Synthesis of bioactive molecule fluoro benzothiazole comprising quinazolinyl oxadiazoles derivative for biological and pharmacological screening

Transcription

1 Oriental Journal of Chemistry Vol. 24(2, (2008 Synthesis of bioactive molecule fluoro benzothiazole comprising quinazolinyl oxadiazoles derivative for biological and pharmacological screening GAJRAJ SHARMA, G.M. SREENIVASA and E. JAYACHANDRAN* P.G. Department of Pharmaceutical Chemistry. SCS College of Pharmacy, Harapanahalli (India (Received: February 08, 2008; Accepted: April 24, 2008 ABSTRACT Various substituted 3-{6-fluoro-7-(substituted-1,3-benzothiazol-2-yl-1-[(4-acetyl-5-methyl-5- phenyl-4,5-dihydro-1,3,4-oxadiazol-2-ylmethyl]-2-thioxo-2,3-dihydroquinazoline-4 (1H -one and 3-{(6- fluoro 7- (substituted - 1,3 -benzothiazol-2-yl-1-({4-acetyl-5-[4-(dimethylaminophenyl]-4,5-dihydro- 1,3,4-oxadiazol-2-yl}methyl -2- thioxo -2,3- dihydroquinazolin 4 (1H-one. containing different functional groups have been synthesized by condensing anthranilic acids with substituted 2-aminobenzothiazoles in dry pyridine and then by condensing with ethylchloroacetate in presence dry acetone and K 2 C. The identity of compounds were confirmed on the basis of their spectral (UV, IR, 1 H NMR and MASS data. Further, they have been screened for their antimicrobial activities. Key words: Fluorine, benzothiazole, quinazoline (Cyclo addition reaction Oxadizole (Schiff base. INTRODUCTION The chemistry and pharmacology of quinazoline have been of great interest because quinazoline derivatives possess various biological activities. This include antimicrobial 1-5, anticonvulsant 6-7, antineoplastic, analgesic and antiinflammatory 8 etc. Therefore in present work we have prepared quinazoline incorporate with fluoro substituted benzothiazole. The oxadiazole drugs were the first effective chemotherapeutic agents to be employed systematically for the prevention and cure of bacterial infection in human beings. Benzothiazole with oxadiazole groups were reported to possess various pharmacological activity of clinical importance. Oxadiazole derivatives are well known to have number of biological and antimicrobial 9-12 activities, this also having antiinflammatory 13, anthelmentic and anticonvulsant activities. MATERIAL AND METHODS Melting point was determined by open capillary tube method and are uncorrected. T.L.C was run on silica gel G plates using butanol, ethyl acetate and chloroform (1:2:1 as developing solvent for the purity of the compounds. I.R. Spectra were recorded on Shimadzu FTIR Spectrophotometer by using NUJOL MULL technique. All the compounds synthesized were screened for antibacterial and antifungal activities at two different concentrations (50µg/ml, 100µg/ml against Staphylococcus aureus, Streptococci, Escherchia coli, Ps. aureus and Candida albicans,

