Synthesis, spectral characterization and antimicrobial activity of thiourea/urea derivatives of amlodipine

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1 Available online at Scholars Research Library Der Pharmacia Lettre, 20, 5 (1):1-204 ( ISS USA CDE: DPLEB4 Synthesis, spectral characterization and antimicrobial activity of thiourea/urea derivatives of amlodipine P. Vedavathi a, K. Chandra Sekhar a and C. aga Raju a, * Department of Chemistry, Sri Venkateswara University, Tirupati, A.P., India ABSTRACT Amlodipine is one of the calcium channel blockers havingdihydropyridine group, used as an antihypertensive drug.a series of novel ureaandthioureaderivativesofamlodipine(1) were prepared by reacting (1) with various substituted isocyanates/isothiocyanates in the presence of triethylamine in TF at 50 C. Their structures were established by IR, 1, CMR, Mass spectral data and C,, elemental analysis. Their antimicrobial activity was evaluated and the title compounds exhibited moderate antimicrobial activity. Key words: Amlodipine, Urea and thiourea derivatives, Antimicrobial activity. ITRDUCTI Amlodipine (3-ethyl-5-methyl(±) 2-((2-aminoethoxy) methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine- 3,5-dicarboxylate), commercially available as orvasc is a long acting calcium channel blocker used as an antihypertensive drug 1 and the mechanism involved in it is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle [2]. The contractile process of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ion into these cells through specific ion channels [3]. It inhibits calcium ion influx across cell membrane selectively, with a greater effect on vascular smooth muscle than on cardiac muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure [4]. Urea and thiourea derivatives possess potent anticancer properties [5-]. Thiourea derivatives display a wide range of biological activity including antibacterial, anti-fungal, antitubercular, antihelmintic, rodenticidal, insecticidal, herbicidal and plant growth regulatory properties [-]. The importance of such work lies in the possibility of the thiourea derivatives might be more efficacious as antimicrobial and anticancer agents. owever, a thorough investigation relating tothe structure and the activity of the thiourea derivatives as well as their stability under biological conditions is required. These detailed investigations could be helpful in designing more potent antimicrobial agents for the therapeutic use. Since varying substituent on abasic structural frame work is a common method for drug design in medicinal chemistry and a useful medical value of substituted thiourea derivatives. Based on the importance of amlodipine, it is designed and synthesized a series of novel urea and thiourea derivatives of amlodipine in high yield. 1

