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Synthesis and biological screening of certain new triazole schiff bases and their derivatives bearing substituted benzot

3-Substituted-4-amino-5-mercapto-1, 2, 4-triazole (3) was obtained in an excellent yield in a single step by the<br>condensation of a well known drug norfloxacin having free carboxyl group (1) with thiocarbohydrazide (2). Various<br>3-Substituted-4-amino-5-mercapto-1, 2, 4-triazoloSchiff bases (4a1-a11) have been synthesized by the condensation<br>of the mercapto triazole (3) with different aromatic aldehydes. The triazolo Schiff bases (4a1-a11) on heating with<br>2-Amino-7-chloro-6-fluorobenzothiazole in equimolar proportions yielded the required 3-Substitued-5-(2’-imino-7-<br>chloro-6-fluorobenzothiazolyl) 1, 2, 4-triazolo Schiff bases (5a1-a11). The structures of newly synthesized<br>compounds have been established on the basis of their spectral data and elemental analysis. Some selected<br>compounds were screened for analgesic and anti-inflammatory activity. Some of the compounds

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Synthesis and biological screening of certain new triazole schiff bases and their derivatives bearing substituted benzot

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  1. Available online www.jocpr.com Journal of Chemical and Pharmaceutical Research, 2012, 4(2):1151-1159 ISSN : 0975-7384 CODEN(USA) : JCPRC5 Research Article Synthesis and biological screening of certain new triazole schiff bases and their derivatives bearing substituted benzothiazole moiety Chandramouli1, M. R. Shivanand1, Thakar Bhaumik Nayanbhai2, Bheemachari2 and R. H. Udupi1* 1Dept. of Pharmaceutical Chemistry, N.E.T. Pharmacy College. Raichur (INDIA) 2Dept. of Pharmacology, N.E.T. Pharmacy College. Raichur (INDIA) ______________________________________________________________________________ ABSTRACT 3-Substituted-4-amino-5-mercapto-1, 2, 4-triazole (3) was obtained in an excellent yield in a single step by the condensation of a well known drug norfloxacin having free carboxyl group (1) with thiocarbohydrazide (2). Various 3-Substituted-4-amino-5-mercapto-1, 2, 4-triazoloSchiff bases (4a1-a11) have been synthesized by the condensation of the mercapto triazole (3) with different aromatic aldehydes. The triazolo Schiff bases (4a1-a11) on heating with 2-Amino-7-chloro-6-fluorobenzothiazole in equimolar proportions yielded the required 3-Substitued-5-(2’-imino-7- chloro-6-fluorobenzothiazolyl) 1, 2, 4-triazolo Schiff bases (5a1-a11). The structures of newly synthesized compounds have been established on the basis of their spectral data and elemental analysis. Some selected compounds were screened for analgesic and anti-inflammatory activity. Some of the compounds exhibited encouraging results. Key words: triazolo Schiff bases, 2-Amino-7-chloro-6-fluorobenzothiazole, analgesic and anti-inflammatory activity, norfloxacin, 3, 5-disubstitued triazolo Schiff bases. ______________________________________________________________________________ INTRODUCTION The 1,2,4-Triazoles and their derivatives constitute an important class of organic compounds with diverse agricultural, industrial and biological activities. The synthesis of these heterocycles has received considerable attention in recent years. During the last two decades worldwide attention has been given to the synthesis of fluroquinolines [1-4] such as Norfloxacin, Pefloxacin etc. This is mainly due to the fact that no other class of antibacterials known today offers a great potential for producing the first truly broad spectrum oral antiinfective and useful activity against gram positive, gram negative, anaerobic and mycobacterium [5]. Hence keeping in mind the broad spectrum antibacterial activity of fluroquinolines, it was thought worthwhile to design the synthesis of triazole derivatives incorporating the active norfloxacin moiety [6,7]. Several triazole derivatives were reported for diverse biological activities [8-10]. Recently [11] triazlo quinolines were reported for broad spectrum antibacterial activity. Further due to therapeutic application of Schiff bases and their importance to serve as synthons