2 430 Sharma et al., Orient. J. Chem., Vol. 24(2, (2008 Aspergillus niger by cup plate method using Procaine Penicillin, Streptomycin and Griseoflavin respectively as standards. The compounds showed considerable activity against all species tested at 50µg/ml, 100µg/ml. Fluoro substituted benzothiazoles series was tested for antibacterial activity. Were calculated which are shown in the table. The compounds showing activity index more than 0.7 were considered to be significantly active. General synthesis of 2-amino-N-(7-chloro-6- fluoro-1,3-benzothiazol-2-ylbenzamide Anthranilic acid (4.0 g, mol and 2- amino-benzothiazole (5.22 g, mol, were dissolved in dry pyridine (20 ml, 0.25 mol. The solution was refluxed for 8 hr. The solution was cooled and poured in water. The separated mass was filtered, washed with water and dried. The product was recrystallized using ethanol. General synthesis of 3-(7-chloro-6-fluoro-1,3- benzothiazol-2-yl-2-thioxo-2,3- dihydroquinazolin- 4(1H-one To an ice cold solution of potassium hydroxide (0.1 g, 0.02 mol in dry ethanol (50 ml, 2-amino-N-(2'-benzothiazolyl 6'-fluoro-7'-chloro benzamide (2.6 g, mol and carbon disulphide (6.0 ml, mol was added with stirring. The solution was refluxed for 10 hr and cooled. The quantity of solvents was reduced by distillation. The separated solid was filtered, washed with dry ether and dried. The product was recrystallized from ethanol. General synthesis of ethyl [3-(7-chloro-6-fluoro- 1,3-benzothiazol-2-yl-4-oxo-2-thioxo-3,4- dihydroquinazolin-1(2h-yl]acetate A mixture of step III (0.01 mole, ethyl chloro acetate (0.1 mole and potassium carbonate (0.15 mole in absolute alcohol (120 ml was refluxed for 7-8 hours on water bath. The reaction mixture was filtered hot and the excess solvent was distilled off from the filtrate. The crude ester IV thus obtained was purified by recrystallisation from ethanol, yield 84%. Table 1: Analytical data S Comp. M.P./ B.P 0 C % yield Mol. Form M.Wt. C% H% N% No. code 1 AP % C 33 F AP % C 33 F AP % C 33 F AP % C 33 N 6 FCl AP % C 33 N 6 FCl AP % C 33 N 6 FCl AP % C 31 H 27 O 4 N 6 F AP % C 34 H 27 N 6 F AP % C 31 H 28 F AP % C 34 H 25 N 6 F BZ % C 34 H 23 N 8 F BZ % C 34 H 23 N 8 F BZ % C 34 H 23 N 8 F BZ % C 34 H 23 FCl BZ % C 34 H 23 FCl BZ % C 34 H 23 FCl BZ % C 34 H 22 FCl BZ % C 34 H 22 FCl BZ % C 35 H 26 O 4 F BZ % C 35 F

3 Sharma et al., Orient. J. Chem., Vol. 24(2, ( Table 2: Characteristics IR absorption bands of similar compounds (AP 1 to AP 10 and BZ 1 to BZ 10 are tabulated below S Spec Compound Ar-NH ArC=C C=N C-F C=O C=S C-C NO 2 CH 3 C-O-C No. No. code stertcm -1 cm -1 cm -1 cm -1 cm -1 cm -1 cm -1 cm -1 cm -1 cm CFA AB AP BZ AP AP AP AP AP AP AP AP AP AP BZ BZ BZ BZ BZ BZ BZ BZ BZ BZ

4 432 Sharma et al., Orient. J. Chem., Vol. 24(2, (2008 General synthesis of 2-[3-(7-chloro-6-fluoro-1,3- benzothiazol-2-yl-4-oxo-2-thioxo-3,4- dihydroquinazolin-1(2h-yl]acetohydrazide A mixture of step IV (0.01 mole and hydrazine hydrate (4 ml in absolute alcohol (30 ml was refluxed for 5 hours on water bath. Cool the solution at room temperature and filter it then recrystallised from ethanol, yield 54%. General synthesis of 3- (7- chloro 6 fluoro - 1,3- benzothiazole-2-yl-n-( 1-phenylethylidene - 4-oxo- 2-thioxo-3,4-dihydroquinazolin-1(2H- carbohydrazide A mixture of step V (0.01 mole, and acetophenone (0.01 mole in glacial acetic acid (20 ml, was refluxed for 1 hour on an oil bath. Distilled off excess solvent and the cooled reaction mixture was poured into ice cold water and the solid was filtered. The dried solid was recrystallised from ethanol-dmf.

5 Sharma et al., Orient. J. Chem., Vol. 24(2, ( R = o, m, p- nitro (AP 1 - AP 3 R' = morpholine (AP 7 = o, m, p- chloro ((AP 4 - AP 6 = piperazine (AP 9 = p-toludine (AP 8 = PABA (AP 10 Scheme 1 General synthesis of 3-(7-chloro-6-fluoro-1,3- benzothiazol-2-yl-1-[(4-acetyl-5-methyl -5- phenyl -4,5- dihydro -1,3,4- oxadiazol -2- yl methyl] -2- thioxo -2,3-dihydroquinazoline-4(1H- one A mixture of step VI (0.005 mole and acetic anhydride (10ml was refluxed for 4 hours. The excess acetic anhydride was distilled off and the residue was poured into ice cold water. The solid was filtered and recrystallised from ethanol-dmf. General synthesis of 3-{6-fluoro-7-(substituted- 1,3-benzothiazol-2-yl}-1-[(4-acetyl-5-methyl-5- phenyl-4,5-dihydro-1,3,4-oxadiazol-2-ylmethyl]- 2-thioxo-2,3-dihydroquinazoline-4(1H-one The Product of step VII (0.002 mole was treated with equimolar quantity (0.002 mole of various substituted aromatic anilines like nitro