2 C. aga Raju et al Der Pharmacia Lettre, 20, 5 (1):1-204 Me Et 3 TF, 50 C 2hr Me Et 3. PhS 3 (1) 2 (2) PhS 3 2 Me (2) R CX TF, Et ο C 2 3(a-d), X= 3(e-k), X=S Me 4(a-d), X= 4(e-k), X=S C X R C C C C 2 C C C 2 CS C 4a 4b 4c F 4d 4e CS C CS CS CS f 4g 4h 4i 4j CS 4k MATERIALS AD METDS Chemistry: All the chemicals were purchased from Sigma-Aldrich and used without further purification. TLC was performed on pre-coated plates with silica gel 60F254 (Merck). Column chromatography was performed on silica gel ( mm, Macherey, agel). Melting points were recorded on Buchi R-535 (Flawil, Switzerland) apparatus and are uncorrected. IR Spectra were recorded on JASC Japan FT/IR , and C MR spectra were recorded on Bruker A VIII 500 Mz MR spectrometer operating at 500 Mz for 1 and 5 Mz for C.MR data were recorded in DMS-d 6 and were referenced to TMS ( 1 and C). Mass spectra were recorded on 200

3 C. aga Raju et al Der Pharmacia Lettre, 20, 5 (1):1-204 LC-MS 20A Shimadzu(Japan), spectrometer at University of yderabad, yderabad. Elementary analyses were performed using EA Thermo Finnigan(France), instrument at University of yderabad, yderabad, India. SYTESIS: General synthetic procedure of synthesis of 4a-k. A solution of Amlodipine benzene sulfonic acid (1.5 g, mole) in 20 ml of dry TF was treated with triethyl amine (0. ml, mole) in 25 ml of TF at o C. After stirring for 2h at 50 o C, formation of 2(free base) was ascertained by TLC analysis run in a 3: mixture of ethylacetate and hexane and the average R f value observed was 0.5. Et 3.PhS 3 was removed by filtration. The filtrate containing 2was used for the next reaction step without further purification. To a stirred solution of Amlodipine (2) in 20 ml dry TF, a solution of 4-chlorophenylisocyanate (3a) (0.001mole) in ml of dry TF was added dropwise at room temperature in the presence of triethylamine (0.001 mole). After the completion of the addition, the temperature of the reaction was raised to o C and the reaction mixture was stirred for 3 h. After the completion of the reaction, as indicated by TLC conducted in 3: mixture of ethyl acetate and hexane, an average R f value of 0.60 was observed. It was purified by column chromatography on silica gel (0-200 mesh) eluting with ethyl acetate: hexane, 1:) to afford the pure compound4a. ther urea derivatives 4 (b-d)and thiourea derivatives 4 (e-k)were synthesized by adopting the above synthetic procedure.the compounds thus obtained were characterized by elemental analysis, 1, C MR, mass spectra and elemental analysis. 3-Ethyl-5-methyl-4-(2-chlorophenyl)-2-((2-(3-(4-chlorophenyl)ureido)ethoxy)methyl)-6-methyl-1,4-dihydro pyridine-3,5-dicarboxylate (4a): Yield0%; mp 1- o C;IR (KBr) (v max cm -1 ):162 (C=), 115 (C=),336 (); 1 -MR (DMS- d 6 ) δ ppm: 1. (t, 3, C 3, -), 2. (s, 3, C 3, -15), 3.1 (dd, 2, C 2, -), 3.30 (s, 3, C 3, -), 3.60 (t, 2, C 2, -), 4.0 (s, 2, C 2, -),4.23 (m, 2, C 2, -),4.40 (s, 1, C, -4), 5.0 (t, 1,, -),.