SYNTHESIS AND ANTIMICROBIAL STUDIES OF NOVEL GLYCOSYL THIOCARBAMIDESHTML Full Text
SYNTHESIS AND ANTIMICROBIAL STUDIES OF NOVEL GLYCOSYL THIOCARBAMIDES
A. D. Mangte *, S. J. Munshi and R. P. Nayak
P. G. Department of Chemistry, Shri P. M. Patel Institute of P. G. Studies & Research in Science, Anand -388001, Gujarat, India.
ABSTRACT: Glycosyl isothiocyanates have been widely used as important intermediates in the synthesis of many biologically active glycosyl derivatives. The glycosyl isothiocyanates have been the focus of synthetic attention during recent years because of their potential pharmacological properties. Thiourea and their derivatives are important versatile reagent in organic synthesis and show strong antibacterial activity. Hence, in view of applications of N-glycosylated compounds in medicinal chemistry and in many other ways, we herein report the synthesis and antimicrobial studies of novel glycosyl thiocarbamides of amino tetrazole and aminopyrimidine. In present investigation, a series of novel protected glycosyl heterocycles were synthesized by reaction of glycosyl isothiocyanate with amino tetrazole and amino pyrimidine. The newly synthesized compounds were characterized on the basis of IR, 1HNMR and Mass spectral studies. Antimicrobial evaluation of the synthesized substituted thiocarbamides is also carried out. Antimicrobial activities of the synthesized compound were evaluated against bacteria E. aerogenesa, B. megaterian, S. marcescens, and M. luteus and Fungi A. niger and Penicillinium. All the newly synthesized glycosyl thiocarbamides exhibit promising antimicrobial activity.
Glycosyl isothiocyanates, Glycosyl thiocarbamides, Glycosyl tetrazoles, Glycosyl pyrimidines, Antimicrobial and Antifungal activities
INTRODUCTION: Carbohydrates have aroused much interest in synthetic and medicinal chemistry because of outstanding biological importance 1, 2. Heterocyclic compounds show good pharmaco-logical activity and used in treatment of many diseases 3, 4, 5. Nitrogen-containing heterocyclic compounds show broad range of pharmaceutical activities.
Glycosyl isothiocyanate is proven to be excellent intermediate and has been used for the preparation of a variety of carbohydrate derivatives of synthetic, biological and pharmaceutical interest 6, 7 since they easily undergo many important reactions such as cycloaddition and nucleophilic substitution 8. Thiocarbamide is important class of organic compound and important precursor in the synthesis of many heterocyclic derivatives 7, 9.
Thiocarbamides are known to exhibit antioxidant, anti-allergens, anti-bacterial, anti-inflammatory, antithyroid, anti-epileptic, antihypertensive and anti-cancer activities 10. Several methods have been reported to synthesize thiocarbamides derivatives in literature but most common is condensation of amine with isothiocyanate. Thiocarbamide derivatives with such diverse biological activities lead us to synthesize some more thiocarbamides containing glycosyl substituent at nitrogen. In continuation of research work 11-14, some new glycosyl thiocarbamides have been synthesized and their antimicrobial activities have been evaluated by the cup plate agar diffusion method 15.
MATERIALS AND METHODS: All reactions are monitored on Merck silica gel plates. Melting points were recorded on electrothermal melting point apparatus without correction. IR spectra were recorded on a Perkin-Elmer Spectrum RXI (4000-450 cm-1) FTIR spectrometer. 1HNMR spectrum was obtained on a Bruker DRX-300 (300 MHz FT NMR) NMR spectrometer in CDCl3 solution with TMS as an internal reference. The Mass spectra were recorded on a Jeol SX-102 Mass spectrometer. Thin Layer Chromatography [TLC] was performed in E. Merck per coated silica gel plates and detected by exposure under short UV light.
General Procedure: A solution of Per-O-acetyl glycosyl isothiocyanate 1a-c (1 mmol) and heterocyclic amines (1 mmol) are refluxed in toluene (50 ml) for 3-4 h. The reaction is monitored by TLC (Ethyl acetate petroleum ether, 1:1). Toluene is distilled off under reduced pressure, sticky mass obtained was triturated with petroleum ether (60-80º). The solid obtained was crystallized from ethanol-water.