6 434 Sharma et al., Orient. J. Chem., Vol. 24(2, (2008 aniline, chloro aniline, PABA, morpholine, piperazine etc. in presence of DMF (dimethyl formamide, 30 ml and refluxed for 2 hours on an oil bath. The reaction mixture was cooled and then poured into crushed ice. The solid separated was filter off, dried and recrystallised from benzene and absolute alcohol (1:1. Scheme II General synthesis of 3- (7- chloro -6 fluoro - 1,3- benzothiazole-2-yl -N - [(1-dimethylamino benzylidene] -4- oxo -2- thioxo -3,4 dihydroquinazolin -1 (2H-carbohydrazide A mixture of step V (0.01 mole, and 4- dimethylaminobenzaldehyde (0.01 mole in glacial acetic acid (20 ml, was refluxed for 1 hour on an oil bath. Distilled off excess solvent and then cooled the reaction mixture was poured into ice cold water and the solid was filtered. The dried solid was recrystallised from ethanol-dmf. Table 3: NMR Spectral Data of Compounds AP 3, AP 6, AP 7, AP 9, BZ 2, BZ 7, BZ 9, BZ 10. S Spectra Compound Hydrogen δ (ppm Multiplity Solvent No. no. code 1 27 AP 3-10H-Ar-H Multiplet DMSO -3H-CH Singlet -3H-COCH Singlet -H-NH 5.5 Singlet 2 28 AP 6-10H-Ar-H Multiplet DMSO 2.2 Singlet 2.9 Singlet 3 29 AP 7-6H-Ar-H Multiplet DMSO 2.2 Singlet 2.8 Singlet 4 30 AP 9-6H-Ar-H Multiplet DMSO 2.1 Singlet 2.9 Singlet 5 31 BZ 2-10H-Ar-H Multiplet CDCl Singlet 2.8 Singlet 6 32 BZ 7-6H-Ar-H Multiplet CDCl Singlet 3.0 Singlet 7 33 BZ 9-10H-Ar-H Multiplet CDCl Singlet 3.2 Singlet 8 34 BZ 10-10H-Ar-H Multiplet CDCl Singlet 3.0 Singlet -H-COOH 9.7 Singlet

7 Sharma et al., Orient. J. Chem., Vol. 24(2, ( General synthesis of 3-(7-chloro-6-fluoro-1,3- benzothiazol-2-yl-1-({4-acetyl-5-[4- (dimethylaminophenyl]-4,5-dihydro-1,3,4- oxadiazol-2-yl}methyl-2-thioxo-2,3- dihydroquinazoline-4(1h-one A mixture of step VI (0.005 mole and acetic anhydride (10ml was refluxed for 4 hours. The excess acetic anhydride was distilled off and the residue was poured into ice cold water. The solid was filtered and recrystallised from ethanol-dmf. General synthesis of 3- { (6- fluoro -7- (substituted -1,3- benzothiazole -2-yl}-1-({4- acetyl-5-[4-(dimethylaminophenyl]-4,5-dihydro- 1,3,4-oxadiazol-2-yl}methyl-2-thioxo-2,3- dihydroquinazolin-4(1h-one The Product of step VII (0.003 mole was treated with equimolar quantity (0.003 mole of various substituted aromatic anilines like nitro aniline, chloro aniline, PABA, anisidine etc. in presence of DMF (dimethyl formamide, 30 ml and refluxed for 2 hours on an oil bath. The reaction