-.0 (m,, Ar-),.20 (s, 1,, -1),.21 (s, 1, -24); C-MR (DMS-d 6 )δ(ppm): 15.2 (C-), 1. (C- 15), 3.2 (C-4), 3.0 (C-), 54.0 (C-), 60.2 (C-), 6. (C-), 6.0 (C-), 3.1 (C-5), 3. (C-3),1.3 (C-2 &C- 6 ), 6.1 (C-21), 6. (C-20),.4 (C-1),.0 (C-1), 0.4 (C-3 &C-5 ), 1.0 (C-1), 3. (C-4 ), 6.5 (C- 1 ) 2. (C-6), 4.3 (C-2), 4.6 (C-16), 15.1 (C-23), (C-), 166.5(C-); LCMSmass m/z (%)562.3 (0%)[M+] +., (65%), 40.5 (60%).Anal.cald.forC :C 5.66; 5.20;.4;FoundC 5.60; 5.16;.41; 3-Ethyl-5-methyl-4-(2-chlorophenyl)-2-((2-(3-(3,4-dichlorophenyl)ureido)ethoxy)methyl)- 6-methyl-1,4- dihydropyridine-3,5-dicarboxylate (4b) Yield 4%; mp o C;IR (KBr) (v max cm -1 ):16 (C=), 11 (C=),336 (); 1 -MR (DMS- d 6 ) δ ppm: 1.2 (t, 3, C 3, -), 2.15 (s, 3, C 3, -15), 3.23 (dd, 2, C 2, -), 3.35 (s, 3, C 3, -), 3.65 (t, 2, C 2, -), 4. (s, 2, C 2, -),4.2 (m, 2, C 2, -),4.45 (s, 1, C, -4), 5.5 (t, 1,, -),.2-.5 (m,, Ar-),.25 (s, 1,, -1),.26 (s, 1, -24); C-MR (DMS-d 6 )δ(ppm): (C-), 1.5 (C-15), 3.25 (C-4), 3.05 (C-), (C-), (C-), 6.5 (C-), 6.05 (C-), 3.15 (C-5), 3.5 (C- 3),2.4 (C-5 ), 5.2 (C-6 ), 6.15 (C-21), 6.5 (C-20),.45 (C-1),.05 (C-1), 0. (C-3 ), 1.3 (C-2 ), 1.1 (C-1),. (C-4 ), 5. (C-1 ),2. (C-6), 4.4 (C-2), 4.65 (C-16), 15. (C-23), (C-), (C-); LCMSmass m/z (%)56.4 (0%)[M+] +., 5.3 (66%), 40.2 (52%).Anal.cald.forC :C 54.33; 4.3;.04;FoundC 54.2; 4.0;.02; 3-Ethyl-5-methyl-4-(2-chlorophenyl)-2-[(2-[(4-isocyanatoanilino)carbonyl]aminoethoxy)methyl]-6-methyl-1,4- dihydro-3,5-pyridinedicarboxylate(4c) Yield 3%; mp5- o C;IR (KBr) (v max cm -1 ):162 (C=), 4 (C=),335 (); 1 -MR (DMS- d 6 ) δ ppm: 1.26 (t, 3, C 3, -), 2. (s, 3, C 3, -15), 3. (dd, 2, C 2, -), 3.34 (s, 3, C 3, -), 3.64 (t, 2, C 2, -), 4. (s, 2, C 2, -),4.2 (m, 2, C 2, -),4.44 (s, 1, C, -4), 5.4 (t, 1,, -), (m,, Ar-),.24 (s, 1,, -1),.15 (s, 1, -24); C-MR (DMS-d 6 )δ(ppm): (C-), 1.4 (C-15), 3.24 (C-4), 3.04 (C-), (C-), (C-), 6.4 (C-), 6.4 (C-), 3. (C-5), 3.4 (C- 3),0.2 (C-2 &C-6 ),6. (C-21), 6.4 (C-20),.44 (C-1),.04 (C-1),.2 (C- ), 6.2 (C-3 &C-5 ),.5 (C-4 ), 1.04 (C-1), 6.1 (C-1 ), 2.4 (C-6), 4.34 (C-2), 4.64 (C-16), 15.2 (C-23), (C-), (C-); LCMSmass m/z (%)56.6 (0%)[M+] +., 51.5 (64%), 40.4 (2%).Anal.cald.forC :C 5.; 5.;.5;FoundC 5.05; 5.0;.0; 201

4 C. aga Raju et al Der Pharmacia Lettre, 20, 5 (1): Ethyl-5-methyl-2-((2-(3-(3-chloro-4-fluorophenyl)ureido)ethoxy)methyl)-4-(2-chlorophenyl)- 6-methyl-1,4- dihydropyridine-3,5-dicarboxylate (4d) Yield %; mp 15-1 o C;IR (KBr) (v max cm -1 ):165 (C=), 1 (C=),336 (); 1 -MR (DMS- d 6 ) δ ppm: 1.25 (t, 3, C 3, -), 2. (s, 3, C 3, -15), 3.21 (dd, 2, C 2, -), 3.33 (s, 3, C 3, -), 3.63 (t, 2, C 2, -), 4. (s, 2, C 2, -),4.26 (m, 2, C 2, -),4.43 (s, 1, C, -4), 5.3 (t, 1,, -), (m,, Ar-),.23 (s, 1,, -1),.24 (s, 1, -24); LCMSmass m/z (%)50.2 (0%)[M+] +., 52.5 (65%), 40.5 (6%).Anal.cald.forC F 3 6 :C 55.; 4.6;.24;FoundC 55.1; 4.;.15; 3-Ethyl-5-methyl-2-((2-(3-allylthioureido)ethoxy)methyl)-4-(2-chlorophenyl)- 6-methyl-1,4-dihydropyridine- 3,5-dicarboxylate (4e) Yield 5%; mp20-20 o C;IR (KBr) (v max cm -1 ): 63 (C=S), 163 (C=), 3321 (); 1 -MR (DMS- d 6 ) δ ppm: 1.24 (t, 3, C 3, -), 2. (s, 3, C 3, -15), 3.20 (dd, 2, C 2, -), 3.32 (s, 3, C 3, -), 3.62 (t, 2, C 2, -), 4.0 (s, 2, C 2, -), 4.25 (m, 2, C 2, -),4.42 (s, 1, C, -4), (m, 5, -C 2 - C=C 2 ), 5.2 (t, 1,, -), (m, 4, Ar-),. (s, 1,, -1),.23 (s, 1, -24); C-MR (DMS-d 6 )δ(ppm): 15. (C-), 1.2 (C-15), 3. (C-4), 3.02 (C-), 40.4 (C-1 ), (C-), 60. (C-), 6.2 (C-), 6.02 (C-), 3. (C-5), 3.2 (C-3),.6 (C-3 ), 6. (C-21), 6.2 (C-20),.42 (C- 1),.02 (C-1), 1.02 (C-1), 4. (C-2 ), 2.2 (C-6), 4.32 (C-2), 4.62 (C-16), (C-), (C- ), 15. (C-23); LCMSmass m/z (%)50.3 (0%)[M+] +., 5.5 (65%), 40.5 (5%). Anal.cald. forc S: C56.4; 5.5;.2;FoundC 56.6; 5.0;.21; 3-Ethyl-5-methyl-4-(2-chlorophenyl)-2-((2-(3-phenylthioureido)ethoxy)methyl)-6-methyl-1,4-dihydropyridine -3,5-dicarboxylate (4f) : Yield 3%; mp 1-11 o C;IR (KBr) (v max cm -1 ):55 (C=S), 166 (C=), 326 (); 1 -MR (DMS- d 6 ) δ ppm: 1.23 (t, 3, C 3, -), 2. (s, 3, C 3, -15), 3.1 (dd, 2, C 2, -), 3.31 (s, 3, C 3, -), 3.61 (t, 2, C 2, -), 4.0 (s, 2, C 2, -),4.24 (m, 2, C 2, -),4.41 (s, 1, C, -4), 5.1 (t, 1,, -), (m,, Ar-),.21 (s, 1,, -1),. (s, 1, -24); C-MR (DMS-d 6 )δ(ppm): 15.2 (C-), 1. (C- 15), 3.2 (C-4), 3.1 (C-), 54.1 (C-), 60.2 (C-), 6. (C-), 6.1 (C-), 3.1 (C-5), 3. (C-3),6.2 (C-2 &C- 6 ),6.1 (C-21), 6. (C-20),.4 (C-1),.6 (C-4 ),.01 (C-1),.2 (C-3 &C-5 ), 1.01 (C-1),.3 (C-1 ), 2.1 (C-6), 4.31 (C-2), 4.61 (C-16), (C-), 166.5(C-),.2 (C-23); LCMSmass m/z (%)544.2 (0%)[M+] +., (33%), 40.2 (66%).Anal.cald.forC S:C 5.61; 5.56;.2;FoundC 5.54; 5.51;.65; 3-Ethyl 5-methyl 4-(2-chlorophenyl)-2-((2-(3-(4-chlorophenyl)thioureido)ethoxy)methyl)- 6-methyl-1,4- dihydro pyridine-3,5-dicarboxylate (4g) Yield 0%; mp o C;IR (KBr) (v max cm -1 ): 4 (C=S), 166 (C=), 324 (); 1 -MR (DMS- d 6 ) δ ppm: 1.1 (t, 3, C 3, -), 2.05 (s, 3, C 3, -15), 3. (dd, 2, C 2, -), 3.25 (s, 3, C 3, -), 3.55 (t, 2, C 2, -), 4.02 (s, 2, C 2, -),4.1 (m, 2, C 2, -),4.35 (s, 1, C, -4), 5.5 (t, 1,, -), (m,, Ar-),.15 (s, 1,, -1),.16 (s, 1, -24); C-MR (DMS-d 6 )δ(ppm): (C-), 1.65 (C-15), 3.15 (C-4), 3.5 (C-), 53.5 (C-), (C-), 6.5 (C-), 6.5 (C-), 3.05 (C-5), 3.65 (C- 3),6.05 (C-21), 6.5 (C-20),.35 (C-1),.5 (C-1), 0. (C-3 &C-5 ), 0. (C-1), 1.2 (C-2 &C-6 ), 2. (C-4 ), 5.2 (C-1 ), 2.65 (C-6), 4.25 (C-2), 4.55 (C-16), (C-), (C-),.4 (C-23); LCMSmass m/z (%)5.2 (0%)[M+] +., 5. (65%), 40.5 (54%).Anal.cald.forC S:C 56.06; 5.05;.26;FoundC 56.02; 5.01;.1; 3-Ethyl 5-methyl 4-(2-chlorophenyl)-2-((2-(3-(4-nitrophenyl)thioureido)ethoxy)methyl)- 6-methyl-1,4-dihydro pyridine-3,5-dicarboxylate (4h) Yield 5%; mp o C;IR (KBr) (v max cm -1 ): 46 (C=S), 166 (C=), 325 (); 1 -MR (DMS- d 6 ) δ ppm: 1.1 (t, 3, C 3, -), 2.06 (s, 3, C 3, -15), 3. (dd, 2, C 2, -), 3.26 (s, 3, C 3, -), 3.56 (t, 2, C 2, -), 4.03 (s, 2, C 2, -),4.1 (m, 2, C 2, -),4.36 (s, 1, C, -4), 5.6 (t, 1,, -),.1-. (m,, Ar-),.16 (s, 1,, -1),.1 (s, 1, -24); LCMSmass m/z (%)5. (0%)[M+] +., 51.5 (33%), 40.2 (4%).Anal.cald.forC S:C 55.05; 4.6;.51;FoundC 55.01; 4.;.42; 3-Ethyl 5-methyl 4-(2-chlorophenyl)-2-((2-(3-(3-nitrophenyl)thioureido)ethoxy)methyl)- 6-methyl-1,4-dihydro pyridine-3,5-dicarboxylate (4i) Yield 0%; mp20-2 o C;IR (KBr) (v max cm -1 ): 4 (C=S), 1662 (C=), 32 (); 1 -MR (DMS-d 6 ) δ ppm: 1.1 (t, 3, C 3, -), 2.0 (s, 3, C 3, -15), 3.15 (dd, 2, C 2, -), 3.2 (s, 3, C 3, -), 3.5 (t, 2, 202