Where, R = a) Per-O-acetyl glucosyl, b) Per-O-acetyl lactosyl, c) Per-O-acetyl maltosyl,
I) 5- Amino tetrazole, Toluene reflux 3-4 h, II) 2- Amino pyrimidine, Toluene reflux 3-4 h.
TABLE 1: LIST OF SYNTHESIZED COMPOUNDS:
TABLE 2: PHYSICAL PROPERTIES OF SYNTHESIZED COMPOUNDS
|Compounds||Molecular formula||Molecular weight||Melting point ºC||% Yield||Rf||Solubility|
|2a||C16 H24O10N6S||492||140oC||76||0.68||Acetone, Ethanol, Chloroform, Benzene Dichloromethane, Dimethyl sulphoxide,|
|3a||C19 H24O9N4S||484||85oC||81||0.72||Acetone, Ethanol, Chloroform, Benzene Dichloromethane, Dimethyl sulphoxide,|
|2b||C28H40O18N6S||780||104oC||63||0.77||Acetone, Ethanol, Chloroform, Benzene Dichloromethane, Dimethyl sulphoxide,|
|3b||C31 H40O17N4S||772||75oC||69||0.70||Acetone, Ethanol, Chloroform, Benzene Dichloromethane, Dimethyl sulphoxide,|
|2c||C28 H40O18N6S||780||98oC||72||0.75||Acetone, Ethanol, Chloroform, Benzene Dichloromethane, Dimethyl sulphoxide,|
|3c||C31 H40O17N4S||772||78oC||80||0.65||Acetone, Ethanol, Chloroform, Benzene Dichloromethane, Dimethyl sulphoxide,|
Biological Evaluation: All newly synthesized compounds were screened for their in-vitro antibacterial activities against various pathogenic bacteria such as Enterobactera aerogenesa (Gram negative), Bacillus megaterian (Gram positive), Serratia marcescens (Gram negative) and Micrococcus luteus (Gram positive) by cup-plate method. Amikacin was used as a standard antibacterial drug. Antifungal activities were screened against Aspergilus niger and penicillium using Fluconazole as standard drug.
Antimicrobial Assay: The nutrient agar medium was prepared by dissolving 20 gm of nutrient agar in 1000 ml distilled water and autoclaved at 121 ºC temperature and 151bs/inch2 pressure for 20 minutes. After sterilization, it was cooled down to about 50 ºC. Inoculation of the medium was done aseptically with 0.5 ml of stains of E. aerogenesa, B. megaterian, S. marcescens and M. luteus at room temperature. A. niger and penicillinium was done in same manner as for bacterial stains. 15 ml of inoculated molten agar medium was poured into each sterile petridish and allowed to solidify at room temperature. A stainless cork borer of 7 mm diameter was used to bore the cavities. All the synthesized compounds and reference were taken at concentration of 1mg/ml using DMSO as a solvent. For antibacterial assay, the plates were incubated for about 24 h and for Antifungal activities incubation of the plates was done for 48 h. The diameter of zone of inhibition observed around the wells was measured in mm Table 4.
RESULTS AND DISCUSSION: All the newly synthesized compounds were characterized by IR16-17, 1HNMR16-17 and Mass spectral analysis. The spectral data of all newly synthesized compounds were found in accordance with the molecular structure Table 3.
