Note. Synthesis and evaluation of some novel 2,4- thiazolidinedione derivatives for antibacterial, antitubercular and antidiabetic activities

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1 Indian Journal of hemistry Vol. 51B, eptember 2012, pp ote ynthesis and evaluation of some novel 2,4- thiazolidinedione derivatives for antibacterial, antitubercular and antidiabetic activities hashikant Pattan* a, Manisha Kedar a, Jayashri Pattan b, antosh Dengale a, Manjusha anap a, Utkarsha Gharate a, Punam hinde a & ushma Kadam c a Department of Pharmaceutical hemistry, Pravara ural ollege of Pharmacy, Pravaranagar , India b Department of Biotechnology, PVP s Art, cience and ommerce ollege, Loni , India c Department of hemisty, Loknete hri Balasaheb Jadhav Art, cience and ommerce ollege Ale, Pune , India shashipattan@yahoo.com eceived 31 August 2010; accepted (revised) 15 May 2012 A series of 2,4-thiazolidinedione have been synthesized and evaluated for antibacterial, antitubercular and antidiabetic activities. The newly synthesized compounds have been characterized by I, 1 H M and elemental analysis. All compounds have shown promising antibacterial, antitubercular and antidiabetic activities when compared with standard drug orfloxacin, treptomycin, and Glibenclamide respectively. ompounds 1a, 2a have shown promising antibacterial activity while compounds 1b, 2b have shown promising antitubercular activity and compounds 1a, 2a and 2c have shown promising antidiabetic activity. Keywords: 2,4-Thiazolidinedione, antibacterial, antidiabetic, antitubercular Diabetes mellitus is heterogeneous group of diseases, characterized by a state of chronic hyperglycemia, resulting from diversity of etiologies, environmental and genetic, acting jointly. The underlining causes of disease are the effective production or action of insulin, a hormone that controls carbohydrate, fat and protein metabolism. haracteristically, diabetes is a long term disease with variable clinical manifestation and progression. hronic hyperglycemia, from whatever cause, leads to number of complications including cardiovascular such as anxiety, stress, ocular and other such inter-connected infections. The treatment includes change in diet, oral medication and, in some cases, daily injection of insulin. A large number of 2,4-thiazolidinediones have been reported to be anti-inflamatory 1 and neuroprotective agents 2. 2,4-Thiazolidinedione is also reported for anti-hyperglycemic activity 3 and antifungal activity 4. This observation promoted the synthesis of a little compound with the presumption that incorporation of aromatic amines and thiazolidinediones nuclei would produce new compounds with significant antidiabetic properties. Thiazolidinediones and their derivatives exhibit a wide variety of biological activities like antidiabetic 5 antimicrobial activity 6, etc. The synthesized compounds (Table I) were evaluated for various biological activities like antibacterial, antitubercular and antidiabetic activity. esults and Discussion ompounds 1a, 2a have shown promising antibacterial activity. The compounds 1b, 2b have shown promising antitubercular activity concentration at 50 µg/ml and 100 µg/ml. ompounds 1c, 2c have shown moderate antitubercular activity at 100 µg/ml concentration. ompounds 1a, 2a and 2c have shown promising antidiabetic activity. The compounds were incorporated with 2 2 in 1a and 2a. Hence they show promising antibacterial activity. The compounds were incorporated with isoniazid and pyrazinamide, hence enhanced antitubercular activity was observed for compounds 1b, 2b, 1c and 2c. ompounds 1a and 2a have resemblance with rosiglitazone having antidiabetic activity. With still further molecular modification and manipulation these compounds are expected to be promising therapeutic agents in the future. Antibacterial activity 7,8 Antibacterial activity study was carried out by cup plate agar diffusion method using nutrient agar. The compounds were tested in vitro for their antibacterial activity against two microorganisms, viz. Escherichia coli (T 10418) AD taphylococcus aureus (T 5671) which are pathogenic to human beings. tandard drug orfloxacin was used (Table II). Antitubercular activity 9 The antitubercular activity was carried out by Middlebrook 7H9 agar medium against H 37 v train. Middlebrook 7H9 contains different derivatives, standard drug as well as control. Middlebrook 7H9 agar medium was incubated with mycobacterium