5 C. aga Raju et al Der Pharmacia Lettre, 20, 5 (1):1-204 C 2, -), 4.04 (s, 2, C 2, -),4.1 (m, 2, C 2, -),4.35 (s, 1, C, -4), 5.5 (t, 1,, -), (m,, Ar-),.15 (s, 1,, -1),.16 (s, 1, -24); LCMSmass m/z (%)5. (0%)[M+] +., 51.5 (33%), 40.3 (50%).Anal.cald.forC S: C 55.05; 4.6;.51; FoundC 55.01; 4.;.42; 3-Ethyl 5-methyl 4-(2-chlorophenyl)-2-((2-(3-(2-nitrophenyl)thioureido)ethoxy)methyl)- 6-methyl-1,4-dihydro pyridine-3,5-dicarboxylate (4j) Yield 3%; mp2-2 o C;IR (KBr) (v max cm -1 ): 51 (C=S), 1663 (C=), 3266 (); 1 -MR (DMS- d 6 ) δ ppm: 1.20 (t, 3, C 3, -), 2.0 (s, 3, C 3, -15), 3.16 (dd, 2, C 2, -), 3.2 (s, 3, C 3, -), 3.5 (t, 2, C 2, -), 4.05 (s, 2, C 2, -),4.21 (m, 2, C 2, -),4.3 (s, 1, C, -4), 5. (t, 1,, -),.-.0 (m,, Ar-),.1 (s, 1,, -1),.1 (s, 1, -24); LCMSmass m/z (%)5. (0%)[M+] +., 51.5 (33%), 40.2 (52%).Anal.cald.forC S: C 55.05; 4.6;.51;FoundC 55.01; 4.;.42; 3-Ethyl 5-methyl 4-(2-chlorophenyl)-2-((2-(3-(2,4-dichlorophenyl)thioureido)ethoxy)methyl)- 6-methyl-1,4- dihydropyridine-3,5-dicarboxylate (4k) Yield 5%; mp -15 o C;IR (KBr) (v max cm -1 ):45 (C=S), 165 (C=),325 (); 1 -MR (DMS- d 6 ) δ ppm: 1.21 (t, 3, C 3, -), 2. (s, 3, C 3, -15), 3.1 (dd, 2, C 2, -), 3.31 (s, 3, C 3, -), 3.61 (t, 2, C 2, -), 4.06 (s, 2, C 2, -),4. (m, 2, C 2, -),4.41 (s, 1, C, -4), 5.1 (t, 1,, -), (m,, Ar-),.21 (s, 1,, -1),.20 (s, 1, -24); LCMSmass m/z (%)6.4 (0%)[M+] +., 6.5 (33%), 40.6 (6%).Anal.cald.forC S:C 52.1; 4.60; 6.6;FoundC 52.2; 4.54; 6.; Table 1 Antifungal activity of compounds 4a-j Compound 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j Griseofulvin Zone of inhibition (in mm) Colletotrichumgloeosporioides Aspergillusniger Table 2 Antibacterial activity of compounds 4a-j Compound Zone of inhibition(in mm) S aureus B subtilis E coli K pneumoniae a 4b 4c 4d 4e 4f 4g 4h 4i 4j Penicillin Antimicrobial activity Susceptibility of test organisms to the title compounds 4(a-k) was determined by employing the standard disc diffusion technique []. All the compounds 4(a-k) were tested for their antifungal activity against the growth of Colletotrichumgleosorioides and Aspergillusnigeralong with the standard fungicide Griseofulvin at concentrations of 250 and 500 µg/disc, according to the reported procedure [].(Table1). Title compounds 4(a-k)were also screened for their anti-bacterial activity against the growth of Staphylococcus aureus, Bacillus subtilis, Escherichia 203

6 C. aga Raju et al Der Pharmacia Lettre, 20, 5 (1):1-204 coli and Klebsiellapeumoniaealong with the standard Penicillin at concentrations of 250 and 500 µg/disc according to the reported method [].(Table2). The results revealed that the title compounds exhibited moderate anti-fungal and good anti-bacterial activity against the tested species. RESULTS AD DISCUSSI Synthesis of a series of urea/thiourea derivatives 4(a-k) was accomplished through a single-step process. Benzene sulfonic acid was removed from Amlodipine by treating with Et 3 in TF at 50 o C. Then Amlodipine was reacted with different isocyanates/isothiocyanates in the presence of Et 3 in TF at o Cto form 4(a-k). The progress of the reaction