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Synthesis of Some N-(4-(Aryl)-2-Thioxo-1,3-Thiazol-3(2H)-yl)Pyridine-4-Carboxamide as Antimicrobial and Anti-inflammatory Agents | OMICS International
ISSN: 2161-0444
Medicinal Chemistry

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Synthesis of Some N-(4-(Aryl)-2-Thioxo-1,3-Thiazol-3(2H)-yl)Pyridine-4-Carboxamide as Antimicrobial and Anti-inflammatory Agents

Vikas G Rajurkar*, Sujata V Lambe and Vinayak K Deshmukh
Department of Pharmaceutical Chemistry, MES`s College of Pharmacy, Sonai, Newasa Taluka, Ahmednagar Dist, Maharashtra-414105, India2University College of Pharmaceutical Sciences, Kakatiya University Warangal, India
Corresponding Author : Vikas Gopalrao Rajurkar
MES`s College of Pharmacy
Sonai, Newasa Taluka, Ahmednagar Dist
Maharashtra-414105, India
Tel: +91- 9860482926
Fax: 02427-230948
E-mail: [email protected]
Received May 19, 2015; Accepted June 22, 2015; Published June 24, 2015
Citation: Rajurkar VG, Lambe SV, Deshmukh VK (2015) Synthesis of Some N-(4- (Aryl)-2-Thioxo-1,3-Thiazol-3(2H)-yl)Pyridine-4- Carboxamide as Antimicrobial and Anti-inflammatory Agents. Med chem 5:285-289. doi:10.4172/2161-0444.1000276
Copyright: © 2015 Rajurkar VG, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

A series of potential bioactive compounds, N-(4-(aryl)-2-thioxo-1,3-thiazol-3(2H)-yl) pyridine-4-carboxamide has been synthesized and screened for antibacterial, antifungal, anti-inflammatory activity by minimum inhibitory concentration and protein denaturation method respectively. The compounds IIc and IIj were found to be broad spectrum antimicrobial agents at minimum inhibitory concentration value against E. coli, K. pneumonia, S. aureus, B. subtilis, A. nigar, and S. cerevisiae respectively. In anti-inflammatory activity, compounds IIc, IIf, IIh, and IIj at 100 mg/ml and compound IIl at 200 mg/ml were found significant active agent.

Keywords
Antimicrobial; Anti-inflammatory; MIC; Thiazol
Introduction
There has been a constant battle between humans and the multitude of microorganismsthat cause infections and diseases; the treatment of bacterial infections remains a challenging job because of the increasing number of multidrug-resistant microbial pathogens. Despite the many chemotherapeutics available, the emergence of old and new antibiotic-resistant bacterial strains, mutations in microbial genomes, the incorrect use of antibiotics has been thoroughly demonstrated to greatly increase the development of resistant genotypes has generated a substantial need for new classes of anti-bacterial agents [1-2]. Various 2-thioxo-1,3-thiazol have been extensively investigated due to their application in different areas of biological activity such as antimicrobial [2-3], hypoglycemic [4], anti-inflammatory and analgesic agents [5], antidiabetic [6], antihyperglycemic [7]. Above mentioned facts prompted us to synthesis a series of N-(4-(aryl)-2-thioxo-1,3-thiazol- 3(2H)-yl)pyridine-4-carboxamide compounds having antimicrobial and anti-inflammatory activity. The structures of the compounds were confirmed by FT-IR, 1H-NMR, GC-mass spectroscopy and elemental analysis data studies; their antibacterial, antifungal, and antiinflammatory activities were performed by MIC (Minimum Inhibitory Concentration) method.