for many biologically important classes of organic compounds, it was thought worthwhile to synthesise better kinds of drugs by reacting 4-amino group of 3-substitued 4-amino-5-mercapto-1,2,4-triazole with aromatic aldehyde[12]. Triazolo Schiff bases obtained are heated with 2-amino-7-chloro-6-fluorobenzothiazole so as to replace mercapto group at the 5th position of 3-substutued-5-(2-amino-7-chloro-6-fluorobenzothiazolyl)-1, 2, 4-triazolo Schiff bases [13]. Synthesised compounds were characterized by their spectral studies and elemental analysis. Thus in search for new biodynamic potent molecule it was thought to incorporate some additional heterocyclic moieties in triazole nucleus and study their biological and pharmacological activity. In the present work the synthesis and biological evaluation of certain new triazolo Schiff bases and their derivatives bearing benzothiazole moiety is described. 1151

  2. R. H. Udupiet al _____________________________________________________________________________ J. Chem. Pharm. Res., 2012, 4(2):1151-1159 EXPERIMENTAL SECTION Melting points were determined by open tube capillary method and are uncorrected IR spectra (Vmax in cm-1) were recorded on Perkin Emler FTIR spectrophotometer 1H NMR spectra were recorded (in DMSO-d6/CDCl3) on Bruker Avance 300 MHz and 400MHz instrument using TMS as internal standard and chemical shifts are expressed in delta ppm. Purity of the compound checked on TLC plates (silica gel G) using iodine vapour as visualizing agent. Norfloxacin obtained as gift sample from pharmaceutical industry was used for the study. Thiocarbohydrazide was obtained by the method reported in the literature. Synthesis of 3-substitued-4-amino-5-mercapto-1,2,4-triazole (3): The well triturated mixture of carboxylic acid (1) (0.01mol) and thiocarbohydrazide (2) (0.01mol) was fused in a round bottomed flask for 1hr. Then it was cooled to room temperature and washed with sodium bicarbonate (5%) solution to remove unreacted acid and again washed with water. The dried compound was crystallized from DMSO and the purity of the sample was confirmed by obtaining single spot on TLC using silica gel G plates. The solvent system used was DMSO: methanol (1:1 ratio).Yield 85%, MP 2200C. Synthesis of Schiff base of 3-substituted-4-amino-5-mercapto-1,2,4-triazolole (4a1-a11): The mixture of triazole (3, 0.01mol) and aromatic aldehyde (0.01 mole) was heated in presence of anhydrous Zinc chloride till the mixture melts. The heating was continued for another 0.5-1.0 hr. The product was cooled and washed with dilute HCl (10%), saturated solution sodium bisulphite and water respectively. It was crystallized from DMSO. Following the same procedure other derivatives of this series were prepared and their characteristic data is depicted in table no.01. Synthesis of 5-Substituted triazolo Schiff base derivatives (5a1-a11): The triazolo Schiff base (4a1-a11,0.01mol) was fused with 6-Amino-7-chloro-6-fluorobenzothiazole until the evolution of hydrogen sulphide gas ceases. It was cooled, washed with methanol and recrystallized from DMSO. The other compounds of this series were prepared by following the same procedure. The characteristic data of the compounds is given in table number 02. Table No.01: Characterization data of Schiff bases of 3-substituted-4-amino-5-mercapto-1, 2, 4-triazolole (4a1-a11) S.No Sample code Substituent (Z) Molecular Formula 01. 4a1 Phenyl- 02. 4a2 4-Aminophenyl- 03. 4a3 4-Chlorophenyl- 04. 4a4 4-Hydroxyphenyl- 05. 4a5 4-Methoxyphenyl 06. 4a6 2-Nitrophenyl- 07. 4a7 4-Fluorophenyl- 08. 4a8 2,4-Dichlorophenyl- 09. 4a9 3,4-Dimethoxyphenyl- 10. 4a10 6-Chloro-2-fluoro phenyl- 11. 4a11 4-N-Dimethyl-aminophenyl- Table No.02: Characterization data of 5-Substituted triazolo Schiff base derivatives (5a1-a11). S.No Sample code Substituent (Z) Molecular Formula 01. 5a1 Phenyl- 02. 5a2 4-Aminophenyl- 03. 5a3 4-Chlorophenyl- 04. 5a4 4-Hydroxyphenyl- 05. 5a5 4-Methoxyphenyl 06. 5a6 2-Nitrophenyl- 07. 5a7 4-Fluorophenyl- 08. 5a8 2,4-Dichlorophenyl- 09. 5a9 3,4-Dimethoxyphenyl- 10. 5a10 6-Chloro-2-fluoro-phenyl- 11. 5a11 4-N-Dimethyl-aminophenyl- Melting point ( 0C ) 245 190 254 242 210 235 250 274 240 260 215 % Yield 60 70 60 73 65 56 62 62 58 67 65 C24H22ON7SF C24H23ON8SF C24H21ON7SFCl C24H22O2N7SF C25H24O2N7SF C24H21O3N6SF C24H21ON7SF2 C24H20ON7SFCl2 C26H26O3N7SF C24H20ON7SFCl C26H26ON8SF Melting point ( 0C ) 210 230 242 253 224 253 238 260 272 278 232 % Yield 58 62 63 64 55 64 55 66 61 58 68 C31H26ON9SF2Cl C31H27ON10SF2Cl C31H25ON9SF2Cl2 C31H27O2N9SF2Cl C32H28O2N9SF2Cl C31H25O3N10SF2Cl C31H25ON9SF3Cl C31H20ON9SF2Cl2 C33H30O3N9SF2Cl C31H25ON9SF3Cl2 C33H31ON10SF2Cl 1152