8 436 Sharma et al., Orient. J. Chem., Vol. 24(2, (2008 R = o, m, p- nitro (BZ 1 - BZ 3 = o, m, p- nitro (BZ 1 - BZ 3 = 2,3 -dichloro (BZ 7 = 3,4- dichloro (BZ 8 = o- anisidine (BZ 9 = PABA (BZ 10 Scheme 2 mixture was cooled and then poured into crushed ice. The solid separated was filter off, dried and recrystallised from benzene and absolute alcohol (1:1. RESULTS AND DISCUSSION Anti-bacterial activity Synthesis and Pharmacological screening of 3-{6-fluoro-7-(substituted-1,3-benzothiazol -2- yl}-1-[(4-acetyl-5-methyl-5-phenyl-4,5-dihydro- 1,3,4-oxadiazol-2-ylmethyl]-2-thioxo-2,3- dihydroquinazolin-4(1h-one and 3-{(6- fluoro-7- (substituted -1,3-benzothiazol-2-yl}-1-({4-acetyl-5- [4-(dimethylaminophenyl]-4,5-dihydro-1,3,4- oxadiazol-2-yl}methyl-2-thioxo-2,3- dihydroquinazolin-4(1h-one were tested for the antibacterial activity against following bacterias; a (i S.aureus, (ii Streptococci (gram +ve and b (iii E.coli, (iv Pseudomonas aureus (gram ve.

9 Sharma et al., Orient. J. Chem., Vol. 24(2, ( The test compounds AP 3, AP 4, AP 7, AP 10 and BZ 1, BZ 4, BZ 7, BZ 9 showed moderate antibacterial activity against S.aureus (gram +ve compare to standard drug Procaine Penicillin. Compounds AP 1, AP 2, AP- 5, and BZ 4, BZ 8, BZ 9 showed promising antibacterial activity against, E. coli (gram ve compared to standard drugs and streptomycin. Compounds AP 1, AP 3, AP 6, AP 9, and BZ 3, BZ 5, BZ 7, BZ 8 showed promising antibacterial activity against, gram +ve (Streptococci at both lower and higher concentration (50 µg/ml and 100 µg/ml. Compound AP 4, AP 6 AP 7, AP 10 and BZ 2, BZ 4 BZ 5 showed moderate activity against gm ve (Pseudomonas aureus at both lower and higher concentration compare to standard drug Streptomycin. Table 4: Antibacterial activity S. Name of the Mean zone of inhibition (in mm* No. compounds Staphylococcus aureus Escherichia coli 50µg 100µg 50µg 100µg 1. Procaine penicillin Streptomycin AP 1 13 ( ( ( ( AP 2 14 ( ( ( ( AP 3 14 ( ( ( ( AP 4 17 ( ( ( ( AP 5 12 ( ( ( ( AP 6 14 ( ( ( ( AP 7 15 ( ( ( ( AP 8 13 ( ( ( ( AP 9 15 ( ( ( ( AP ( ( ( ( BZ 1 14 ( ( ( ( BZ 2 12 ( ( ( ( BZ 3 14 ( ( ( ( BZ 4 16 ( ( ( ( BZ 5 14 ( ( ( ( BZ 6 15 ( ( ( ( BZ 7 14 ( ( ( ( BZ 8 15 ( ( ( ( BZ 9 17 ( ( ( ( BZ ( ( ( (0.60

10 438 Sharma et al., Orient. J. Chem., Vol. 24(2, (2008 Anti-fungal activity The above screened compounds were tested for antifungal activity against Candida albicans and Aspergillus niger. Among the compounds tested; AP 2, AP 5, AP 9 and BZ 2, BZ 3 showed good activity against Candida albicans at both concentrations compare to standard Griseofulvin. AP 4, AP 5, AP 7, AP 10, and BZ 5, BZ 7, BZ 9 showed significant activity against Aspergillus niger compared to standard Griseofulvin. Table 5: Antibacterial activity S. Name of the Mean zone of inhibition (in mm* No. compounds Streptococci Pseudomonas aureus 50µg 100µg 50µg 100µg 1. Procaine penicillin Streptomycin AP 1 13 ( ( ( ( AP 2 14 ( ( ( ( AP 3 16 ( ( ( ( AP 4 13 ( ( ( ( AP 5 14 ( ( ( ( AP 6 13 ( ( ( ( AP 7 12 ( ( ( ( AP 8 14 ( ( ( ( AP 9 15 ( ( ( ( AP ( ( ( ( BZ 1 14 ( ( ( ( BZ 2 14 ( ( ( ( BZ 3 16 ( ( ( ( BZ 4 13 ( ( ( ( BZ 5 13 ( ( ( ( BZ 6 14 ( ( ( ( BZ 7 16 ( ( ( ( BZ 8 15 ( ( ( ( BZ 9 13 ( ( ( ( BZ ( ( ( (0.69

