Synthesis and biological evaluation of some novel 1,3,4 ...

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Scholars Research Library Der Pharmacia Lettre, 2013, 5 (1):366-370 (http://scholarsresearchlibrary.com/archive.html) ISSN 0975-5071 USA CODEN: DPLEB4

Synthesis and biological evaluation of some novel 1,3,4-oxadiazoles derived from bi phenyl 4- carboxylic acid Rakesh Kumar1*, M. Shahar Yar2, A. K. Rai1 and Saurabh Chaturvedi1 1

2

Pranveer Singh Institute of Technology, Kanpur Dept. of Pharmaceutical Chemistry, Faculty of Pharmacy Jamia Hamdard, Hamdard Nagar, New Delhi

_____________________________________________________________________________________________ ABSTRACT A new class of 1,3,4-Oxadiazoles, have been synthesized from Biphenyl 4-carboxylic acid on treatment with various chemicals & prepared 2-(biphenyl-4-yl)-5-phenyl-1,3,4-oxadiazole derivatives. Then uses various reagents get 1,3,4-Oxadiazoles was carried out with appropriate reagents. The structures of these compounds have been elucidated by elemental and spectral (IR, 1HNMR & Mass) analysis. Furthermore, compounds were screened for in vitro antimicrobial activity against the representative panel of gram positive and gram negative bacteria. The various compounds show potent inhibitory action against test organism. Key words: Bi Phenyl acid, Substituted 1,3,4-Oxadiazoles, antimicrobial activity. _____________________________________________________________________________________________ INTRODUCTION Heterocyclic is the largest classical division of medicinal chemistry and is Importance industrially and biologically. Development of novel chemotherapeutic agents an important and challenging task for the medicinal chemists and many research programs are directed towards the design and synthesis of new drugs for their chemotherapeutic usages. The majority of pharmaceutical and biologically active agrochemicals are heterocyclic while countless additives and modifiers used in industrial application ranging from reprography, Information storage, cosmetics and plastics are heterocyclic in nature. Oxadiazoles constitute an important class for new drug development in order to discover an effective compound against multi drug resistant microbial infection A large number of heterocyclic compounds containing the 1, 3, 4-Oxadiazoles ring are associated with diverse pharmacological properties such as anti-inflammatory, antimicrobial, fungicidal and anti viral activity1-4. Substituted 1,3,4-oxadiazole have revealed antibacterial5, antimycobacterail6, anti fungal activity7, anti-inflammatory activity8, analgesic 9, anticonvulsant 10 and anticancer 11 properties. Prompted by the observed biological activities of the above mentioned derivatives and in continuation of our ongoing studies on novel biologically active molecules, we have designed and synthesized new 1,3,4-Oxadiazoles As a potential antimicrobial and Anti-Inflammatory agent. The results of this study are discussed in this paper. MATERIALS AND METHODS Experimental protocolsThe Melting points were determined in open capillary tube and are uncorrected. Infra red spectra were recorded on Perkin Elmer spectrum spectrophotometer. 1HNMR spectra were run on BRUCKER spectrometer (300MHz) using TMS as internal standard. Elemental analyses were doing using Carbo Erba 1106 CHN analyses. The progress of the reaction was monitored by thin layer chromatography on TLC silica gel plates. The purity of synthesized compounds was as curtained by TLC on silica gel G in various solvent systems using Iodine vapors as detecting agents.

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Rakesh Kumar et al Der Pharmacia Lettre, 2013, 5 (1):366-370 _____________________________________________________________________________ SCHEME

COOH

EtoH Conc.H 2So4

COOC2H5

NH2.NH2.H2O EtOH

CONHNH2

EtOH PoCl 3, Ar-COOH

N

N

O

R=

R-11

R-12

R-13

R-14

OH OH OH R-15

NH 2

Cl

NH2

OH

R

Cl R-16

R-17

NH 2

R-18

HO

NH 2

ChemistryThe preparation of target compounds is out lined in scheme. The Biphenyl 4- Carboxylic acid (I) was first reacted with ethanol in sulphuric acid yielded corresponding ethyl ester of Biphenyl 4- Carboxylic acid (II) in very good yield 80%. This ester was then converted almost quantitatively to the hydrazide (III) after treatment with hydrazine hydrate. A mixture of biphenyl 4-carbohydrazide (0.001M) and the appropriate aromatic acid (0.001M) in phosphorus oxychloride (10 ml) was refluxed 5-7 hr. The reaction mixture was slowly poured over Crushed ice and kept overnight. The solid thus separated out was filtered treated with dil. NaOH washed with water and recrystalysed from ethanol gives 2-(biphenyl-4-yl)-5-phenyl-1,3,4-oxadiazole derivatives.