Experimental
Material and methods
All reagents and solvents used in the present study were of analytical grade and procured from Loba Chemie (India). The progress of the reactions were monitored by TLC using Merck silica gel precoated plate, with appropriate mobile phase, visualization by iodine vapour and UV chamber and product are purified by recrystallization technique. All the melting points recorded on a Veego apparatus (Mumbai, India) and were uncorrected. All the synthesized compounds were characterized by their FT-IR, 1H-NMR, GC Mass spectroscopy. FT-IR spectra were recorded in KBr on Bruker FT-IR instrument (Germany), 1H-NMR spectra were recorded on Bruker Avance 1H-NMR spectrometer (Germany), at 400 MHz in DMSO-d6, by using varian instrument using TMS as internal standard and chemical shift values are given in ppm downfield to TMS (tetramethylsilane), GC Mass were recorded on GCMS-QP-5050 Schimadzu (Japan), and Perkin Elmer 2400 Series II CHN Elemental Analyzer. The standard drugs norfloxacin, ketoconazole, and ibuprofen were obtained as gift sample from Wockhardt Ltd., Aurangabad, India.
Synthesis of potassium-pyridine-dithiocarbazate (I)
In a 250 ml round bottom flask, isoniazide (0.075 mol, 10.28 g) was dissolved in a solution of potassium hydroxide (0.075 mol, 4.2 g) in 100 ml of absolute ethanol and carbon disulphide (0.075 mol). The reaction mixture was agitated overnight and diluted with 200 ml of dry ether. The solid obtained was filtered and washed with dry ether, yield 15.05 g ( 80%) [8].
General procedure for synthesis of N-(4-(aryl)-2-thioxo- 1,3-thiazol-3(2H)-yl)pyridine-4-carboxamide (II)
In a 250 ml round bottom flask, potassium-pyridine-dithiocarbazate I (0.01 mol, 2.51 g) was dissolved in a solution of α-bromo ketone (0.01 mol) in 100 ml of absolute ethanol and was refluxed for 8 h. The resultant solution was concentrate, and the precipitate obtained filtered, washed with cold water, dried and recrystalized from ethanol to give good yield [9,10]. All the compounds were obtained in good yield, TLC mobile phase - benzene:pet. ether (6:4). Scheme 1 and Table 1.
N-(4-biphenyl-4-yl-2-thioxo-1,3-thiazol-3(2H)-yl)pyridine-4- carboxamide IIa: FT-IR ν max (KBr, cm-1): 1368 (C=S), 1402(C=C), 1651 (O=C), 1661(C=N), 2235(C-N), 3150(N-H). 1H-NMR (DMSO, 400 MHz) δ: 5.50(s, 1H, ethylene), 7.41-7.59 (m, 9H, aromatic), 8.1(s, 1H, sec. amide), 8.89-7.81(m, 4H, pyridine). MS: [M]+ at m/z 389.
N-[4-(2-hydroxyphenyl)-2-thioxo-1,3-thiazol-3(2H)-yl] pyridine-4-carboxamide IIb: FT-IR ν max (KBr, cm-1): 1000 (CO), 1370 (C=S), 1453 (C=C), 1636 (O=C), 1665 (C=N), 2250 (C-N), 3120 (N-H), 3645 (OH). 1H-NMR (DMSO, 400 MHz) δ: 5.15 (s, 1H, ethylene), 8.0 (s, 1H, sec. amide), 8.80-7.75 (m, 4H, pyridine), 6.60-7.32 (m, 4H, aromatic), 4.90 (s, 1H, OH). MS: [M]+ at m/z 329.
N-[4-(4-chlorophenyl)-2-thioxo-1,3-thiazol-3(2H)-yl]pyridine- 4-carboxamide IIc: FT-IR ν max (KBr, cm-1): 750 (C-Cl), 1360 (C=S), 1600 (C=C), 1610 (O=C), 1709 (C=N), 2275 (C-N), 3160 (N-H). 1H-NMR (DMSO, 400 MHz) δ: 5.20 (s, 1H, ethylene), 7.38-7.50 (m, 4H, aromatic), 7.90 (s, 1H, sec. amide), 8.70-7.95 (m, 4H, pyridine). MS: [M]+ at m/z 347.
N-[4-(4-bromophenyl)-2-thioxo-1,3-thiazol-3(2H)-yl]pyridine- 4-carboxamide IId: FT-IR ν max (KBr, cm-1): 995 (C-Br), 1393 (C=S), 1604 (C=C), 1677 (O=C), 1755 (C=N), 2260 (C-N), 3190 (N-H). 1H-NMR (DMSO, 400 MHz) δ: 5.22 (s, 1H, ethylene), 7.22-7.54 (m, 4H, aromatic), 8.15 (s, 1H, sec. amide), 8.99-7.76 (m, 4H, pyridine). MS: [M]+ at m/z 392.
