 W) for 4 mins. The completion of the reaction was confirmed by TLC (Ethyl acetate: Hexane 1:9). The reaction mixture was allowed to cool at room temperature and poured into crushed ice. The solid separated was filtered, washed with little ethanol and purified by recrystallization from ethanol to get pure product 6a.

2-(2, 4-Dichloro-phenyl)-3-(5-phenyl-6H-[1, 3, 4] thiadiazin-2-yl)-thiazolidin-4-one 6(a):

Molecular Formula: C₁₈H₁₃Cl₂N₃OS_2,

Melting Point: 228 °C,

IR (KBr) ν_max:750 (C–Cl), 1040 (C-N), 1750 (C=O), 3000 (Ar-CH), cm^–1. H¹ NMR (DMSO, 400 MHz): δ 2.49 (s, 2H, >CH₂), 3.26 (s, 2H, >CH₂), 6.06(s, 1H, >CH), 7.31-8.27(m, 8H, Ar-H), ppm. ¹³C NMR(DMSO, 100 MHz): 21.29, 33.50, 67.50, 107.18, 117.95, 127.02, 128.07, 129.43, 130.58, 132.56, 132.87, 134.60, 135.07, 137.83, 152.18, 171.18 ppm. Similarly derivatives 6(b-f) are synthesized.

2- (4-Chloro-phenyl)- 3-(5-phenyl- 6H- [1, 3, 4] thiadiazin-2-yl)-thiazolidin-4-one6(b):

Molecular Formula: C₁₈H₁₄ClN₃OS_2,

Melting Point: 202 °C,

IR (KBr) ν_max:700 (C–Cl), 1040 (C-N), 1750 (C=O), 2950 (Ar-CH), cm^–1. H¹ NMR (DMSO, 400 MHz): δ 2.66 (s, 2H, >CH₂), 3.26 (s, 2H, >CH₂), 6.08 (s, 1H, >CH), 7.31-8.11(m, 9H, Ar-H), ppm. ¹³C NMR(DMSO, 100 MHz): 21.00, 25.22, 71.50, 117.65, 127.02, 128.07, 129.63, 130.56, 132.50, 132.87, 134.60, 135.00, 137.89, 174.02 ppm.

2-(2, 4 Dichloro-phenyl)-3-[5-(3-nitro-phenyl)-6H-[1,3,4]thiadiazin-2-yl]-thiazolidin-4-one 6(c):

Molecular Formula: C₁₈H₁₂Cl₂N₄O₃S₂,

Melting Point: 210 °C,

IR (KBr) ν_max:700 (C–Cl), 1020 (C-N), 1355-1375 (N=O), 1740 (C=O), 2950 (Ar-CH), cm^–1. H¹ NMR (CDCl₃, 400 MHz): δ 2.50 (s, 2H, >CH₂), 3.55 (s, 2H, >CH₂), 5.97 (s, 1H, >CH), 7.11-8.04 (m, 7H, Ar-H), ppm. ¹³C NMR(CDCl₃, 100 MHz): 22.54, 29.48, 63.64, 114.81, 124.69, 130.65, 133.32, 136.62, 138.68, 141.81, 144.14, 145.44, 148.26, 149.59, 154.65, 161.33, 163.49, 180.08 ppm.

2-(4-Chloro-phenyl)-3-[5-(3-nitro-phenyl)-6H-[1, 3, 4]thiadiazin-2-yl]-thiazolidin-4-one6(d),

Molecular Formula: C₁₈H₁₃ClN₄O₃S_2,

Melting Point: 204 °C,

IR(KBr) ν_max:700 (C–Cl), 1020 (C-N), 1355-1375 (N=O), 1740 (C=O), 2950 (Ar-CH),cm^–1. H¹ NMR (CDCl₃, 400 MHz): δ 2.50 (s, 2H, >CH₂), 3.55 (s, 2H, >CH₂), 6.01 (s, 1H, >CH), 6.79-7.65 (m, 8H, Ar-H), ppm. ¹³C NMR(CDCl₃, 100 MHz): 21.08, 29.48, 67.48, 115.84, 118.84, 121.48, 124.69, 127.77, 130.65, 132.25, 135.21, 149.05, 153.03, 160.49, 161.33, 181.01 ppm.