  3. R. H. Udupiet al _____________________________________________________________________________ J. Chem. Pharm. Res., 2012, 4(2):1151-1159 SCHEME-I O F COOH S H2N HN C NH NH2 N N HN (2) C2H5 (1) O N N F N SH NH2 N N HN C2H5 (3) CHO R O N N F SH N N N R N C H HN C2H5 (4a1-a11) N NH2 S F Cl O N N N F HN N S F N N Cl N C H HN C2H5 R (5a1-a11) Compound 3: IR (KBr) cm-1:3416(broad band of NH2 and NH), 2852, 2940(Ali. C-H str. of CH2 and CH3 groups), 1692(C=O), 1630(N-H bending of NH2), 1620(C=N), 1579, 1486(C=C ring str.), 1382, 1333(Ali. C-H bending of CH2 and CH3), 1265(C=S), 698(C-S). 1H NMR: δ 15.20(1H,s,H of SH), 9.00(3H,m,3H of heterocyclic ring), 4.60-4.40(3H,s,2H of 1153

  4. R. H. Udupiet al _____________________________________________________________________________ J. Chem. Pharm. Res., 2012, 4(2):1151-1159 NH2 and 1H of NH), 3 and 2.8 (8H,d,4xCH2,8H of piperazine ring CH2 groups ),1.60-1.20(5H,m,2H of CH2 and 3H of CH3). [Found C, 52.02; H, 04.84; N, 24.89%; C17H20ON7SF requires C, 52.44; H, 05.14; N, 25.19%] Compound 4a1: IR (KBr) cm-1:3393(NH), 3068(Ar.C-H str.), 2974, 2849(Ali. C-H str.of CH2 and CH3 groups), 1697(C=O), 1616(C=N), 1558, 1489, 1449(C=C ring str.), 1381, 1310 (C-H bending of CH2 and CH3 groups), 891 750(substituted aromatic rings), 700(c-s).1H NMR: δ 15.3(1H,s, of SH), 8.9 (1H,s, of N=CH), 8.3-6.6 (8H, m, 5H of Ar -H +3H of heterocyclic ring), 6.0(1H,s, of N-H of Piperazine ring), 4.4-3.6 (10H,m, 8H of Piperazine ring + 2H of CH2 of CH2CH3), 2.2-1.1 (3H ,m, 3H of CH3 of CH2CH3).MS (m/z): 478[Found C, 60.14; H, 04.17; N, 20.38; %; C24 H22 O N7 S F requires C, 60.63; H, 04.63; N, 20.63; %] Compound 4a2: IR(KBr)cm-1 :3339, 3200(NH, NH2), 3070(Ar.C-H str.), 2974, 2837,(Ali.C-H str. of CH2 and CH3 groups), 1697(C=O), 1616(C=N), 1616, 1558,1489(C=C ring str.), 1460,1375(Ali.C-H bending),1242(C=S),826(1,4- disubstitued phenyl ring), 702(C=S). 1H NMR : δ 15.30(1H,s, of SH), 8.9(1H,s, of N=CH), 8.30-6.60 (7H,m,4H of Ar-H and 3H of heterocyclic ring),6.0 (2H,s,2H of NH2), 5.80(1H,s,1H of NH),4.82-3.00(10H,m,8H of Piperazine ring and 2H of CH2 of CH2-CH3), 2.20-0.90(3H, m, 3H of CH3 of CH2CH3) MS(m/z):493(M+),494(M+1) and 495(M+2).Other prominent peaks were observed at m/z 457,439,,393,345,323,285,200,174,99,78etc., [Found; C,58.17; H,04.29; N,22.15 %C24H23ON8SF requires C,58.77; H,04.69; N,22.85 %] Compound 4a3: IR (KBr) cm-1:3402(NH), 3072(Ar.C-H str.), 2974, 2837, (Ali. C-H str. Of CH2 and CH3 groups), 1697(C=O), 1616(C=N), 1616, 1558, 1489 (C=C ring str.), 1400, 1295 (Ali.C-H bending),1242(C=S),826(1,4-substitued phenyl ring), 702(C=S),782(C-Cl). 1H NMR : δ 15.3(1H,s, of SH), 8.9(1H,s, of N=CH), 6.60-8.35(7H,m, 4H of Ar-H and 3H of heterocyclic ring),6.0(2H,s, of NH2),5.8(1H,s, of NH),4.82-3.0 (10H,m,8H of Piperazine ring +2H of CH2 of CH2-CH3) 0.9-2.2 (3H,m,3H of CH3 of CH2CH3);MS(m/z):512(M+),[Found C,56.16; H,003.87; N,19.01%; C24H21ON7SFCl requires C,56.47; H,04.11; N,19.21; %] Compound 4a4: IR (KBr)cm-1:3376(a very broad band OH and NH), 3060(Ar C-H str.),2920-2810(Ali C-H str. Of CH2 and CH3 groups), 1695(C=O), 1619(C=N), 1558, 1485 (C=C ring str.), 1485-1375 (C-H bending of and CH2 and CH3 groups), 1247(C=S), 826 (1, 4-disubstituted phenyl rings), 700(C-S).1H NMR:δ 15.3(1H,s,S-H), 11.7(1H,s,N=CH), 10.6(1H,s,O-H), 5.8-9.8(8H,m,3H of hetero cyclic ring + 4H of Ar-H +1H of N-H), 3.1-4.7(10H,m, 4xCH2 group of Piperazine + 2H of N-CH2CH3), 0.9-1.3(3H ,d, 3H of CH3).MS(m/z):494(M+) [Found; C,58.02; H,04.17; N,19.34% ;C24H22O2N7SF requires C,58.22; H,04.45; N,19.83 %]. Compound 4a5: IR (KBr) cm-1:3398(NH), 3078(Ar C-H str.), 2974 and 2858(Ali C-H str. Of CH2 and CH3 groups), 1695(C=O), 1615(C=N),1600, 1562, 1528(C=C ring str.),1440,1358 (C-H bending of CH3 and