2 1422 IDIA J. HEM., E B, EPTEMBE 2012 Table I Physical and analytical characterization data of synthesized compounds ompd Mol. formula Mol. Wt. Yield (%) m.p. f value 1a 19 H ( b 19 H ( c 18 H ( a 18 H ( b 18 H ( c 17 H (55.17 alcd %(Found) H ) ) ) ) ) ) The combustion analysis compounds synthesized is within the limits permissible errors (±0.4). tuberculosis H37v strain. The incubated bottles were incubated at 37 for 4 weeks they were checked for growth. tandard drug, streptomycin was used (Table III). Antidiabetic activity 10,11 The compounds were subjected to antidiabetic activity study using Wistar albino rats by alloxan induced tail tipping method. The animals were maintained under standard laboratory conditions like temperature and relative humidity of 60-70%. The mean +/-.E. of the blood glucose level was calculated for each group and the results were analyzed by AVA and Dunnet t test which were compared with the results obtained for standard drug Glibenclamide (Table IV). Experimental ection The melting points were determined by open capillary method, and are uncorrected. Homogeneity of compounds was checked on silica gel TL plates. I spectra were reported on Thermo icolet I 200 spectrophotometer using KBr disc method. 1 H M spectra were recorded on Bruker AMX-400 with Dl 3 as solvent and TM as internal standard. ombustion analyses were found to be within the limit of permissible error. Mass spectra were recorded on Jeol X 102/DA 6000 mass spectrometer using Argon/ Xenon (6 kv, 10 ma) as FAB gas. Accelerator voltage was 10 kv. Table II Anti-bacterial activity of synthesized compounds ompd Zone of inhibition at 100 µg/ml (in mm) 1a E. coli. aureus 1b c a b c orfloxacin Table III Anti-tubercular activity of synthesized compounds r.no. ompd 25 µg/ml 50 µg/ml 100 µg/ml 1 1a 2 1b 3 1c 4 2a 5 2b 6 2c td. treptomycin esistant; ensitive. \ynthesis of 2,4-thiazolidinedione 12, 1 In a 250 ml three necked flask was placed a solution containing 56.4 g (0.6 mol) of chloroacetic acid in 60 ml of water and 45.6 g (0.6 mol) of thiourea dissolved in 60 ml of water. The mixture was stirred for 15 min to form a white precipitate,

3 TE 1423 Drug Table IV Antidiabetic activity of synthesized compounds Blood glucose level mg/dl 0 hr 1 hr 3 hr 6 hr ontrol 123.1± ± ± ±8.78 Glibenclamide 382.4± ± ± ± a 305.6±21.56* 242.6±20.87** 185.3±19.58** 145.3±17.85* 1b 295.2± ± ± ± c 314.2± ± ± ± a 310.4±15.64* 268.3±14.85** 182.6±13.84** 135.2±12.87* 2b 298.5± ± ± ± c 325.6±24.57* 258.7± ±22.94* 123.8±14.38* *p<0.01, **p<0.001, tatistical one way AVA followed by Dunnet s t test accompanied by considerable cooling. To the contents of the flask, was then added slowly 60 ml of concentrated Hl from a dropping funnel. The flask was then connected with a reflux condenser and gentle heat applied to effect complete solution. Thereafter, the reaction mixture was stirred and refluxed for 8-10 hr at The mixture was cooled and product was filtered and washed with water to remove traces of hydrochloric acid. The product was purified by recrystallization from ethyl alcohol. The yield was 85%, m.p ynthesis of 4'-chloroacetyl-benzylidene 2,4-thiazolidinedione 13, 2 5-(p-Methoxybenzylidine)-2,4-thiazolidinedione (8 g, mol) was placed in a 100 ml roundbottomed flask equipped with a condenser and a dropping-funnel. hloroacetyl chloride (18.08 g, mol) was added at T using the dropping funnel. The reaction was found to be exothermic. After addition of chloroacetyl chloride was over, the reaction mass was refluxed for 1 hr on a water bath. The reaction was cooled and poured in a thin stream with stirring into crushed ice contained in a 1 litre beaker. The product was filtered and dried. The product was purified by recrystallization from ethanol. Yield 68%, m.p ynthesis of 4'-chloroacetyl-benzylidene 2,4- thiazolidinedione 14, 1a-c odium bicarbonate (35 g), 35 ml of water and 124 g (1.33 mol) of amine were placed in the flask and 42 g (0.33mol) of compound 1 was added. The flask with the contents was heated to for 3 hr. After cooling, the product was filtered, and purified by recrystallization from light petroleum. The solution was cooled in a freezing mixture to induce crystallization. The crystals were filtered at the pump (cheme I). ynthesis of 5-(p-methoxy benzylidine)-2,4-thiazolidinedione 14, 2a-c A mixture of compound 2 (0.01 mol), 2 ml of methanol, formaldehyde (0.02 mol), aromatic amine (0.02 mol) and 1-2 drops of Hl were refluxed for 2-4 hr. The solvent was distilled off and the residue poured into crushed ice. The resulting solids were filtered off, dried and purified by recrystallization from alcohol (cheme I). pectral data 1a: I (KBr): (Ar-H str), (H=H str), (H 2 str), (= str), (-- str), (== str), (---str), (-str), cm -1 (-str); 1 H M: δ 2.0 (s 2H 2 ), (m 8H Ar- H), 4.0 (t 1H ), 4.22 (d 2H H 2 ), 5.1 (s 2H H), 7.57 (s 1H H), 10 (s 1H ); M: m/z (%) (100). 1b: I (KBr): (Ar-H str), (H 2 str), (= str), (-- str), (=-str), (---str), (-str), cm -1 (--str); M: m/z (%) (100). 1c: I (KBr): (Ar-H str), (H 2 str), (= str), (-- str), (=-str), (---str), (-str), cm -1 (--str); M: m/z (%) (100). 2a: I (KBr): (Ar-H str), (H 2 str), (= str), (-- str), (== str), (---str), (-str), cm -1 (--str); M: m/z (%) (100). 2b: I (KBr): (Ar-H str), (H 2 str), (= str), (-- str),