N-[4-(2-oxo-2H-chromen-4-yl)-2-thioxo-1,3-thiazol-3(2H)-yl] pyridine-4-carboxamide IIe: FT-IR ν max (KBr, cm-1): 1448 (C=S), 1600 (C=O), 1711 (C-O-C), 1711 (C=N), 2210 (C-N), 3105 (N-H). 1H-NMR (DMSO, 400 MHz) δ: 5.21 (s, 1H, ethylene), 7.72-7.90 (m, 5H, coumarin), 7.96 (s, 1H, sec. amide), 8.68-7.94 (m, 4H, pyridine). MS: [M]+ at m/z 381.
N-[4-(4-methylphenyl)-2-thioxo-1,3-thiazol-3(2H)-yl]pyridine- 4-carboxamide IIf: FT-IR ν max (KBr, cm-1): 1444(C=S), 1490 (CCH 3), 1448 (C=S), 1635(O=C), 1675(C=N), 2240(C-N), 3210(N-H). 1H-NMR (DMSO, 400 MHz) δ: 2.38(s, 3H, CH3), 5.57 (s, 1H, ethylene), 7.18-7.26 (m, 4H, aromatic), 8.20(s, 1H, sec. amide), 8.95-7.61(m, 4H, pyridine). MS: [M]+ at m/z 327.
N-[4-(4-methoxyphenyl)-2-thioxo-1,3-thiazol-3(2H)-yl] pyridine-4-carboxamide IIg: FT-IR ν max (KBr, cm-1): 1448(C=S), 1587(C=C), 2252(C-N), 1490(C-OCH3), 1636(O=C) 1675(C=N), 2220 (C-N), 3208 (N-H). 1H-NMR (DMSO, 400 MHz) δ: 3.85 (s, 3H, OCH3), 5.65 (s, 1H, ethylene) 7.27-7.36(m, 4H, aromatic), 7.96 (s, 1H, sec. amide), 8.79-7.69(m, 4H, pyridine). MS: [M]+ at m/z 343.
N-[4-(4-aminophenyl)-2-thioxo-1,3-thiazol-3(2H)-yl]pyridine- 4-carboxamide IIh: FT-IR ν max (KBr, cm-1): 1452(C=S), 1556(C=C), 1597(O=C), 1733(C=N), 2354 (C-N), 2919 (N-H), 3548 (C-NH2). 1H-NMR (DMSO, 400 MHz) δ: 8.25(s, 1H, sec. amide), 5.42(d, 2H, NH2), 5.69 (s, 1H, ethylene), 6.25-7.64(m, 4H, aromatic), 8.69-7.94(m, 4H, pyridine). MS: [M]+ at m/z 328.
N-[4-(4-hydroxyphenyl)-2-thioxo-1,3-thiazol-3(2H)-yl] pyridine-4-carboxamide IIj: FT-IR ν max (KBr, cm-1): 1233(C-O), 1453(C=S), 1540(C=C), 1636(O=C), 1734(C=N), 2290(C-N), 2915(NH), 3647(OH).1H-NMR (DMSO, 400 MHz) δ: 5.37(s, 1H, ethylene), 6.74-7.59(m, 4H, aromatic), 8.16 (s, 1H, sec. amide), 8.82-7.61 (m, 4H, pyridine), 5.68(s, 1H, OH). MS: [M]+ at m/z 328.
N-(4-phenyl-2-thioxo-1,3-thiazol-3(2H)-yl)pyridine-4- carboxamide IIk: FT-IR ν max (KBr, cm-1): 1402 (C=S), 1539 (C=C), 1651 (O=C), 1754 (C=N), 2408 (C-N), 3023 (N-H). 1H-NMR (DMSO, 400 MHz) δ: 5.33 (s, 1H, ethylene), 7.32-7.74 (m, 5H, aromatic), 8.13 (s, 1H, sec. amide), 8.69-7.75 (m, 4H, pyridine). MS: [M]+ at m/z 313.
