Synthesis and Biological Evaluation of Triazole linked Thiazolidenone Glycosides

In a one pot procedure a series of novel triazole linked thiazolidinone derivatives 8a–g and 9a–g was prepared by condensation of (3aR,5S,6R,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydro[2,3-d] [1,3]dioxole-5-carbaldehyde 7 with mercapto acids and primary amines in the presence of ZnCl2 under both microwave irradiation and conventional heating conditions. Compound 7 was prepared from diacetone D-glucose with oxidation followed by reduction, click reaction, primary acetonide deprotection and with oxidative cleavage. Characterization of new compounds has been done by means of IR, NMR, MS and elemental analysis. The nematicidal and antibacterial activity of the compounds has also been evaluated.


Introduction
1,2,3-Triazoles are one of the most important classes of heterocyclic organic compounds, which are reported to be involved in a plethora of biological activities and important for diverse therapeutic areas. 1 The 1,2,3-triazole motif is associated with diverse pharmacological activities such as antibacterial, antifungal, hypoglycemic, antihypertensive and analgesic properties.Polysubstituted five-membered aza heterocyclices rank as the most potent glycosidase inhibitors. 2 Further, this nucleus in combination with or in linking with various other classes of compounds, such as amino acids, steroids, aromatic compounds, carbohydrates etc., becames prominent in having various pharmacological properties. 31,2,3-Triazole modified carbohydrates have became easily available after the discovery of the Cu(I) catalyzed azide-alkynes 1,3-dipolar cycloaddition reaction 4 and quickly became a prominent class of non-natural sugars.The chemistry and biology of triazole modified sugars is dominated by triazole glycosides. 5Therefore, the synthesis and investigation of biological activity of 1,2,3-triazole glycosides is an important objective, which also received the considerable attention by the medicinal chemists.
Thiazolidenone and its derivatives are known to possess significant pharmacological 6 and biological activities, 7 like sedative, 8 anti inflammatory, 9 anti tubercular, 10 anticancer, 11 antitumor, 12 anti-HIV, 13 antibacterial, 14 antifungal, 15 analgesic, hypothermic, 16 anesthetic, 17 nematicidal 18 and CNS stimulant. 19Furthermore, thiazolidenones have been used for the treatment of cardiac diseases, 20 diabetic complications, like cataract nephropathy, neuropathy, 21 and as selective anti platelet activating factor. 22ematodes are tiny worms, some of them are plant parasites, and can play an important role in the predisposition of the host plant to the invansion by secondary pathogens. 23Plants attacked by nematodes show retarded growth and development, as well as loss in the quality and quantity of the harvest.The use of nematicides is slated for reduction due to environmental problems, and human and animals health concerns.For example, effective namaticides such as dibromochloropropane (DBCD) and ethylene dibromide (EDB) have been withdrawn from the market due to their deleterious effects on humans and the environment.Methyl bromide, the most effective and widely used fumigant for soil borne pests including nematodes, has already been banned.Srinivas et al.: Synthesis and Biological Evaluation ... The use of nonfumigant nematicides, based on organophosphates and carbamates, is expected to increase after the withdrawal of methyl bromide, which will bring about new environmental concerns.In fact, the highly toxic Aldicarb used to control insects and nematodes has been already detected in ground water. 24Therefore alternative nematode control methods or less toxic nematicides need to be developed.One way of searching for such nematicidal compounds is to screen naturally occurring compounds in plants.Several such compounds, e.g.alkaloids, phenols, sesquiterpenes, diterpenes, polyacetylenes, and thienyl derivatives have nematicidal activity. 25or example, -terthienyl is a highly effective nematicidal compound. 26Other compounds with nematicidal activity have been isolated from plants, mainly from the family Asteraceae. 25However, compounds of plant origin and their analogs have not been developed into commercial nematicides; hence there is a need to develop commercial synthesis.

Result and Discussion
Diacetone D-glucose (1), prepared from D-(+)-glucose by treating with acetone in the presence of catalytic amount of sulphuric acid according to the literature procedure, 40 reduction of 2 (prepared by Swern oxidation of 1) with NaBH 4 in aq.ethanol at 0 °C for 1 h gave 3 (77%), which on subsequent propargylation in DMF in the presence of NaH for 1 h afforded propargyl ether 4 (80%).Next, the propargyl ether 4 was converted into triazole 5 (82%) by using 1,3-dipolar cycloaddition with p-chlorophenyl azide carried out at ambient temperature in the presence of CuSO 4 and sodium ascorbate in a mixture of 1:1 t-BuOH-H 2 O, as reported by Sharpless.Acid hydrolysis of 5,6-acetonide 5 in 60% AcOH furnished the diol 6 (85%), which on oxidative cleavage with NaIO 4 gave the aldehyde 7. Subsequently, one pot synthesis of triazole linked thiazolidenone glycosides was carried out by the condensation reaction between 7, primary aromatic amine and a thioglycolic acid in the presence of ZnCl 2 under microwave irradiation or conventional heating (Scheme 2).In classical method the reactions were performed in dry toluene at reflux for a long time (2-4 h), often leading to degradation processes and consequent low yields of isolated products, whereas with the application of microwave assisted technology, the reaction was completed in only 5-10 min and the compounds, isolated by conventional work-up, were obtained in satisfactory yields, often hig-her than those achieved by traditional methods (Table 1).The structures of synthesized compounds were confirmed by IR, NMR, MS and elemental analysis.Further the compounds were subject to nematicidal and antibacterial testing.

Antibacterial Activity
Compounds 8a-g and 9a-g were screened for their antibacterial activity using the tube dilution method 41 by measuring the minimum inhibitory concentration (MIC) in μg/mL against four representative organisms, viz.Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Staphylococcus pyogenus.Standard antibacterial agents, such as streptomycin and Neomycin, were also screened under identical conditions for comparison.The minimum inhibitory concentrations are given in Table 2.However, it has been observed that the test compounds exhibited an interesting biological activity, with degree of variation.
Compounds in series 8 and 9, which contain 4-Cl or 3-OH groups, displayed good antibacterial activity against all the organisms.Compounds 8b and 9f were highly active against all the organisms.Compounds 8b and 9f were highly active against B. subtilis, S. aureus and S. pyogenus, compound 9f was highly active against B. subtilis, S. aureus, E. coli, compound 9b was highly active against B. subtilis, E. coli and S. pyogenus and the compound 8c was highly active against E. coli and S. pyogenus.Compounds 9a and 9d did not exhibit any activity against E. coli, even at 100 μg/mL concentration.The alkyl substituted derivatives displayed moderate levels of antibacterial activity (Table 2).

Nematicidal Activity
Compounds 8a-g and 9a-g were also screened for their nematicidal activity against Ditylenchus mycliophagus and Caenorhabditis elegans by aqueous in vitro screening technique 42 at various concentrations.The results have been expressed in terms of LD 50 , i.e. median lethal dose at which 50% of nematodes became immobile.The screened data reveal that compound 8f and 9f are the most effective against D. myceliophagus and C. elegans with LD 50 values of 210 and 240 ppm, respectively.

Conclusions
A series of novel triazole linked thiazolidenone derivatives 8a-g and 9a-g was prepared and evaluated for their antibacterial and nematicidal activity against various bacterias and nematodes.The screened compounds 8b, 9f exhibited potent antibacterial activity compared to standard drugs at the tested concentrations and 8f, 9f exhibited potent nematicidal activity compared to standard drugs at the tested concentrations.