was monitored by TLC analysis at different time intervals and the crude products obtained after removing the solvent were purified by column chromatography on silica gel using ethylacetate and hexane (2:3) as step grade mixtures as eluents. The structures of 4(a-k) were established by elemental analysis, IR, 1, C MR and mass spectral data (Scheme 1). The synthetic and analytical data of title compounds 4(a-k) are given in the experimental part. All the compounds4(a-k) exhibited absorption bands for C= and - in the regions and cm -1. In the 1 MR spectra (400 Mz) of 4(a-k), aromatic protons resonated as multipletsin the region ppm. The proton signals were observed in the region ppm as singlets. The C MR spectra for a few compounds were recorded and the data are given in the experimental part. The C= and C=S carbons gave signals in the regions and.2-15.ppmrespectively. The remaining carbon signals are observed in the expectedregions. The LC-MS of a few of the title compounds were recorded and the data are given in the experimental part. CCLUSI Amlodipine was treated with differentisocyanates/isothiocyanates to form urea/thiourea derivatives with high yields5-5%. Modification of Amlodipine as its urea/thiourea derivatives exhibited good antibacterial activity against two Gram positive and two Gram negative bacteria andmoderate antifungal activity against two different fungi. Acknowledgements The authors express their grateful thanks to UGC, ew Delhi, for giving financial assistance through BSR fellowship. REFERECES [1] D. V. M. Renaud Tissier, P. Sebastien, D. V. M. Brigitte Enriquez, J. Vet. Cardi.,2005,, 53. [2] R. A. enik, P. S. Snyder, L. M. Volk, J. Vet. Intern. Med.,14,,. [3] D. M. Considine, G. D. Considine, Van ostrand Reinhold Encyclopedia of Chemistry.Vanostrand Reinhold Company,ew York,14. [4] (a) F. M. Uckun, S. Pendergrass, D. Maher, D. Zhu, L. Tuel-Ahlgren, C. Mao, T. K. Venkatachalam, Bioorg. Med. Chem. Lett., 1,, 34. (b) R. Vig, C. Mao, T. K. Venkatachalam, L. Tuel-Ahlgren, E. A. Sudbeck, F. M. Uckun, Bioorg. Med. Chem.,1, 6, 1. [5] C. Sanmartin, M. Echeverria, B. Mendvil, L. Cordeu, E. Cubedo, J. Garcia-Fon-Cillas, M. Fontc, J. A. Palop, Bioorg. Med. Chem., 2005,, [6] G. allur, A. Jimeno, S. Dalrymple, T. Zhu, M.K. Jung, M. idalgo, J.T. Isaacs,S. Sukumar, E. amel, S.R. Khan, J. Med. Chem., 2006, 4, 235. [] S.. Manjula,. M. oolvi, K. V. Parihar, S. A. M. Reddy, V. Ramani, A. K. Gadad, G. Sing,.G. Kutty, C. M. Rao, Eur. J. Med. Chem., 200, 44, 3. [] Y.M. Zhang, T.B.Wei, L. Xian, L.M. Gao, Phosphorus, Sulphur Silicon Relat. Elem., 2004, 1, 200. [] W. Q. Zhou, B. L. Li, L. M. Zhu, J. G. Ding, Z. Yong, L. Lu, X.J. Yang, J. Mol. Struct., 2004, 60, 5. [] M. Eweis, S.S. Elkholy, M.Z. Elsabee, Int. J. Biol. Macromol.,2006, 3, 1. [] A. W. Bauer, W. M. Kirby, J. C, Sherris, M. Truck,Am. J. in. Pathol.,166, 45, 43. [] Y. B. Kiran, M. Kasthuraiah, C. aga Raju, D. GunaSekhar, S. V. S. MadhuBabu, C. Devendranath Reddy, Indian J. Chem., 2005, 44B, 211. [] Sanjeevkumar, Turk J Chem.,20, 35,. 204