N-[4-(4-nitrophenyl)-2-thioxo-1,3-thiazol-3(2H)-yl]pyridine- 4-carboxamide IIl: FT-IR ν max (KBr, cm-1): 1342 (C-NO2), 1449 (C=S), 1596 (C=C), 1635 (O=C), 1682 (C=N), 2357 (C-N), 2914 (NH). 1H-NMR (DMSO, 400 MHz) δ: 5.61 (s, 1H, ethylene), 7.29-7.86 (m, 4H, aromatic), 7.96 (s, 1H, sec. amide), 8.68-7.82 (m, 4H, pyridine). MS: [M]+ at m/z 358.
N-[4-(3-nitrophenyl)-2-thioxo-1,3-thiazol-3(2H)-yl]pyridine- 4-carboxamide IIm: FT-IR ν max (KBr, cm-1): 1344 (C-NO2), 1456 (C=S), 1607 (C=C), 1637 (O=C), 1681 (C=N), 2282 (C-N), 2913 (NH). 1H-NMR (DMSO, 400 MHz) δ: 5.67 (s, 1H, ethylene), 7.66-8.24 (m, 4H, aromatic), 8.13 (s, 1H, sec. amide), 8.66-7.91 (m, 4H, pyridine). MS: [M]+ at m/z 358.
Biological evaluation
Antimicrobial activity [11]: All the synthesized derivatives were screened for in vitro antimicrobial activity against two gram positive strains S .aureus (S. aureus, NCIM 2079), B. subtilis (B. subtilis, NCIM 2711) and two gram negative strains E. coli (E. coli, NCIM 2685), K. pneumonia (K. pneumoniae, NCIM 2957) and two fungal strainsA. nigar (A. nigar, NCIM 596), S. cerevisiae (S. cerevisiae, NCIM 3102), using the broth micro dilution method. Minimum inhibitory concentration (MIC) was determined and compared with standard drugs norfloxacin for antibacterial and ketoconazole for antifungal activity and statistical analysis was performed using ANOVA to find the significance of the test, dimethyl sulfoxide used as inert solvent (Table 2).
in vitro anti-inflammatory activity by inhibition of protein denaturation [12]: The standard drug and synthesized derivative were dissolved in minimum quantity of dimethyl formamide (DMF) and diluted with phosphate buffer ((0.2M, pH 7.4). Final concentration of DMF in all solution was less than 2.5%. Test solution (1ml) containing different concentrations of drug was mixed with 1 ml of 1mM albumin solution in phosphate buffer and incubated at 27° ± 1°C in BOD incubator for 15 min. Denaturation was induced by keeping the reaction mixture at 60° ± 1°C in water bath for 10 min. After cooling, the turbidity was measured at 660 nm (UV-Visible Spectrophotometer). Percentage inhibition of denaturation was calculated from control where no drug was added and the ibuprofen was used as standard drug.
The percentage inhibition of denaturationwas calculated by using following formula and statistical analysis was performed using ANOVA to find the significance of the test (Table 3).
% of Inhibition=100 × [1- Vt / Vc]
Where, Vt=Mean absorbance of test sample, Vc=Mean absorbance of control
Structure Activity Relationship
The general structural formula of basic compound can be written as follows:
image
The relationship between chemical structure and antimicrobial, anti-inflammatory activity is summarized as follows.
The aryl ring should contain one substituent. Some substituent’s that seem to enhance antimicrobial, anti-inflammatory activity are chloro, methyl, methoxy, hydroxyl, amino and nitro groups. Compounds containing the p-Cl or -OH substituent are orders of broad spectrum than the original (first generation) compounds. It is believed that the high activity of these compounds is a function of the electron withdrawing group’s substitution on aryl ring at position no. 4 on thiazol ring. Among these compounds, it is thought that the spatial relationship between the electron donating groups contain compounds are less or inactive.