CH2 groups), 1140(C-O-C), 838 (1,4-disubstituted aromatic ring), 699(C-S).1H NMR: δ 15.30(1H, s, S-H), 8.90(1H,s,1H of N=CH), 8.40-6.60 (7H,m,4H of Ar-H and 3H of heterocyclic ring ), 5.95(1H,s,1H of N-H ),4.60(3H,s,OCH3), 4.45- 3.60(10H,m,8H,m,4xCH2 group of Piperazine ring + 2H of CH2 of CH2CH3),2.20-1.10(3H,m,3H of CH3 of CH2CH3). MS (m/z): 508(M+) other prominent peaks are observed at 485, 464, 403, 330, 312, 280, 167, 134, 97, 77 etc., [Found; C, 59.11; H, 04.23; N, 19.05%; C25H24O2N7SF requires C, 59.40; H, 04.75; N, 19.40 %] Compound 4a6: IR (KBr) cm-1:3392(NH), 3072(Ar C-H str.), 2976 and 2860(Ali C-H str. Of CH2 and CH3 groups), 1690(C=O), 1612(C=N),1602, 1588, 1492(C=C ring str.),1554 and 1360(NO2),1465 and1360 (C-H bending of CH3 and CH2 groups), 728 (1,2-disubstituted aromatic ring), 698(C-S).1H NMR: δ 15.30(1H, s, S-H), 9.10(1H,s,1H of N=CH), 8.60-6.70 (7H,m,4H of Ar-H and 3H of heterocyclic ring ), 6.00(1H,s,1H of N-H ),4.50-3.70(10H,m,8H,m,4xCH2 group of Piperazine ring + 2H of CH2 of CH2CH3), 2.20(3H,s,OCH3). MS (m/z):523(M+) [Found C,57.88; H,03.83; N,16.44 %; C24H21O3N6SF requires C,58.06; H,04.23; N,16.93; %]. Compound 4a7: IR (KBr) cm-1:3381(NH), 3064(Ar C-H str.), 2924, 2810(Ali C-H str. of CH2 and CH3 groups), 1697(C=O), 1616(C=N), 1543, 1489(C=C ring str.), 3384 (C-H bend), 1230(C=S), 893 and 827 (substituted aromatic rings), 700(C-S).1H NMR: δ 13.80(1H, s, S-H), 8.90(1H,s,1H of N=CH), 8.40-6.70(7H ,m,4H of Ar-H and 3H of heterocyclic ring ), 6.20(1H,s,1H of N-H ), 4.80-3.10(10H,m,4xCH2 group of Piperazine ring + 2H of CH2 of CH2CH3), 2.20-1.10(3H, m, 3H of CH3 of CH2CH3). MS (m/z):496(M+),[Found C,58.06; H,03.93; N,19.43 % C24H21ON7SF2 requires C,58.06; H,04.23; N,19.73 %] 1154

  5. R. H. Udupiet al _____________________________________________________________________________ J. Chem. Pharm. Res., 2012, 4(2):1151-1159 Compound 4a8: IR (KBr) cm-1:3400(NH), 3070(Ar C-H str.), 2978 and 2854(Ali C-H str. Of CH2 and CH3 groups), 1696(C=O), 1616(C=N),1605, 1568, 1490, 1454 (C=C ring str.), 1454 and 1362 (C-H bending of CH3 and CH2 groups), 870(substituted aromatic ring), 699(C-S).1H NMR: δ 15.20(1H, s, S-H), 9.10(1H,s,1H of N=CH), 8.70-6.60 (7H,m,4H of Ar-H and 3H of heterocyclic ring ), 5.90(1H,s,1H of N-H ), 4.50-3.60 (10H,m,8H,m,4xCH2 group of Piperazine ring + 2H of CH2 of CH2CH3), 2.20 (3H,s,OCH3). MS (m/z):546(M+) [Found C, 52.26; H, 03.17; N, 17.38 % C24H20ON7SFCl2 requires C, 52.84; H, 03.66; N, 17.98 %]. Compound 4a9: IR (KBr) cm-1:3405(NH), 3081(Ar C-H str.), 2978 and 2860(Ali C-H str. Of CH2 and CH3 groups), 1698(C=O), 1620(C=N),1602, 1546, 1490, (C=C ring str.), 1462 and 1366 (C-H bending of CH3 and CH2 groups),1164(C-O-C), 876(substituted aromatic ring), 701(C-S).1H NMR: δ 15.30(1H, s, S-H), 9.00(1H,s,1H of N=CH), 8.40-6.70 (7H,m,4H of Ar-H and 3H of heterocyclic ring ), 5.90(1H,s,1H of N-H ),4.60(6H,s,2xCH3 of OCH3 groups)4.50- 3.60(10H,m,8H,m,4xCH2 group of Piperazine ring + 2H of CH2 of CH2CH3), 2.20(3H,m,CH3). MS(m/z):[Found C,58.04; H,04.12; N,17.97 % C26H26O3N7SF requires C,58.31; H,04.85; N,18.31 %]. Compound 4a10: IR (KBr) cm-1:3388(NH), 3080(Ar C-H str.), 2948 and 2854(Ali C-H str. Of CH2 and CH3 groups), 1698(C=O), 1616(C=N),1600, 1556, 1482, (C=C ring str.), 1456 and 1356 (C-H bending of CH3 and CH2 groups),1026(C-F), 870(substituted aromatic ring), 701(C-S).1H NMR: δ 15.20(1H, s, S-H), 9.20(1H,s,1H of N=CH), 8.80-6.80 (6H,m,3H of Ar-H and 3H of heterocyclic ring ), 5.95(1H,s,1H of N-H ), 4.50-3.60(10H,m,8H,m,4xCH2 group of Piperazine ring + 2H of CH2 of CH2CH3), 2.20(3H,m,CH3). MS(m/z):Found C,54.14; H,03.34; N,18.14 % C24H20ON7SFCl requires C,54.54; H,03.78; N,18.56 %]. Compound 4a11: IR (KBr) cm-1:3386(NH), 3068(Ar C-H str.), 2938 and 2826(Ali C-H str. of CH2 and CH3 groups), 1696(C=O), 1618(C=N),1604, 1588,1546, (C=C ring str.), 1468 and 1372 (C-H bending of CH3 and CH2 groups),1247(C=S), 1028(C-F), 829(disubstituted aromatic ring), 700(C-S).1H NMR: δ 15.20(1H, s, S-H), 9.40(1H,s,1H of N=CH), 8.50-6.70 (7H,m,4H of Ar-H and 3H of heterocyclic ring ), 5.80(1H,s,1H of N-H ), 4.88-3.20(10H,m,8H,m,4xCH2 group of Piperazine ring + 2H of CH2 of CH2CH3), 2045(6H,s,2xCH3 of N(CH3)2, 2.20-0.90(3H,m,3H