Microwave Assisted Synthesis of Novel 1 , 2 , 3 , 4-Tetrahydrocarbazolyl thiazolidin-4-ones and Azetidin-2-ones and its Biological Behavior

A new family of 1,2,3,4 – tetrahydrocarbazolyl thiazolidin-4-ones (4a-e) and 1,2,3,4–tetrahydrocarbazolyl azetidin-2-ones (5a-e) were individually derived using N-[(α-substituted bezylidenehydrazino) acetyl] -1,2,3,4-tetrahydrocarbazoles 3a-e by cyclization with thioglycolic acid and chloroacetylchloride respectively. The compounds (3a-e) were prepared by condensation of N-(hydrazinoacetyl) 1,2,3,4-tetrahydrocarbazole (2) with a series of aldehydes. The compound 2 was obtained by the hydrazinolysis of N-(chloroacetyl)-1,2,3,4-tetrahydrocarbazole (1). These products were characterized by IR, NMR, MASS spectra and by elemental analysis. All the titled compounds (4a-e) and 5(a-e) were screened for antibacterial and antifungal activities.


Introduction
Carbazole derivatives are important class of heterocyclic compounds possessing variety of biological activity [1][2] .Carbazole skeleton bearing natural products fused with heterocyclic ring have drawn significant attention due to excellent pharmacological activities of their analogues [3][4] .There are numerous evidences illustrating that the fused ring of heterocycles at N th position have gained unique importance on pharmacological studies [5][6] .Azetidinone derivatives have found to possess a wide spectrum of biological activity 7 .Thiazolidinone derivatives are also reported for antibacterial 8 and antiotubercular [9][10] activities.Keeping this in mind, it was worthwhile to develop the synthesis of title compounds i.e. 1,2,3,4-tetrahydrocarbazolyl azetidinones and tetrahydrocarbazolyl thiazolidinones.Moreover, the microwave assisted reactions 11 using dry media 12 have attracted much interest because of the simplicity in operation, greater selectivity and rapid synthesis of a variety of heterocyclic compounds 13 .

Antimicrobial studies
Newly synthesized compounds (4a-e) and (5a-e) were screened for their in vitro antibacterial activity against Bacillus cereus, Bacillus subtilis, Streptococci mutans, and Micrococcus luteus, at concentration of 25 µg using ciprofloxacin as standard and antifungal activity against Aspergillus niger, Candida albicans Altenaria macrospora and Fusarium oxysporum at concentration of 25 µg using ketoconazole as standard.DMF was used as solvent control, nutrient agar was used as culture medium and method employed was cup plate method 16 .The zones of inhibition formed were measured in mm and are shown in Tables 2 & 3 respectively to antibacterial and antifungal activities.

Experimental
All melting points were taken by open capillary method and are uncorrected.TLC analysis were done on glass plates coated with Silicagel-G and spotting was done using iodine.IR (KBr) spectra were recorded on Jasco FT-IR 5300 spectrometer. 1H and 13 C NMR spectra were in CDCl 3 using Jeol GSX 400 (400 MHz) and Jeol ECA500 (500 MHz) NMR spectrometer.Mass spectra were recorded using Joel GC mate and MAL-DI-TOF LD spectrometer.Column chromatography was performed using silica gel (100-200 mesh).

Synthesis of N-(α-substituted bezylidenehydrazino acetyl) -1,2,3,4-tetrahydrocarbazole (3a-e)
Compound (2) (0.01 mole), a pinch of p-toluene sulphonic acid and appropriate aromatic aldehydes (a-e) (0.01 mole) were mixed.Acidic alumina was added to the above mixture at room temperature.The reaction mixture was adsorbed, dried and kept inside the alumina bath and irradiated for 40-80 s.The mixture was cooled and the products was extracted with dry methanol and poured into crushed ice.The solid thus separated was filtered, washed thoroughly with water and recrystallized from ethanol to furnish (3a-e).

Synthesis of 1,2,3,4 -tetrahydrocarbazolyl thiazolidin-4-ones (4a-e)
Schiff bases (3a-g) (0.01 mole) was added to mercaptoacetic acid (1.40 mL, 0.02 mole) anhydrous aluminium chloride (0.05 g).Acidic alumina was added to the above solution at room temperature.The reaction mixture was mixed for 40-80 s.The reaction mixture was then cooled and triturated with an excess of 10% sodium bicarbonate solution.The product obtained was filtered, washed in several times with water and crystallized with isopropanol.

Synthesis of 1,2,3,4 -tetrahydrocarbazolyl azetidin-2-ones(5a-e)
Schiff bases (3a-g) (0.01 mole) was mixed with triethylmaine (2.80 mL, 0.02 mole)and chloroacetyl chloride (1.60 mL, 0.02 mole) was added dropwise over a period of 30 min.Acidic alumina was added to the above solution at room temperature .The reaction mixture was added to the above solution at room temperature.The reaction mixture was adsorbed, dried and kept inside the alumina bath and irradiated for 40-80 s.The mixture was cooled and the product was extracted with absolute ethanol and poured into crushed ice.The solid thus separated was filtered, washed thoroughly with water and recryastallized from aqueous ethanol.Other azetidine 2 -ones (5a-e) were derived by using the similar procedure.
Antibacterial activities of all the newly prepared compounds against four bacteria are presented in Table 2.The antibacterial activity of compounds (4b), (5b), (4e) and (5e) are respectively having hydroxyl and methoxy groups in heterocyclic moieties found to be excellent.The compounds (4d) and (5d) are having methyl group exhibited better activity than compounds (4a) and (5a) and (4c) and (5c) are respectively having unsbstituted phenyl and nitrophenyl groups in heterocyclic moieties.(Table 2).
Antifungal activities of all the newly prepared compounds against fungi are presented in Table 2.The antifungal activity of compounds (4b) and (4e) are excellent activity towards Fusarium oxysporum and Altenaria macrospore among the four organisms.The compounds (4c) and (5c) and (4d) and (5d) are having moderate activity where as (4a) and (5a) are having considerable activities for the tested organisms (Table 3)