TABLE 3: SPECTRAL DATA OF NEWLY SYNTHESIZED COMPOUNDS
|Compounds||IR KBR (cm-1)||1HNMR (CDCl3) (ppm)||FAB- MS (m/z)|
|2a||3280(N-H), 2974(C-H aliphatic), 1751(C=O), 1369 (C-N), 1226(C-O) 1036(C=S), 1037 & 902 (glucose unit)||d3.4-5.4 (7H, m, glucose unit), d1.9-2.0 (12H, m, 4COCH3)||492 (M+)|
|3a||3400(N-H), 2991(C-H aliphatic), 1743(C=O), 1371 (C-N), 1222 (C-O), 1145(C=S), 1087 & 904 (glucose unit)||d3.2-5.3 (7H, m, glucose unit), d1.9-2.2(12H, m, 4COCH3)||484 (M+)
|2b||3298(N-H), 2966(C-H aliphatic), 1745(C=O), 1367 (C-N), 1170(C=S),1217(C-0),1056 & 900 (lactose unit)||d3.82-5.2(14H, m, lactose unit), d1.9-2.11 (21H, m, 7COCH3)||780 (M+)|
|3b||3500(N-H), 2983(C-H aliphatic), 1760(C=O), 1369 (C-N), 1226 (C-O), 1174 (C=S), 1049 & 910 (lactose unit)||d3.80-5.4(14H, m, lactose unit), d1.9-2.11 (21H, m, 7COCH3)||772 (M+)|
|2c||3400(N-H), 2960(C-H aliphatic), 1751(C=O), 1369(C-N), 1159(C=S), 1230(C-0), 1043 & 900 (maltose unit)||d3.60-5.3(14H, m, maltose unit), d1.9-2.2 (21H, m, 7COCH3)||780 (M+)|
|3c||3014(N-H), 2962(C-H aliphatic), 1751(C=O), 1369(C-N), 1168(C=S), 1226(C-0),1039 & 900 (maltose unit)||d3.84-5.24(14H, m, maltose unit), d1.9-2.11 (21H, m, 7COCH3)||772 (M+)|
Antimicrobial Assay: Amongst the compounds tested for antibacterial activity, compounds 2a, 3a & 3c were found to be moderately active while 2b, 2c & 3b were almost weakly active against E. aerogenesa. Compounds 2c, 3c was found to be more active while 2b moderately active and 2a, 3b weakly active against B. megaterian. Compounds 2a, 3b, 3c were moderately active, 2b, 3a weakly active against S. marcescens. Compounds 2a, 2b & 2c were moderately active while 3a, 3b & 3c were found to be weakly active against M. lutues.
The synthesized compounds were also tested for their antifungal activities against Aspergilus niger and penicillium using Fluconazole as the standard drug. Compound 2c was more active while compounds 2a and 3c were moderately active and compounds 3a, 2b, 3b weakly active against A. niger. Compound 3c was more active while compounds 3b and 2c were moderately active, compounds 2a, 2b weakly active and compound 3a inactive against Penicillinium.
Hence from the screening results, it was found that most of the compounds are found to be more or less effective against microorganisms. Hence, for treatment of diseases these compounds can be used only when they do not have any toxic or other side effects.
TABLE 4: DIAMETER OF ZONE OF INHIBITION (mm) OF COMPOUNDS
|Compounds||E. aerogenes||B. megaterium||S. marcescens||M. luteus||A. niger||Penicillinium|
++++ Strongly active (above 20 mm), +++ Moderately active (15mm to 20mm), ++ Weakly active (8m to 14mm), -- Inactive (below 8 mm)
CONCLUSION: Novel glycosyl thiocarbamides (2a-c) & (3a-c) were successfully synthesized and characterized on the basis of IR, 1HNMR and Mass spectral studies. All newly synthesized glycosyl thiocarbamides exhibit comparable antimicrobial and antifungal activities. Most of the compounds show promising antimicrobial activity.
The method used in the present study is simple, efficient and inexpensive and has useful applications in the synthesis of pharmacologically important molecules.
ACKNOWLEDGEMENT: Authors are thankful to Centre of Excellence, Department of chemistry, Saurashtra University, Rajkot for providing IR, 1HNMR and Mass spectra of the newly synthesized compounds. Authors are also thankful to the Adv Shree Bipinchandra P. Patel, President, APMS, Anand for providing necessary research facilities.
CONFLICT OF INTEREST: The authors declare that there is no conflict of interests regarding the publication of this article.
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How to cite this article:
Mangte AD, Munshi SJ and Nayak RP: Synthesis and antimicrobial studies of novel glycosyl thiocarbamides. Int J Pharm Sci & Res 2019; 10(10): 4552-56. doi: 10.13040/IJPSR.0975-8232.10(10).4552-56.
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A. D. Mangte *, S. J. Munshi and R. P. Nayak
P. G. Department of Chemistry, Shri P. M. Patel Institute of P. G. Studies & Research in Science, Anand, Gujarat, India.
24 January 2019
17 June 2019
24 September 2019
01 October 2019