11 Sharma et al., Orient. J. Chem., Vol. 24(2, ( Table 6: Antifungal activity S Name of the Mean zone of inhibition (in mm* No. coompounds Candida albicans Aspergillus niger 50µg 100µg 50µg 100µg 1. Griseofulvin AP 1 12 ( ( ( ( AP 2 14 ( ( ( ( AP 3 13 ( ( ( ( AP 4 13 ( ( ( ( AP 5 15 ( ( ( ( AP 6 12 ( ( ( ( AP 7 10 ( ( ( ( AP 8 11 ( ( ( ( AP 9 11 ( ( ( ( AP ( ( ( ( BZ 1 12 ( ( ( ( BZ 2 14 ( ( ( ( BZ 3 14 ( ( ( ( BZ 4 10 ( ( ( ( BZ 5 12 ( ( ( ( BZ 6 11 ( ( ( ( BZ 7 13 ( ( ( ( BZ 8 13 ( ( ( ( BZ 9 10 ( ( ( ( BZ ( ( ( (0.68 ACKNOWLEDGEMENTS The authors are thankful to Shri. Sha. Bra. Chandramouleshwara Shivacharya Swamiji, President, Sri. T. M. Chandrashekaraiah M.A. Secretary, T.M.A.E. Society Harapanahalli. for providing necessary facilities through the Principal, S.C.S. college of Pharmacy, Harapanahalli to carryout this work. REFERENCES 1. Patel NB, Lilakar JD. Synthesis of newsubstituted-4(3h-quinazolinones and their antibacterial activity. Indian J Heterocyclic Chem 11: ( Shivarama Holla B, Padmaja P, Shivananda MK, Akbarali PM. Synthesis and antibacterial activity of nitro-furylvinylquinazolinones. Indian J Chem 37B: ( Afsah SA, Jawaid Ahmad, Purbey R, Kumar A. Synthesis of some new heterocyclic systems bearing 2-methylquinazolin-4(3H- ones and their antimicrobial effects. Oriental J Chem 18(3: ( Varsha Jatav, Jain SK, Kashaw SK, Mishra P. Synthesis and antimicrobial activity of Nover 2- methyl - 3- ( thiadiazoyl

12 440 Sharma et al., Orient. J. Chem., Vol. 24(2, ( (3H quinazolinones. Indian J Pharmaceutical Sci ( Gangwal NA, Kothwade UR, Galande AD, Pharande DS, Dhake AS. Synthesis of 1- substituted-2-chloromethyl-4-(1h- quinazolinones as antimicrobial agents. Indian J Heterocyclic Chem 10: ( Archana, Srivastava VK, Ramesh Chandra, Ashok Kumar. Synthesis of potential quinazolinonyl pyrazolines and quinazolinyl isoxazolines as anticonvulsant agents. Indian J Chem 41B: ( Amar R Desai, Kishor R Desai. Niementowski reaction microwave induced and conventional synthesis of quinazolinones and 3-methyl-1H-5-pyrazolones and their antimicrobial activity. ARKIVOC 2005 (xiii, (AKRAT USA, Inc Rama Sarma GVS, John Thomas, Murugan V, Elango K. Nicotinyl incorporated quinazolinonyl thiadiazoles as possible NSAIDS. Indian J Heterocyclic Chem 9: ( Mashooq.A.Bhat, Khan S.A, Siddiqui N. Synthesis and antibacterial activity of coumarin incorporated 1,3,4-oxadiazoles. Indian J Heterocyclic Chem 14: ( Khan MSY, Khan RM, Sushmadrabhu. Anticonvulsant and antibacterial activity of some new 1,3,4-oxadiazole derivatives. Indian J Heterocyclic Chem 11: ( Dharmveer Singh, Atma Ram Mishra, Rakesh Mai Mishra. Synthesis and antifungal activity of new1,3,4-oxadiazolo[3,2-b]-striazine-5-ones and their thiones analogues. Indian J Heterocyclic Chem 14: ( Viral Shah, Milan Vadodaria Parikh AR. Synthesis of 1,3,4-oxadiazoles having nicotinamide moiety as potential antimicrobial agents. Indian J Chem 36B: ( Sawhney SN, Asha Gupta. synthesis of some 2-(5-substituted 1,3,4- oxadiazol-2-yl-,2-(5- substituted 1,3,4-thiadiazol-2-yl- and 2-(3- mercapto-4-substituted-4h-1,2,4-trizol-5-yl- benzimidazoles as potent anti-inflammatory agents. Indian J Chem 30B: (1991.