Results and Discussion
The synthesis of N-(4-(aryl)-2-thioxo-1,3-thiazol-3(2H)-yl) pyridine-4-carboxamide derivatives are depicted in Scheme 1. The IR spectra, reveals that functional groups present in the molecule appeared at their characteristic frequency characteristic frequency C=S, str. between 1360-1456 cm-1, C-N, str. between 2408-2210 cm-1, C-NH, str. between 3210-2913 cm-1, C=N, str. between 1661-1755 cm-1, C=C, str. between1402-1607 cm-1, O-H, str. between 3645-3647 cm-1, C-Cl, str. at 750 cm-1, C-Br, str. between 995 cm-1, C-CH3, str. 1490 cm-1, C-NH2, str. between 3548-3565 cm-1, C-NO2, str. between 1342-1344 cm-1, C=O, str. between 1597-1677 cm-1, C-O-C, str. at 1711 cm-1, C-CH3, str. at 1490 cm-1 etc. The chemical shift (δ) for sec. amide hydrogen was observed in the range of 7.90-8.25 ppm, δ value for methyl hydrogen was observed at 2.38 ppm, δ value for methoxy hydrogen was observed at 3.85 ppm, δ value for ethylene hydrogen was observed in the range of 5.15-5.69 ppm, δ value for hydroxyl hydrogen was observed in the range of 4.90- 5.68 ppm, δ value for amino hydrogen was observed in the range of 5.41-5.42 ppm, δ value for aromatic hydrogen was observed in the range of 6.25-8.24 ppm, δ value for pyridine hydrogen was observed in the range of 7.61-8.99 ppm. The m/e value was observed, e.g., in case of IIa-IIm at 313-392 (M)+. So, from the physical and spectral data, we can conclude that the desired compounds synthesized successfully.
Antimicrobial and anti-inflammatory activity
From in vitro antibacterial activity, In case of E. coli, K. pneumonia, S. aureus and B. subtilis compounds IIc, IIg, IIj and IIm (p-Cl-Ph, p-OCH3-Ph, p-OH, and m-NO2-Ph ) were found to have significant activity which is 1 folds less than the standard drug norfloxacin, while in vitro antifungal activity, In case of A. nigar and S. cerevisiae compounds IIc, IIf, and IIj (p-Cl-Ph, p-CH3-Ph, and p-OH) were found to have significant activity which is 1 folds less than the standard drug ketoconazole. In anti-inflammatory activity, compounds IIc, IIf, IIh, and IIj at 100 mg/mL (p-Cl-Ph, p-CH3-Ph, p-NH2-Ph, and p-OH) were found to have significant activity which is 1/10th less than the standard drug ibuprofen and at 200 mg/mL compound IIl (p-NO2-Ph) found significant active which is 1/10th less than standard drug ibuprofen (Tables 2 and 3). Thus from the obtained antibacterial, antifungal and anti-inflammatory activity data we could conclude that the electronwithdrawing groups substituted at specific position on phenyl ring i.e., (p-Cl-Ph, p-OCH3-Ph, p-OH, m-NO2-Ph, p-CH3-Ph, p-NH2-Ph and p-NO2-Ph) are contributing positively for antibacterial and antiinflammatory activity.
Conclusion
A series of N-(4-(aryl)-2-thioxo-1,3-thiazol-3(2H)-yl)pyridine-4- carboxamide had been synthesized in quantitative yields with the use of conventional method and evaluated for their in vitro antimicrobial and anti-inflammatory activity result are shown in Tables 2 and 3. On the basis of observed results, we concluded that additions of different functional groups have varying effects. In addition, the greater biological profiles were observed when the electron-withdrawing groups were incorporated at o-, m- and p- position of the phenyl ring.
Acknowledgements
The authors thank Shri. Prashant Patil Gadakh, President, Mula Education Society and Dr. V.K. Deshmukh, Principal, MES`s College of Pharmacy, Sonai for providing all laboratory facilities, UDCT Dr. BAMU, Aurangabad for recording FT-IR Spectra , 1H-NMR spectra at SAIF Punjab University, Chandigarh, GC-MS spectra at Savitribai Phule Pune University, Pune for recording spectra.
References

 

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Table 1 Table 2 Table 3

 

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Scheme 1
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