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Synthesis of 4-Triazolylamino- and 4-Benzothiazolylamino-3-nitro-2H-[1]-Benzopyran-2-ones and their Antimicrobial Activity.

1. INTRODUCTION

2H[1]-Benzopyran-2-one derivatives are heterocyclic oxygen compounds which find wide usage in pharmacy [1]. Many of them are plant components and play an important role in various processes of life. A significant number of them show different biological activities [2-3] as antimicrobial [4-6], antioxidant [7-9], antifungal [10-11], antimalarial [12-14] and hepatoprotective activities [15-17]. Many of substituted benzopyran-2-one derivates showed anticoagulant, HIV protease [18] inhibition, sedative, analgesic and antitubercular [19] activity. Biological activity of these derivatives is conditioned by their structure. The presence of different substituents on benzopyran ring shows impact on the type and potency of biological activity. Despite efforts to find sufficient connection between the structure and biologic activity of these derivatives, until now there was no such general connection. Extraordinary biological importance of such derivatives has generated a great interest in their synthesis. In support of this, these compounds are the subject of study by many researchers. In continuation of our previous studies and our attempts for synthesis of new derivatives [20-21], in this paper we aimed to synthesize some new derivatives by condensation reaction of 4-hydrazinyl-3-nitrobenzopyran-2-one and aromatic aldehydes, and through other condensation reactions, who could serve as parapharmaceutical products.

2. MATERIAL AND METHODS

All experiments were carried out in acetonitrile as an aprotic solvent, under reflux reaction conditions. The reactions were monitored by TLC using Merck Kieselgel-60 (F-254) on benzene: toluene: glac. acetic acid bath (ratio 85:10:5, by volume, and observed by UV-lamp). Purification of products was done by recrystallization from various solvents. Melting points were measured on a paraffin oil bath in open capillary tubes and they were not corrected. The IR spectra were recorded in KBr discs on a Shimadzu 8400S FTIR Spectrometer with 4 [cm.sup.-1] resolution. [sup.1]H-NMR spectra were obtained in DMSO-[d.sub.6] on UNITY plus 500 "NMR 1" Spectrometer. Chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane as an internal standard ([delta]0.00). Microanalyses were preformed on a Perkin-Elmer 240 B CHN analyzer.

Antibacterial activity of compounds were screened applying the Kirby-Bayers method (discs d = 5.5 mm, max. capacity 10 [micro]g), measuring of inhibition zones around the discs which are marked with DMF, concentration 2 mg/mL, 4 mg/mL and 6 mg/mL solutions) were investigated.

4-Triazolylamino- and 4-benzothiazolylamino-3-nitro-2H[1]-benzopyran-2-ones 4(a-e), (general procedure)

In a typical reaction, 4-chloro-3-nitro-2H-[1]benzopyran-2-one 2, equimolar amounts of 3aminotriazole 3(a-b), respectively 2aminobenzothiazole 3(c-e) and a catalytic amount of triethylamine in acetonitrile were refluxed in a water bath for 1-16 h. The product was filtered off under vacuum and the crude product was purified by recrystallization.

4-(5-Mercapto-1,2,4-triazolyl-3-amino)-3-nitro-2H[1]benzopyran-2-one (4a)

A mixture of 4-chloro-3-nitro-2H-1benzopyran-2-one 2 (0.22 g, 1 mmol) in acetonitrile (5 mL) and 3-amino-5-mercapto-1,2,4-triazole 3a (0.115 g, 1 mmol) in acetonitrile (15 mL), containing triethylamine (two drops) was refluxed in a water bath. A Ca[Cl.sub.2] guard tube was mounted and the reaction mixture was stirred under reflux for 6 h and then cooled at room temperature. The crude product was filtered off under vacuum, then washed with two portions of 0.5 mL acetonitrile, and dried. Finally crude product was crystallized from methanol yielding 0.20 g (68%) of grey crystalline product 4a, mp > 270[degrees]C.