4 1424 IDIA J. HEM., E B, EPTEMBE 2012 l H + H 2 2.Hl, WATE (1) Piperidine, Toluene H 3 H H 3 (2) lh 2 l 2, HH l H 2 H 2 H 3 H 2 2 H 2 H 2 1a-1c ompound 1a, 2a H 2 2 H 1b, 2b 1c, 2c cheme I

5 TE 1425 (=-str), (---str), (-str), cm -1 (--str); 1 H M: δ (m 8H Ar-H), 8.0 (d 1H ); 2.0 (q 1H ), 4.84 (d 2H H 2 ), 7.57 (s 1H H), 3.73 (s 3H H 3 ); M: m/z (%) (100). 2c: I (KBr): (Ar-H str), (H 2 str), (= str), (-- str), (=-str), (---str), (-str), cm -1 (--str); M: m/z (%) (100). Acknowledgement The authors wish to express their sincere thanks to Honorable hri. adhakrishna Vikhe Patil, Minister for Agricultural and Marketing, Govt. of Maharashtra and hri Adv. ajendra Vikhe Patil, Director, Pravara ural Education ociety, Loni, for their constant encouragement and support. eferences 1 Pattan, eddy V V K, Pawar P D, Khade A B, Desai, Bhat A & Taranalli A D, Indian Drugs, 44, 2007, Youssef A M, White M, Villanueva E B, El-Ashmawy I M & Klegeris A, Bioorg Med hem, 18, 2010, havan A A & Pai, Indian J Heterocycl hem, 17, 2007, Maccari, Paoli P, ttana, Jacomelli M, iurleo & Manao G, Bioorg Med hem, 15, 2007, Pattan, Khade A B, Bukitagaar A A, asal V P & Kakadia K, Indian J Heterocycl hem, 17, 2008, Bilek M T & Altanlar, Il Farmaco, 54, 1999, Indian Pharmacopoeia, Vol. 2A (Govt. of India, ew Delhi), 1996, pp Barry A L, The Antimicrobial usceptibility Test, Principle and Practices (Leu and Febiger, Philadelphia, Pa, UA), p180; Biol Abstr, 64, 1976, Koneman E W, Allen D, Janda M W & Washington W, Text Book of Diagnostic Microbiology, 5 th Edn, (J B Lippincott ompany Pvt. Ltd, Philadelphia), 1997, pp Kulkarni K, Mehta A K & Kunchandy J, Arch Int Pharmacodyn Therap, 279, 1986, Vogel H G, Drug Discovery and Evaluation, Pharmacological Assays, 2 nd Edn, pp Pattan, eddy V V K, Pawar P D, Khade A B, Desai, Bhat A & Taranalli A D, Indian Drugs, 44, 2007, havan A M & Pai, Indian J Heterocycl hem, 17, 2007, Vogel s Text Book of Practical rganic hemistry, 5th Edn, revised by Furniss B, Hannaford A J & mith P W J (ELB Publication), pp.902.