of CH3). MS(m/z):[Found C,58.15;H,04.01; N,19.55 % C24H21ON7SF2 requires C,58.65;H,04.27; N,19.95 %]. Compound 5a1: IR (KBr) cm-1:3335(NH), 3060(Ar C-H str.), 2936 and 2854(Ali C-H str. Of CH2 and CH3 groups), 1695(C=O), 1616(C=N),1590,1546,1465 (C=C ring str.), 1479 and 1358 (C-H bending of CH3 and CH2 groups),1247(C=S), 1040(C-F), 885(disubstituted aromatic ring), 778(C-Cl).1H NMR: δ 8.50-6.60(11H,m,10H of aryl and heterocyclic 1H of N=CH), 6.00(2H, s, 2H of 2 NH groups),4.40-3.10(8H,m,8H of piperazine),2.30(2H,s,CH2 of C2H5),1.30(3H,s,CH3 of C2H5) MS(m/z): 647. [Found C,57.28; H,03.84; N,19.15 %;C31H26ON9SF2Cl requires C,57.58; H,04.02; N,19.50 %]. Compound5a2: IR(KBr)cm-1: 3335,3200(NH & NH2),3065(Ar C-H str.),2924,2851(Ali C-H str. Of CH2 and CH3 groups),1694(C=O),1612(C=N),1541,1489,1449(C=C ring str.),1379,1308 (C-H bending of CH2 and CH3 groups), 1021(C-F),821,885(substituted phenyl rings).1H NMR: δ8.5-6.6(10H,m,9H of Ar-H + 1H of N=CH). 6.0(2H,s,2H of 2xNH), 5.8(2H,s, 2H of NH2), 3.1-4.4(8H,m,8H of CH2 of piperazine ring), 2.3(2H,s,CH2 of NC2H5), 1.3( 3H,s,CH3 of NC2H5).MS(m/z):662(M+),664(M+2,ratio of peak heights 3:1 indicating the presence of Cl),Other prominent peaks are observed at m/z 606,550,474,239,121,107,96,82,55 etc., [Found C,56.07; H,03.88; N,21.00 %;C31H27ON10SF2Cl requires C,56.27; H,04.08; N,21.18 %]. Compound 5a3: IR(KBr)cm-1: 3385,(NH),3073(Ar C-H str.),2920 and 2810(Ali C-H str. of CH2 and CH3 groups), 1690(C=O), 1609(C=N), 1606,1541,1490,(C=C ring str.),1448 and1352 (C-H bending of CH2 and CH3 groups), 1385(C-N), 1026(C-F),887,827(substituted phenyl rings),765(C-Cl); 1H NMR: δ8.60-6.55(10H,m,9H of Ar-H + 1H of N=CH). 6.10(2H,s,2H of 2xNH), 4.50-3.20 (8H,m,8H of CH2 of piperazine ring), 2.30 (2H,s,CH2 of NC2H5), 1.30( 3H,s,CH3 of NC2H5).MS (m/z): 681(M+), [Found C,57.17; H,03.12; N,19.21 % C31H25ON9SF2Cl2 requires C,57.67; H,03.87; N,19.53 %]. Compound 5a4: IR(KBr)cm-1: 3380(broad peak of OH and NH), 3080(Ar C-H str.), 2938 and 2861(Ali C-H str. of CH2 and CH3 groups), 1694(C=O), 1610(C=N), 1601, 1589, 1538 (C=C ring str.), 1466 and1352 (C-H bending of and CH2 and 1155

  6. R. H. Udupiet al _____________________________________________________________________________ J. Chem. Pharm. Res., 2012, 4(2):1151-1159 CH3 groups),1395(C-N),1290(O-H bending) , 1030,(C-F),874 and 829 (1,4-disubstituted phenyl rings),778(C-Cl).1H NMR: δ 10.20(1H,s,O-H), 8.68-6.62(10H,m,9H of aryl and heterocyclic rings and 1H of N=CH), 4.70-3.10(8H,m, 4xCH2 group of Piperazine), 2.30(2H,s,2H CH2 of N-C2H5), 1.30(3H,s,CH3 of C2H5).MS (m/z):663(M+),Other prominent peaks observed at 647, 607, 530, 420, 240,122,108,96,82etc., [Found C,55.64; H,03.83; N,19.00 %;C31H27O2N9SF2Clrequires C,56.10; H,04.07; N,19.00 %]. Compound 5a5: IR(KBr)cm-1:3372(NH), 3085(aromatic C-H str.), 2939 and 2822(C-H str. of CH3 and CH2 groups), 1694(C=O), 1612(C=N), 1602,1588,1526,1498(ring str.),1459 and 1347(C-H bending),1388(C-N),1176(C-O-C),1038(C-F),874 and 836(substituted phenyl rings),781(C-Cl), 1H NMR: δ 8.55-6.61(10H,m,9H of aryl and heterocyclic rings and 1H of N=CH), 6.00(2H,s,2H of 2 NH groups), 4.62(3H,s,OCH3), 4.46-3.18(8H,m, 4xCH2 group of Piperazine), 2.30(2H,s,2H CH2 of N-C2H5), 1.30(3H,s,CH3 of C2H5).MS(m/z):677(M+),679(M+2)(peak height 3:1 indicating the presence of Cl), [Found C,56.20; H,03.74; N,18.03% ;C32H28O2N9SF2Clrequires C,56.80; H,04.14; N,18.63%]. Compound 5a6: IR(KBr)cm-1:3376(NH), 3072(aromatic C-H str.), 2942 and 2858(C-H str. of CH3 and CH2 groups), 1696(C=O), 1612(C=N), 1604,1576,1512,(C=C ring str.),1552 and 1354(NO2), 1461 and 1354(C-H bending of CH3 and CH2 groups),1390(C-N),1032(C-F), 878 and 735(substituted phenyl rings), 778(C-Cl), 1H NMR: δ 8.58-6.66(10H,m,9H of aryl and heterocyclic rings and 1H of N=CH), 6.00(2H,s,2H of 2 NH groups), 4.48(3H,s,OCH3), 4.48-3.18(8H,m, 4xCH2 group of Piperazine), 2.28(2H,s,2H CH2 of N-C2H5), 1.26(3H,s,CH3 of C2H5).MS(m/z):691(M+), 693(M+1)(peak height 3:1 indicating the presence of Cl), [Found C,53.34; H,03.14; N,20.01%; C31H25O3N10SF2Cl requires C,53.83; H,03.61; N,20.26%]. Compound 5a7: IR(KBr)cm-1:3381(NH), 3070(aromatic C-H str.), 2920 and 2810(C-H str. of CH3 and CH2 groups), 1690(C=O), 