IR (KBr, [cm.sup.-1]): 3345, 3116, 3077, 2913, 2721, 1688, 1672, 1613, 1524, 1420, 1305, 1204, 750, 705. [sup.1]H-NMR (5): 9.80 (s, 1H), 7.65 (d, .j = 8,6 Hz, 1H), 7.40 (dd, .[J.sub.1] = 8,6 Hz, [J.sub.2] = 2 Hz, 1H), 7.25 (d, J = 2 Hz, 1H), 7.10 (dd, [J.sub.1] = 8.5 Hz, [J.sub.2] = 2 Hz 1H), 4.60 (s, 1H), 2.10 (s, 1H). 13C-NMR ([delta]): 164.5, 151.6, 147.2, 145.5, 144.9, 128.1, 125.3, 125.0, 124.9, 119,6, 114,1. Anal: Calculated for [C.sub.11][H.sub.7] [N.sub.5] [O.sub.6] : (C, 43.28%), (H, 2.31%), (N, 22.95%), (O, 20.97%), (S, 10.49%). Found: (C, 43.35%), (H, 2.39%), (N, 22.84%), (S, 10.37%).

4-(5-Carboxy-1,2,4-triazolyl-3-amino) -3-nitro-2H[1]-benzopyran-2-one (4b)

To 3-amino-5-carboxy-1,2,4-triazole hemihydrate 3b (0.62 g, 4.62 mmol) in 40 mL of acetonitrile solution, triethylamine (0.5 mL) and 4chloro-3-nitro-2H-[1]-benzopyran-2-one 2 (1 g, 4.6mmol) was added. The mixture was heated slightly and refluxed for 3 h then cooled on an ice bath. The crude product was filtered off under vacuum, washed with acetonitrile (3 x 0.5 mL) and dried. Recrystallization from methanol gave 0.68 g (47%) of green crystalline product 4b. mp > 270[degrees]C

IR (KBr, [cm.sup.-1]): 3345, 3283, 3160, 2910, 1735, 1611, 1560, 1545, 1499, 1375, 1335, 1238, 1200, 766. [sup.1]H NMR (5): 11.20 (s, 1H), 9.60 (s, 1H), 7.70 (d, 7 = 8.6 Hz, 1H), 7.55 (d, J = 2 Hz, 1H),7.50 (m, 2H), 4.30 (s, 1H). [sup.13]C-NMR ([delta]) 167.6, 157.6, 154.5,153.6,152.4, 150.6, 125.9, 125.6, 125.3, 124.9, 122.9, 104.0. Anal: Calculated for [C.sub.12][H.sub.7][N.sub.5][O.sub.6] : (C, 45.42%), (H, 2.23%), (N, 22.08%), (O, 30.27%). Found: (C, 45.33%), (H, 2.12%), (N, 21.99%).

4-(4-Methoxy-2-benzothiazolyl amino)-3-nitro-2H1-benzopyran-2-one (4c)

A mixture of 4-chloro-3-nitro- 2H- 1 benzopyran-2-one 2 (0.221 g, 1 mmol) and 2-amino 4-methoxy-benzothiazole 3c (0.180 g, 1 mmol), containing triethylamine (three drops) in acetonitrile (5 mL) was refluxed on a water bath. A Ca[C.sub.l2] guard tube was mounted and after 15 min. a yellow crystalline product was formed. The reaction mixture was stirred under reflux for 2 h, then cooled to room temperature and filtered off under vacuum. The residue was washed with 2 x 1 mL portions of acetonitrile. Recrystallization from methanol gave 0.32g (87%) of yellow crystalline product 4c, mp = 219 C.

IR (KBr, [cm.sup.-1]): 3325, 3177, 2940, 1709, 1646, 1596, 1481, 1367, 1281, 1041, 764. [sup.1]H-NMR (5): 7.92 (d, 7 = 6.5 Hz, 1H), 7.84 (d, 7 = 6.8 Hz, 1H), 7.74 (t, 7 = 6.8 Hz, 1H), 7.28 (m, 2H), 7.16 (d, 7 = 8.8 Hz, 1H), 7.03 (d, 7 = 2 Hz, 1H), 4.65 (s, 1H), 3.90 (s, 3H). [sup.13]C-NMR ([delta]): 162.4, 146.5, 134.6, 132.1, 126.6, 125.7, 125.1, 124.5, 124.3, 122.9, 117.2, 116.1, 114.6, 114.5, 109.4, 109.3, 56.2. Anal: Calculated for [C.sub.17][H.sub.11][N.sub.3][O.sub.5]S: (C, 55.27%), (H, 3.00%), (N, 11.37%), (O, 21.67%), (S, 8.67%). Found: (C, 55.47%), (H, 3.02%), (N, 11.26%), (S, 8.72%).