2-(2,4Dichloro-phenyl)-3-[5-(4-methoxy-phenyl)-6H-[1,3,4]thiadiazin-2-yl]-thiazolidin-4-one6(e):

Molecular Formula: C₁₉H₁₅Cl₂N₃O₂S_2,

Melting Point: 212 °C,

IR (KBr) ν_max:700 (C–Cl), 1020 (C-N), 1300 (C-O), 1600 (C=C), 1740 (C=O), 2950 (Ar-CH), cm^–1. H¹ NMR (CDCl₃, 400 MHz): δ 2.38 (s, 2H, >CH₂), 3.22 (s, 2H, >CH₂), 3.92 (s, 3H, >OCH₃), 6.00 (s, 1H, >CH), 7.14-7.66 (m, 7H, Ar-H), ppm. ¹³C NMR(CDCl₃, 100 MHz): 21.17, 33.78, 55.10, 70.18, 107.11, 122.20, 126.88, 139.02, 140.07, 142.23, 143.38, 145.14, 145.87, 147.00, 147.77, 150.37, 179.89 ppm.

2-(4-Chloro-phenyl)-3-[5-(4 - methoxy - phenyl)-6H-[1, 3, 4]thiadiazin-2-yl]-thiazolidin-4-one6(f):

Molecular Formula: C₁₉H₁₆ClN₃O₂S₂,

Melting Point: 230 °C,

IR (KBr) ν_max:700 (C–Cl), 1020 (C-N), 1300 (C-O), 1600 (C=C), 1740 (C=O), 2950 (Ar-CH), cm^–1. H¹ NMR (CDCl₃, 400 MHz): δ 2.38 (s, 2H, >CH₂), 3.22 (s, 2H, >CH₂), 3.90 (s, 3H, >OCH₃), 6.01 (s, 1H, >CH), 7.20-7.60 (m, 8H, Ar-H), ppm. ¹³C NMR(CDCl₃, 100 MHz): 21.17, 33.78, 55.10, 70.18, 107.11, 122.20, 126.88, 139.02, 140.07, 142.23, 143.38, 145.87, 147.77, 150.37, 179.89 ppm.

TABLE 1: ANALYTICAL DATA OF THE COMPOUNDS 3(a-c)

TABLE 2: ANALYTICAL DATAOF THE COMPOUNDS 6(a-f)

RESULTS AND DISCUSSION: The confirmed structures were subjected to computer programme PASS for the prediction of their biological activities. Compound 3(a-c) were predicted for three activities with top probability.

• Mucomembranous protector
• Arylacetonitrilase inhibitor
• Macrophage elastase inhibitor

TABLE 3: BIOLOGICAL PREDICTION ANALYSIS OF ACTIVITIES OF DERIVATIVES 3(a-c)

Compounds 6(a-f) were predicted for two activities with top probability.

1. CC chemokine 4 receptor antagonist
2. Phosphatase inhibitor

TABLE 4: BIOLOGICAL PREDICTION ANALYSIS OF ACTIVITIES OF DERIVATIVES 6(a-f)

CONCLUSION: In summary, we have developed an efficient method for the synthesis of [1, 3, 4] thiadiazin-2-ylamine 3(a-c) and [1, 3, 4] thiadiazin-2-yl)- thiazolidin- 4- one 6(a-f) derivatives with excellent yield under microwave irradiation, which attains completion in 5 - 7 min in an organic medium and may provide a useful route for the rapid drug discovery. Biological prediction analysis revealed that the 2-(2, 4 dichloro-phenyl)-3-(5-phenyl-6H-[1, 3, 4] thiadiazin-2-yl)-thiazolidin-4-one6(a) is predicted to be moderately active as CC chemokine 4 receptor antagonist. 2-(4-chloro-phenyl)-3-(5-phenyl-6H-[1, 3, 4] thiadiazin-2-yl)-thiazolidin-4-one 6(b) can be most active in the series as phosphatase inhibitor and hence it is recommended for the screening of the same activity.

ACKNOWLEDGEMENT: The authors acknowledge UGC for providing financial assistance under the scheme of Major Research Project 41-305/2012 (SR) for availing research facilities in Research Laboratory in Heterocyclic Chemistry at Devchand College, Arjunnagar, Maharashtra, India.

CONFLICT OF INTEREST: Nil

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    How to cite this article:

    Dhongade SR and Kenawade SA: An efficient, greener microwave assisted multi-component one pot synthesis of [1, 3, 4] thiadiazin-2-yl-thiazolidin-4-ones. Int J Pharm Sci Res 2018; 9(2): 650-55.doi: 10.13040/IJPSR.0975-8232.9(2).650-55.

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