1609(C=N),1606,1541,1490,(C=C ring str.),1552 and 1354(NO2), 1448 and 1352(C-H bending of CH3 and CH2 groups),1390(C-N),1035(C-F), 887 and 821(substituted phenyl rings), 780(C-Cl), 1H NMR: δ 8.54-6.62(10H,m,9H of aryl and heterocyclic rings and 1H of N=CH), 6.10(2H,s,2H of 2 NH groups), 4.48-3.20(8H,m, 4xCH2 group of Piperazine), 2.28(2H,s,2H CH2 of N-C2H5), 1.28(3H,s,CH3 of C2H5).MS(m/z):663(M+), 665(M+2)(peak height 3:1 indicating the presence of Cl), [Found C,55.62; H,03.14; N,18.45 % C31H25ON9SF3Clrequires C,56.02; H,03.76; N,18.97 %]. Compound 5a8: IR(KBr)cm-1:3388(NH), 3078(aromatic C-H str.), 2932 and 2828(C-H str. of CH3 and CH2 groups), 1692(C=O), 1616(C=N),1608,1564,1514 and 1492(C=C ring str.),1450 and 1358(C-H bending of CH3 and CH2 groups),1384(C- N),1028(C-F), 877 and 786(substituted phenyl rings), 769(C-Cl), 1H NMR: δ 8.68-6.53(10H,m,9H of aryl and heterocyclic rings and 1H of N=CH), 6.18(2H,s,2H of 2 NH groups), 4.44-3.16(8H,m, 4xCH2 group of Piperazine), 2.34(2H,s,2H CH2 of N-C2H5), 1.26(3H,s,CH3 of C2H5).[Found C, 5.72; H, 02.62; N, 19.14 %; C31H20ON9SF2Cl2 requires C,58.12; H,03.12; N,19.68 %]. Compound 5a9: IR(KBr)cm-1:3380(NH), 3080(aromatic C-H str.), 2950 and 2826(C-H str. of CH3 and CH2 groups), 1696(C=O), 1609(C=N),1606,1590,1536 (C=C ring str.),1465 and 1358(C-H bending of CH3 and CH2 groups),1382(C- N),1180(C-O-C),1040(C-F),880 and 838(substituted phenyl rings), 779(C-Cl), 1H NMR: δ 8.50-6.58(9H,m,8H of aryl and heterocyclic rings and 1H of N=CH), 6.20(2H,s,2H of 2 NH groups), 4.60(6H,s,2xOCH3 groups),4.42- 3.18(8H,m, 4xCH2 group of Piperazine), 2.35(2H,s,2H CH2 of N-C2H5), 1.30(3H,s,CH3 of C2H5).[Found C, 55.80; H, 04.04; N, 17.22%; C33H30O3N9SFCl2 requires C, 56.09; H, 04.24; N, 17.84%]. Compound 5a10: IR(KBr)cm-1:3382(NH), 3076(aromatic C-H str.), 2952 and 2846(C-H str. of CH3 and CH2 groups), 1695(C=O),1620(C=N),1603,1568,1518 and 1484(C=C ring str.),1460 and 1355(C-H bending of CH3 and CH2 groups),1036(C-F), 880 and 788(substituted phenyl rings), 760(C-Cl), 1H NMR: δ 8.60-6.50(10H,m,9H of aryl and heterocyclic rings and 1H of N=CH), 6.00(2H,s,2H of 2 NH groups), 4.40-3.20(8H,m, 4xCH2 group of Piperazine), 2.30(2H,s,2H CH2 of N-C2H5), 1.30(3H,s,CH3 of C2H5).MS(m/z):697(M+), 699(M+2)(peak height 3:1 indicating the presence of Cl), [Found C,52.74; H,03.32; N,17.63%; C31H25ON9SF3Cl2 requires C,53.14; H,03.57; N,18.00%]. Compound 5a11: IR(KBr)cm-1:3389(NH), 3080(aromatic C-H str.), 2946 and 2835(C-H str. of CH3 and CH2 groups), 1698(C=O), 1620(C=N),1610,1599,1538 (C=C ring str.),1468 and 1354(C-H bending of CH3 and CH2 groups),1392(C- N),1033(C-F), 838 (1,4-disubstituted phenyl rings), 762(C-Cl), 1H NMR: δ 8.60-6.60(10H,m,9H of aryl and 1156

  7. R. H. Udupiet al _____________________________________________________________________________ J. Chem. Pharm. Res., 2012, 4(2):1151-1159 heterocyclic rings and 1H of N=CH), 6.10(2H,s,2H of 2 NH groups), 4.38-3.20(8H,m, 4xCH2 group of Piperazine), 2.30(2H,s,2H CH2 of N-C2H5), 1.30(3H,s,CH3 of C2H5).MS(m/z):690(M+), [Found C,57.12; H,07.34; N,09.94%; C33H31ON10SF2Clrequires C,57.47; H,07.96; N,20.31%]. BIOLOGICAL ACTIVITY Antibacterial Activity: All the synthesized triazolo Schiff bases and their benzothiazole substituted derivatives were screened for their antibacterial activity following agar diffusion assay procedure [14]. Antibacterial screening was tested on nutrient medium against following microorganisms, which are representative type of gram +ve and gram –ve organisms respectively. 1. Staphylococcus aureus (ATCC 25923, MRO 00001 (ORSA)) 2.Staphylococcus epidermidis (MRO 02046 (OSSE), MRO 02002 (ORSE)I 3.Enterococcus faecalis ( MRO 04050 (VSE), MRO 04205 (VRE)) 4.K. pneumoniae ATCC 700603 5.P. aeruginosa ATCC 27853 6.Escherichia coli ATCC 25922 Antifungal activity: Thirteen of the total nineteen compounds synthesized were screened for antifungal activities by agar diffusion method [14] against five yeasts (fungi).The following fungi were used for the study. 