4-(6-Nitro-2-benzothiazolylamino)-3-nitro-2H-[1]benzopyran-2-one (4d)

2-Amino-6-nitrobenzothiazole 3d (0.7 g, 3.55 mmol) was added to a 4-chloro-3-nitro-2H-[1]-benzopyran-2-one (2) (0.8 g, 3.55 mmol) in 12 mL of acetonitrile solution, then three drops of triethylamine was added. The mixture was heated slightly and then refluxed for 16 h. The crude product was filtered off under vacuum and washed with 2 mL of acetonitrile. Recrystalization from ethanol gave 0.78 g (56%) of 4(6-nitro-2-benzothiazolylamino)-3-nitro-2H-[1]benzopyran-2-one 4d as orange crystalline product. mp = 205-207 C.

IR (KBr, [cm.sup.-1]): 3280, 3107, 2740, 1695, 1632, 1580, 1521, 1460, 1355, 1210, 1080, 900, 775. [sup.1]H-NMR (5): 8.69 (s, 1H), 8.30 (d, J = 6.8 Hz 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.44 (m, 2H), 7.19 (d, J = 2 Hz, 1H), 4.97 (s, 1H). [sup.13]C-NMR ([delta]): 171.8, 167.5, 157.6, 156.4, 132.5, 141.1, 132.7, 130.7, 125.6, 123.0, 122.3, 120.6, 118.1, 116.5, 116.1, 115.8.

4-(6-Fluoro-2-benzothiazolamino)-3-nitro-2H-[1]benzopyran-2-one 4e

To a solution of 4-chloro-3-nitro-2H-[1]benzopyran-2-one (2) (0.6 g, 2.66 mmol) in 5 mL acetonitrile, 2-amino-6-fluorobenzothiazole (3e) (0.45 g, 2.66 mmol) in acetonitrile (6 mL) and three drops of triethylamine was added under vigorous stirring. Immediately a yellow crystalline product was formed, then the mixture was stirred for 2 h under reflux. The crude product was filtered off under vacuum and then washed with acetonitrile (2 mL) and ethanol (1 mL). Recrystallization from absolute ethanol gave 0.9 g (95% yield) of orange crystalline product of 4-(6-fluoro-2-benzothiazolamino)-3-nitro-2H-[1]-benzopyran-2-one (4e), mp = 211-213[degrees]C .

IR (KBr, [cm.sup.-1]): 3430, 3270, 3082, 1719, 1625, 1497, 1475, 1360, 1290, 922, 750. [sup.1]H-NMR (5): 8.76 (s, 1H), 7.88 (d, J = 6.6 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.55 (d, J = 6.6 Hz 1H), 7.41 (m, 2H), 7.20 (d, J = 2 Hz, 1H), 4.76 (s, 1H). [sup.13]C-NMR ([delta]): 168.3, 167.6, 159.3, 156.9, 152.5, 140.5, 132.1, 127.8, 125.6, 123.0, 122.2, 120.5, 116.4, 116.1, 114.4, 109.5.

2-Hydroxy-ra-nitroacetophenone (5)

Heteroarylamino-2H-[1]-benzopyran-2-ones 4(a-e) (2 mmol) was dissolved in a 10 mL aqueous 5% sodium hydroxide solution and heated at 95 C for 1 h. The reaction mixture was cooled and acidified with diluted hydrochloric acid and ice to pH = 1. The crude product was filtered off and washed with 3 x 2 mL portions of water. Recrystallization from ethanol gave 0.3 g, (84%) of product 5, mp = 106-107 [degrees]C (lit. mp = 105-106[degrees]C).

