Synthesis, Nematicidal and Antifungal Properties of Hybrid Heterocyclics

A new series of 5-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)-2,6-diphenyl-3,3a,5,6-tetrahydro-2H-pyrazolo[3,4-d]thiazoles 10a–r was synthesized by the reaction of chalcone derivatives of 2-((3aR,5S,6S,6aR)-6-((1-(4-chlorophenyl)-1H-1,2,3-triazol4-yl)methoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-3-phenylthiazolidin-4-one 9 with aryl/alkyl hydrazines. The chemical structures of newly synthesized compounds were elucidated by IR, NMR, MS and elemental analysis. The compounds 10a–r were evaluated for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans by aqueous in vitro screening technique. Among them, compounds containing N-benzylpyrazole moiety (10d, 10j, 10p), and Nmethylpyrazole moiety (10f, 10i, 10r) showed significant nematicidal activity against both tested nematodes with LD50 160–210 ppm, almost equal to oxamyl standard. Further, these compounds 10a–r were screened for their antifungal (MZI, MIC, and MFC) activity against four fungal organisms viz, Candida albicans (ATCC 102331), Aspergillus fumigates (HIC 6094), Trichophyton rubrum (IFO 9185) and Trichophyton mentagrophytes (IFO 40996). Most of the new compounds showed appreciable activity against the tested fungi, and emerged as potential molecules for further development.


Introduction
1,2,3-Triazoles are one of the most important classes of heterocyclic organic compounds, which are reported to be present in a plethora of biological activities in 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 heterocycles rank as the most potent glycosidase inhibitors. 2 Further, this nucleus in combination (or linked) with various other classes of compounds, such as amino acids, steroids, aromatic compounds, carbohydrates etc., became prominent in having various pharmacological properties. 3 1,2,3-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 pronounced class of non-nat-ural sugars. The chemistry and biology of triazole modified sugars is dominated by triazole glycosides. 5 Therefore, the synthesis and investigation of biological activity of 1,2,3-triazole glycosides is an important objective, which also received a considerable attention by the medicinal chemists.
Thiazoles are familiar group of heterocyclic compounds possessing a wide variety of biological activities and their utility as medicine is very much estabilished. 6 Thiazole nucleus is also an integral part of all the available pencillins which have revolutionized the therapy of bacterial diseases. 7 Furthurmore, there has been considerable interest in the chemistry of thiazolidine-4-one ring system which is the core structure in various synthetic pharmaceuticals displaying a broad spectrum of biological activities. [8][9][10] The thiazolidine-4-one ring also occurs in nature; thus actithiazic acid isolated from Streptomycis strains exhibits highly specific in vitro activity against mycobacteri-um Tuberculosis. 11 Thiazolidine-4-ones are known to exhibit diverse bioactivities, such as antiplatelet activating factor, 12 antihistaminic, 13 COX inhibitory, 14 Ca +2 channel blocking, 15 PAF antagonist, 16 cardioprotective, 17 anti-ischemic 18 and nematicidal activities. 19 Moreover, pyrazoles and their derivatives could be considered as possible antimicrobial agents. 20 The other derivatives display antidepressant, 21 antiarthritic 22 and cerebroprotecting 23 properties. Some aryl pyrazoles were reported to be non-nucleoside human immunodeficiency virus (HIV-1) reverse transcriptase inhibitor, 24 COX-2 inhibitor, [25][26][27] activator of the nitric oxide receptor and to have soluble guanylate cyclase activity. 28 Nematodes 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. 29 Plants attacked by nematodes show retarded growth and development, as well as loss in the quality and quantity of the harvest. The namaticides currently still in use are slated for reduction due to the 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.
The use of nonfumigant nematicides, based on organophosphates and carbamates, is expected to increase concomitantly with 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 detected in ground water. 30 Therefore, alternative nematode control methods or less toxic nematicides need to be developed. 31 One way of searching for such nematicidal compounds is to screen naturally occurring compounds in plants. Several such compounds, e.g. alkaloids, sesquiterpenes, diterpenes, polyacetylenes have nematicidal activity. [32][33] For example, a-terthienyl is a highly effective nematicidal compound. Other compounds with nematicidal activity have been isolated from plants, mainly from the family Asteraceae. [32][33] However, compounds of plant origin and their analogs have not been developed into commercial nematicides yet; hence there is a need to develop commercial syntheses.
Following the successful introduction of antimicrobial and nematicidal agents, inspired by the biological profile of triazoles, thiazolidinones, pyrazoles and their increasing importance in pharmaceutical and biological fields and in continuation of our work on biologically active molecules [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] and in order to enhance the biological activity of triazoles, thiazolidinones and pyrazole moieties, it was thought to be of interest to accomodate triazole, thiazolidinones and pyrazole moieties in single molecular framework. In this article we report the synthesis of a new class of hybrid heterocycles 10a-g in good yields and their evaluation for in vitro antifungal and nematicidal activity.

Results and Discussion
The key intermediate 8 required for the synthesis of title compound was prepared according to the procedure outlined in the Scheme 1. Diacetone D-glucose (1) prepared from D-(+)-glucose by treating with acetone in the presence of a catalytic amount of sulphuric acid according to the literature procedure, 49 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%). Now the propargyl ether converted into triazole 5 (82%) by using 1,3-dipolar cycloaddition with p-chlorophenyl azide was 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 to 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/conventional heating (Scheme 2). In the 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 the application of microwave assisted technology, the reaction is completed in only 5-10 minutes and the compounds, isolated by conventional work-up, are obtained in satisfactory yields, often higher

Nematicidal Activity
The compounds synthesized 10a-g in this study were also screened for their nematicidal activity against Dietylenchus myceliophagus and Caenorhabditis elegans by aqueous in vitro screening technique 52 at various concentrations. The nematicidal activity of each tested compound was compared with the standard drug Levamisole. The results have been expressed in terms of LD 50 i.e. median le-thal dose at which 50% of nematodes became immobile (dead). The screened data reveal that compounds 10e and 10f are the most effective against Dietylenchus myceliophagus and Caenorhabditis elegans with LD 50 190 and 220 × 10 -6 respectively, whereas the other tested compounds showed moderate activity. The LD 50 values of the compounds screened are presented in Table 2.

Experimental
Commercial grade reagents were used as supplied. Solvents except analytical reagent grade were dried and purified according to literature when necessary. Reaction progress and purity of the compounds were checked by

Conclusion
In conclusion, a series of a new class of hybrid heterocycles 10a-r have been synthesized and evaluated for their nematicidal activity, most of the compounds showed appreciable nematicidal activity. The antifungal activities of these compounds were evaluated against various fungi. Many of the synthesized compounds showed good activity against the tested fungi and therefore have emerged as potential molecules for further development.