1C. parapsilosis ATCC 22019 ` 2 C. krusci ATCC 6258 3 C. albicans MRO 20001 4 C. albicans MRO 20009 5 C. tropicalis MRO 20011 Antiinflammatory activity: Determination of acute toxicity (LD50): The oral acute toxicity of synthesized compounds was determined by using albino mice of either sex (20-30gms) maintained under standard husbandry conditions. The animals were fasted overnight prior to the experiment and fixed dose (OECD guidelines No. 420) method of CPCSEA was adopted for toxicity studies. 1/5th of the lethal dose was taken as effective dose ED50(Therapeutic dose). PROCEDURE: CARRAGEENAN INDUCED RAT PAW OEDEMA MODEL [15]: Albino rats of either sex weighing 150 – 200 g were selected. They were maintained on standard pellet diet and free access to water. The animals were divided into different groups each having six animals. The normal control, Ibuprofen and test compounds were administered to the rats 30 minutes before the injection of 0.1ml of 1% carrageenan suspension in normal saline. The carrageenan suspension was injected into the sub-planar region of the left hind paw of the test animal, and the right hind paw served as reference. Immediately thereafter the oedema volume of the injected paws was measured by plethysmograph mercury displacement method. Table No.03: Anti inflammatory activity of triazolo Schiff bases (4a1-a11) Dose mg/kg Mean±SEM % redn Mean±SEM Toxicant (Carrageenan) Ibuprofen 54 0.82±0.02 34.14 0.90±0.03 4a1 150 0.95±0.02 15.78 0.91±0.04 4a2 150 0.92±0.02 19.28 1.11±0.04 4a3 150 0.98±0.03 12.24 1.18±0.02 4a6 150 0.94±0.03 17.02 1.16±0.01 4a7 150 0.96±0.02 14.58 0.89±0.04 4a9 150 0.94±0.02 17.02 0.90±0.02 4a11 150 0.99±0.02 11.11 1.29±0.02 For comparison purpose, the volume of oedema at various prefixed time intervals was measured. The difference between paw volumes of the treated animals was measured and the mean oedema volume was calculated. Percentage reduction in oedema volume was calculated by using the formula, Paw oedema volume in ml and % of reduction 2 hr % redn 1 hr 4 hr 8 hr Compound Mean±SEM % redn Mean±SEM % redn 1.57±0.06 1.32±0.05 1.08±0.04 __ 1.10±0.02 __ __ __ __ 0.85±0.03 0.89±0.03 1.22±0.04 1.21±0.02 1.08±0.03 0.89±0.04 0.92±0.03 1.13±0.02 0.81±0.03 0.85±0.02 0.96±0.02 0.95±0.03 0.88±0.04 0.87±0.04 0.94±0.02 0.98±0.02 74.5 72.5 41.44 33.05 35.34 76.40 74.44 21.70 55.29 48.31 08.19 14.04 22.22 48.31 43.47 16.81 33.33 27.05 12.50 6.86 22.72 24.13 14.89 10.20 1157

  8. R. H. Udupiet al _____________________________________________________________________________ J. Chem. Pharm. Res., 2012, 4(2):1151-1159 Percentage Reduction = Vo-Vt x 100 Vo where Vo = Volume of the paw of control at time‘t’. Vt = Volume of the paw of drug treated at t e ‘t’ Table No. 04: Antiinflammatory activity of triazolo benzothiazolyl Schiff base derivatives (5a1-a11) Paw oedema volume in ml and % of reduction 2 hr Mean±SEM % redn Dose mg/kg Compound 1 hr 4 hr 8 hr Mean±SEM % redn Mean±SEM % redn Mean±SEM % redn Toxicant (Carrageenan) Ibuprofen 5a1 5a2 5a3 5a4 5a7 5a9 5a10 5a11 1.33±0.06 1.23±0.05 1.04±0.04 __ 1.17±0.02 __ __ __ __ 0.94±0.02 1.02±0.02 0.98±0.02 1.08±0.03 0.98±0.03 1.02±0.02 1.10±0.02 1.03±0.02 1.06±0.02 0.90±0.03 1.14±0.04 0.98±0.04 1.12±0.02 0.96±0.01 0.99±0.04 1.05±0.02 1.13±0.02 1.11±0.02 0.86±0.03 0.98±0.03 0.92±0.04 0.96±0.02 0.95±0.03 0.98±0.04 0.99±0.03 1.11±0.02 1.04±0.02 0.76±0.03 0.88±0.02 0.89±0.02 0.92±0.03 0.86±0.04 0.93±0.04 0.89±0.02 0.98±0.02 0.95±0.02 54 150 150 150 150 150 150 150 150 24.46 14.70 19.38 08.33 19.38 14.70 06.36 13.59 10.37 47.77 16.66 35.71 18.75 38.54 34.34 26.66 15.03 19.81 43.02 25.51 33.69 28.12 29.47 25.51 24.24 10.81 18.26 36.84 18.18 16.85 13.04 20.93 11.82 16.85 06.12 09.47 RESULTS AND DISCUSSION Triazolo Schiff bases (4a1-a11) and their derivatives bearing substituted benzothiazole moiety (5a1-a11) were prepared from the reaction of 3-substitued 4-amino-5-mercapto-1, 2, 4-triazole with different aromatic aldehydes followed by further reaction with 2-amino-7-choloro-6-fluorobenzothiazole (Scheme-I). The IR, 1H NMR and mass spectra of above synthesized compounds are in agreement with proposed structure. The compounds screened for antibacterial activity against the organism Staphylococcus aureus (ATCC 25923), Staphylococcus epidermidis (MRO 02046), Enterococcus faecalis (MRO 04050), K. pneumoniae (ATCC 700603) and P. aeruginosa (ATCC 27853) exhibited weak activity at concentration