IR (KBr, [cm.sup.-1]): 3400, 3085, 2950, 1637, 1613, 1560, 1449, 1369, 754.

3. RESULTS AND DISCUSSION

Our study on physiologically active compounds shows a preparative method for obtaining new substituted benzopyran-2-ones via condensation reactions. We report that 4-chloro-3-nitro-2H-[1]benzopyran-2 one (2) reacts readily with various substituted aminotriazoles and 2-benzothiazoles to form the corresponding 4-triazolylamino-, respectively 4-benzothiazolylamino-3-nitro-2H-[1]benzopyran-2-ones 4(a-e).

4-Chloro-3-nitro-2H-[1]-benzopyran-2 one (2) was obtained in 92% yield by reacting equimolar amounts of 4-hydroxy-3-nitro-2H-[1]-benzopyran-2one (1) with phosphorus oxychloride and N, Ndimethylformamide [24]. Product 2 was subjected to condensation with substituted aminotriazoles 3(a-b) and 2-aminobenzothiazoles 3(c-e) in acetonitrile under reflux to yield the respective 4-triazolylamino 3- nitro-2H-[1]-benzopyran-2-ones 4(a-b) and 4benzothiazolylamino-3-nitro-2H-[1]-benzopyran-2ones 4(c-e).

Condensation of 2 with 3-amino-5-mercapto1, 2, 4-triazole (3a) in acetonitrile solution under reflux yielded 4-(5-mercapto-1, 2, 4-triazolyl-3amino)-3-nitro-2H-[1]-benzopyran-2-one (4a). Similarly, treatment of 2 with 3-amino-5-carboxy-1, 2 4- triazole (3b) gave 4-(5-carboxy-1, 2, 4-triazolyl-3amino)-3-nitro-2H-[1]-benzopyran-2-one (4b). Moreover, compound 2 reacts with 2-amino-4 methoxybenzothiazole (3c), to afford 4-(4methoxybenzothiazolylamino)-3-nitro-2H-[1]benzopyran-2-one (4c). When compound 2 reacts with 2-amino-6-nitrobenzothiazole (3d) gives 4-(6nitro-2-benzothiazolylamino)-3-nitro-2H-[1]benzopyran-2-one (4d) and when it reacts with 2amino-6-fluorobenzothiazole (3e) in the presence of catalytic amount of triethylamine gives 4-(6-fluoro-2benzothiazolylamino)-3 -nitro-2H-[1]-benzopyran-2one (4e). Alkali hydrolysis of the products 4(a-e) affords 2-hydroxy-ra-nitroacetophenone (5).

By tautomerization of precursors of the product 5 an imine intermediate was formed. Then, reaction is followed by imine hydrolysis and decarboxylation respectively (See Scheme 1).

[FORMULA EXPRESSION NOT REPRODUCIBLE IN ASCII]

The structure of the resulting products was analyzed using IR, [sup.1]H-NMR and 13C-NMR spectra, as well as their elemental analysis.

Formation of 4a was confirmed by using [sup.1]HNMR (DMSO-[d.sub.6]) spectrum. A proton singlet at [delta]2.10 ppm corresponds to S-H proton, the proton doublet at [delta]7.65 ppm, corresponds to H-5 and doublet at [delta]7.25 ppm resulted from H-8 of benzene ring. The spectrum also displayed a doublet of doublet at [delta]7.40 ppm resulted from aromatic H-6 and a doublet of doublet at [delta]7.10 ppm, from H-7. Signals at [delta]9.80 and [delta]4.60 ppm assigned for triazole NH and coumarin NH group also are displayed. [sup.13]C-NMR spectrum of 4a showed characteristic absorptions responsible for 11 carbon atoms at [delta]164.5 ppm for C = O, [delta]151.6 and [delta]114,1 ppm for pyrone C, [delta]147.2 ppm and [delta]145.5 ppm for triazole C and 5144.9, [delta]128.1, [delta]125.3, [delta]125.0, [delta]124.9, [delta]119,6 ppm for aromatic C.

IR spectrum of 4a is characterized with an absorption appearing at 3345 [cm.sup.-1] due to typical vNH stretching of secondary amines. IR spectrum of this product also showed the absorption modes at 31163077 and 2721 [cm.sup.-1] corresponding to vCH stretching of aromatic ring and vSH stretching of mercapto group. Typical vCO absorption of unsaturated six-membered lactones is observed at 1722 [cm.sup.-1]. Signals which are responsible for aromatic vC = N and vC = C vibrations appears at 1677 and 1613 [cm.sup.-1], respectively. At 1420 and 1305 [cm.sup.-1] we see the absorptions of the stretching vN[O.sup.2] (as) and vN[O.sup.2] (sym), and at 750 [cm.sup.-1] absorption of the bending [delta]CH out of plane of the aromatic system were also appeared.

In the [sup.1]H-NMR spectrum of compound 4b, appeared a doublet at [delta]7.70 ppm (assigned from H-5), a doublet at [delta]7.55 ppm, from H-8, and a multiplet at [delta]7.50 ppm responsible for H-6 and H-7. Two singlets at [delta]11.20 ppm and [delta]9.60 ppm correspond to OH and triazole NH proton absorptions, whereas a singlet at [delta]4.3 0 ppm resulted from coumarin NH.

In the [sup.13]C-NMR spectrum of 4b, 12 characteristic absorptions are displayed at [delta]167.6 and [delta]157.6 ppm for COOH and C = O, [delta]154.5 and [delta]104.0 ppm for pyrone C, [delta]153.6 and [delta]152.4 ppm for triazole C and [delta]150.6, [delta]125.9, [delta]125.6, [delta]125.3, [delta]124.9, [delta]122.9 ppm for aromatic C.

IR spectrum of 4b showed a broad absorption at 3250-3600 [cm.sup.-1] resulted from decoupled vNH (str) and vCOOH (str) vibrations. Signals at 3160 [cm.sup.-1] and at 2980 [cm.sup.-1] present the stretching of aromatic vCH (as) and vCH (sym) vibrations. A sharp peak at 1735 [cm.sup.-1] and the peaks at 1611 [cm.sup.-1] and 1560 [cm.sup.-1] are responsible for vCO str, vC = N and vC = C (ar), respectively. Two absorptions at 1545 [cm.sup.-1] and 1335 [cm.sup.-1] correspond to vN[O.sub.2] (as) and vN[O.sub.2] (sym), and the [delta]CH bending (ip) and [delta]CH bending (oop) mode at 1200 [cm.sup.-1] and 766 [cm.sup.-1] also were observed. A sharp peak at 1238 [cm.sup.-1] is responsible for [delta]C-O of six-membered lactonic ring.

Formation of 4c is identified from [sup.1]H-NMR (dmso-[d.sub.6]) spectrum where the absorption of a singlet at [delta]3.90 ppm (3H, methoxy protons) appeared. The spectrum also displayed a signal at [delta]4.65 ppm (s, 1H, assigned for NH), and for aromatic protons: [delta]7.92 ppm (d, 1H, H'-5), [delta]7.84 ppm (d, 1H, H'-7), [delta]7.74 ppm (t, 1H, H'-6), [delta]7.28 ppm (m, 2H, H-6 and H-7), [delta]7.16 ppm (d, 1H, H-5) and [delta]7.03 ppm (d, 1H, H-8) (H- benzopyrane-2-one aromatic protons, H' benzothiazole aromatic protons).

[sup.13]C-NMR spectrum of 4c showed quality absorption peaks responsible for 17 carbon atoms at [delta]162.4 ppm for C = O, [delta]146.5, [delta]134.6 ppm for benzopyrone C-N and benzothiazole C-N and [delta]132.1, [delta]126.6, [delta]125.7, [delta]125.1, [delta]124.5, [delta]124.3, [delta]122.9, [delta]117.2, [delta]116.1, [delta]114.6, [delta]114.5, [delta]109.4, [delta]109.3, [delta]56.2 ppm for aromatic benzothiazole and benzopyrone C.