level 50µg/well. However the compounds containing the substituents like 4- Chlorophenyl (4a3/ 5a3), 2,4-Dichlorophenyl (4a8/5a8) and 4-Fluorophenyl (4a7/5a7) showed moderate activity against E.coli. Among the synthesized compounds screened for antifungal activity against C. parapsilosis (ATCC 22019), C. krusci (ATCC 6258), C. albicans (MRO 20009), C. tropicalis (MRO 20011) the derivatives having substituted groups like 2-nitrophenyl (4a6/5a6), 6-Chloro-2-fluorophenyl (4a10/5a10), 4-Chlorophenyl (4a3/5a3) and 4-Fluorophenyl (4a7/5a7) exhibitedmoderate activity only against C.krusci and the compounds were proved to be inactive against all other fungi. However the comparative study of antibacterial and antifungal activity of triazolo schiffs bases and their benzothiazole derivatives indicated that both antibacterial and antifungal activity are higher in the of benzothiazole derivatives. Thus the modification of the moiety has resulted enhancement in the said activities. The triazolo Schiff bases (4a1-a11) and their derivatives (5a1-a11) obtained by replacing mercapto group with substituted benzothiazole moiety were screened for their anti-inflammatory activity using rat hind paw method. The study revealed that the triazoloschiff bases exhibited weak to moderate anti-inflammatory activity. How ever their derivatives bearing substituted benzothiazole moiety showed much improved activity. The compounds 5a1, 5a3, 5a4, and 5a9 showed significant activity. The result indicates that the substituents like 3,4-dimethoxy phenyl, 4- hydroxy phenyl, 4-Cholorophenyl present may contribute to enhance the anti-inflammatory activity of triazolo derivatives in presence of substituted benzothiazole moiety at 5th position. Perhaps these compounds exhibit activity through inhibition of cyclooxygenase I and II enzymes depending on the position and type of the substituent group present at the 1,2,4-triazole system. In conclusion it can be said that few compounds have exhibited moderate antifungal and anti-inflammatory activity. However further work such a synthesis and activity of some more compounds before one could conclude any thing definite about the therapeutic potential of these compounds .However proper molecular modification and detailed toxicity studies may help to get better therapeutic agents. Acknowledgements The authors thankful to Sri S.R.Reddy, Chairman Navodaya Education trust and H. Doddayya, principal NET Pharmacy College, Raichur, Karnataka, India for their help and support to carry out this research. The authors are also thankful to Sri Sriramgopal, vice-president, Orchid Chemicals, Chenni, India for providing facility for anti- microbial activity. 1158

  9. R. H. Udupiet al _____________________________________________________________________________ J. Chem. Pharm. Res., 2012, 4(2):1151-1159 REFERENCES [1]S Chorbdzhiev. Synth Commun , 1990, 20,22. [2]SF Camohell; JD Hardstone and MJ Pahmer. Tetrhedron Lett., 1984, 48B, 28. [3]RC Tripathi; M Saxena; S Chandra and AK Saxena. Indian J.Chem., 1995, 34B, 164. [4]H Koga; A Itosh; S Murayama; S Suzue; T Irikura. J. Med. Chem ,1980, 231-235 [5]MA Cohen; TJ Griffin; PA Bien; CL Heifetz and JM Domagala. Antimicrobial agents Chemothe., 1985, 28, 766. [6]RH Udupi; S Ramachandra Setty; N Srinivasulu; TY Pasha; A Nandakishore; GV Suresh. Indian J. Heterocyclic Chem.,2002, 12, 33-36. [7]Pramodh kumar; RH Udupi and PK Dubey. Int. J. Pharm. Tech., 2009, 4, 1654-1662. [8]A Padmaja; C Rajasekhar; A Muralikrishna and V Padmavathi. J Chem Pharm Res, 2012,4(1):294-302. [9]Neha Singhal; PK Sharma; Rupesh Dudhe and Nitin Kumar. J. Chem. Pharm. Res.,2011, 3(2):126-133. [10]DK Swamy; SV Kuberkar and MV Deshmukh. J. Chem. Pharm. Res.,2010, 2(3):411-416. [11]MK Shivananda and M Shet Prakash. J. Chem. Pharm. Res.,2011, 3(5):61-66. [12]Chandramouli; RH Udupiand Hima Bindu. Oriental journal of chemistry, 2007,23(3): 1077-1080. [13]RH Udupi; Bheemachari;N Srinivaslu; Rajesh Vernekar; Purushottamachar puranik. Bull. Korean. Soc.,2007, 28, 12. [14]JP Cruickshank; BP Duguid; Marimon and RHA Swain. Medical microbiology-2, Churchil Livingstone, Edinburg, 1975, 190. 1159

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