In the IR spectrum for 4c an absorption peak appeared at 3325 [cm.sup.-1] due to typical vNH stretching of secondary amines. Absorption at 1709 [cm.sup.-1] attributed to a typical vCO of unsaturated six-membered lactones was observed. IR spectrum of this product also showed the absorption modes at 30003190 [cm.sup.-1] responsible for vCH stretching absorption of aromatic ring, at 2940 [cm.sup.-1] for vCH stretching of methoxy group and at 1646 [cm.sup.-1] and 1596 [cm.sup.-1] which are responsible for aromatic vC = N and vC = C absorption. At 1481 [cm.sup.-1] and 1367 [cm.sup.-1] for the stretching vN[O.sub.2] (as) and vN[O.sub.2] (sym), and at 764 [cm.sup.-1] for the bending [delta]CH (ar) absorption peaks were also appeared.

The IR spectrum of 4d showed a characteristic mode at 3280 [cm.sup.-1] as a result of vNH stretching absorption. The absorption peaks at 3107 [cm.sup.-1] are responsible for aromatic u CH stretching vibrations. The characteristic band which may have resulted from stretching carbonyl vibration was appeared at 1695 [cm.sup.-1]. Absorptions at 1632 [cm.sup.-1] and at 1580 [cm.sup.-1] are responsible for vC = N and vC = C (ar) vibrations. The absorption modes at 1521 [cm.sup.-1] and 1355 [cm.sup.-1] may be assigned to stretching vN[O.sub.2] (as) and vN[O.sub.2] (sym). Absorption for vC-O-C of lactonic system appears at 1210 [cm.sup.-1]. A sharp peak at 775 [cm.sup.-1] resulted from aromatic [delta]CH absorptions.

In the [sup.1]H-NMR spectrum of compound 4d two singlets at [delta]4.97 ppm (1H, assigned from amine proton absorption) and at [delta]8.69 ppm (1H, responsible for H'-7) were observed. Doublets at [delta]8.30, [delta]7.88, [delta]7.52 ppm, and [delta]7.19 ppm, correspond to aromatic H'-5, H'-4, H-5 and H-8, whereas a triplet signal at [delta]7.44 ppm resulted from H-6 and H-7 protons' absorptions.

IR spectrum of 4e showed the absorption at 3430 [cm.sup.-1] responsible for vNH stretching. The vCH stretching vibrations from aromatic ring appeared at 3082 [cm.sup.-1]. A sharp peak at 1719 [cm.sup.-1] and peaks at 1625 [cm.sup.-1] and 1497 [cm.sup.-1] responsible for vCO str., vC = N and vC = C (ar) were observed. Two absorptions at 1476 [cm.sup.-1] and 1360 [cm.sup.-1] attributable to vN[O.sub.2] (as) and vN[O.sub.2] (sym), and the 5CH (oop) mode at 754 [cm.sup.-1] also were observed. The peak at 1275 [cm.sup.-1] may have resulted from vC-F absorption of aromatic benzothiazole system. The vC-O of lactonic system is assigned at 1350 [cm.sup.-1].

[sup.1]H-NMR spectrum of 4e showed a singlet at 54.76 ppm resulting from NH proton. Doublets at 57.88 and 57.55 ppm are responsible for H'4 and H'-5 absorptions, whereas a singlet peak at [delta]8.76 ppm resulted from H' -7 proton. A multiple peak at [delta]7.41 ppm corresponds to aromatic H-6 and H-7, whereas doublets at [delta]7.63 and [delta]7.20 ppm resulted from H-5 and H-8 absorptions. 13C-NMR spectrum of 4e showed characteristic absorptions at [delta]168.3, [delta]167.6, and [delta]159.3 ppm for C = O, C'-2 and C-4. Characteristic peaks at [delta]156.9, [delta]152.5, [delta]140.5 and, [delta]109.5 ppm results from C'-7, C-O, C-N (benzothiazole) and C-3 whereas signals at [delta]132.1, [delta]127.8, [delta]125.6, [delta]123.0, [delta]122.2, [delta]120.5, [delta]116.4, [delta]116.1, [delta]114.4 are responsible for aromatic carbon atoms.

Hydrolysis of products 4(a-e) in alkaline media resulted in formation of 2-hydroxy-conitroacetophenone (5). This argues that derivatives which contain benzopyran-2-one moiety are very sensitive to basic conditions. The characteristic IR absorptions of product 5 appeared at 3080-3400[cm.sup.-1] (a broad band) and 2950 [cm.sup.-1] which are responsible for vOH stretching, vOH (chelate), aromatic vCH and methylene vCH absorptions. The characteristic peak derived from lactonic carbonyl as a result of intramolecular hydrogen bond appears to have moved down at 1637 [cm.sup.-1]. In the IR spectrum of the hydrolysis product 5 also showed bands at 1560 [cm.sup.-1] for vC = C (ar), 1449 [cm.sup.-1] for vN[O.sub.2] (as), 1369 [cm.sup.-1] for vN[O.sub.2] (sym) and 754 [cm.sup.-1] aromatic 5CH (oop). These values and melting point have been compared to the previous reported analysis [22] and show similar results.

We also have examined the antibacterial activity of the synthetic compounds. Our investigation is directed toward testing their activity against S. aureus, E. coli and Klebsiella. Applying the Kirby-Bayer method [23] we measured diameters of the inhibition zone around discs which are previously marked with DMF solutions of 2 mg/mL, 4 mg/mL and 6 mg/mL.

These derivates have shown moderate to high activity against S aureus, E. coli and Klebsiella. A series of methoxybenzotiazolyl- fluorobenzothiazolyland nitrobenzothiazolyl-derivatives were more active against S. aureus. Emphatic activity against E. coli exhibited triazolylcarboxylic- fluorobenzothiazolyl derivatives, whereas methoxybenzothiazolyl- and nitrobenzothiazolyl-derivatives are more active against Klebsiella. Product 4c was more active against S. aureus relative to compound 2 ([d.sub.4c] /[d.sub.2] = 1.4-1.6), whereas the same product was more active against Klebsiella ([d.sub.4c] /[d.sub.2] = 1.2-1.5). Furthermore, product 4b was more active against E. coli ([d.sub.4b] /[d.sub.2] = 1.5 -1.9). In general, increasing the concentration causes high activity against these microorganisms (figures 1, 2 and 3).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

4. CONCLUSION

By catalytic condensation reaction of 4-chloro-3-nitro-2H-[1]-benzopyran-2-one (2) and substituted aminotriazoles 3(a-b) and 2-aminobenzothiazoles 3(c-e), 4-triazolylamino-3 -nitro-2H-[1]-benzopyran-2-ones 4(a-b) and 4-benzothiazolylamino-3-nitro-2H[1]-benzopyran-2-ones 4(c-e) are synthesized in good yield. We may conclude that these derivates have shown moderate to high activity against S aureus, E. coli and Klebsiella. Compounds 4c, 4e and 4d are more active against S. aureus. Emphatic activity against E. coli exhibited compounds 4b and 4e, whereas 4c and 4d are more active against Klebsiella. In general, products of series 4 are more active against these microorganisms relative to compound 2. Increasing the concentration causes high activity against these microorganisms.

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Ramiz Hoti (a*), Aferdita Nura-Lama (a), Gjyle Mulliqi-Osmani (b), Naser Troni (a), Fatbardh Gashi (a), Hamit Ismaili (a), and Veprim Thaci (a)

(a) Faculty of Nature Sciences - Department of Chemistry, University of Prishtina, "Mother Teresa " street, nn. 10000 Prishtina, Kosovo

(b) Institute of Public Health of Kosovo, "Rrethi i Spitalit" nn. 10000 Prishtina, Kosovo

Corresponding author. E-mail: ramizhoti@yahoo. com.

Article history: Received: 07 February 2014; revised: 13 June 2014; accepted: 23 June 2014. Available online: 01 October 2014.
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Title Annotation:Full Paper
Author:Hoti, Ramiz; Nura-Lama, Aferdita; Mulliqi-Osmani, Gjyle; Troni, Naser; Gashi, Fatbardh; Ismailia, Ha
Publication:Orbital: The Electronic Journal of Chemistry
Article Type:Report
Date:Jul 1, 2014
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