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Rakesh Kumar et al Der Pharmacia Lettre, 2013, 5 (1):366-370 _____________________________________________________________________________ R-11- 5-(5-(biphenyl-4-yl)-1,3,4-oxadiazol-z-yl)benzene-1,2,3-triolIR (γ max cm-1): 2930 ( C-H ), 1610 ( C=N ), 1153 (C-O-C). ; 1 HNMR (300 MHz, CDCl3, δ ppm ): (CDCl3) δ (ppm ): 7.25-8.13 (m, 14H, aromatic ).; MS: m/z 346 (M+ ); Anal. Cacld. For C20H14N2O4 : C,69.36; H,4.07; N,8.09 Found C,69.56; H,4.10; N,7.68. R-12- 4-(5-biphenyl-4-yl)-1,3,4-oxadiazol-2-yl)phenol. IR (γ max cm-1): 2936 ( C-H ), 1615 ( C=N ), 1240(C-O-C), 3415 (-OH). ; 1 HNMR (300 MHz, CDCl3, δ ppm ): 7.29-7.95 (m, 14H, aromatic ), 4.6 (s,1H,-OH) .; MS: m/z 314 (M+ ); Anal. Cacld. For C20H14N2O2: C,76.42, H,4.49, N,8.91 Found C,76.50; H,4.45; N,8.93. R-13- 4-(5-biphenyl-4-yl)-1,3,4-oxadiazol-2-yl)aniline. IR (γ max cm-1): 2928 ( C-H ), 1612 ( C=N ), 1239 (C-O-C), 3419 (-NH2). ; 1 HNMR (300 MHz, CDCl3, δ ppm ): 7.30-7.57 (m, 14H, aromatic ), 5.9 (s,2H,NH2). ; MS: m/z 313 (M+ ).; Anal. Cacld. For C20H15N3O : C=76.66%, H=4.82, N=13.41Found C,76.59, H,4.80, N=13.39. Table- 1 Analytical Data S.N

Compound

R

Yield

M.P. ( 0c)

346

80 %

120

Chemical Formula

Mole.Wt.

OH

C20H14N2O4

OH 1

R-11

OH 2

R-12

OH

C20H14N2O2

314

65%

98

3

R-13

NH2

C20H15N3O

313

70%

103

4

R-14

C20H12Cl2N2O

367

78%

116

C20H12N4O5

388

80%

128

C20H12N3O3

343

65%

105

Cl Cl NH 2

5

R-15

NH2

6

R-16

NH2 7

R-17

C20H14N2O

298

70%

136

8

R-18

C20H14N2O2

314

75%

124

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Rakesh Kumar et al Der Pharmacia Lettre, 2013, 5 (1):366-370 _____________________________________________________________________________ R-14- 2-(biphenyl-4-yl)-5-(2,4-dimethylphenyl)-1,3,4-oxadiazol IR (γ max cm-1): 2937 ( C-H ), 1598( C=N ), 1230 (C-O-C), 3419. ; 1 HNMR (300 MHz, CDCl3, δ ppm ): 6.99-7.86 (m, 12H, aromatic ). ; MS: m/z 367 (M+ ), 369 (M++2).; Anal. Cacld. For C20H12Cl2N2O : C,65.41, H,3.29, Cl,19.31, N,7.63 Found C,64.38, H,3.31, Cl,19.34, N,7.59. R-15- 2-(biphenyl-4-yl)-5-(3,5-dinitrophenyl)-1,3,4-oxadiazol IR (γ max cm-1): 2922 ( C-H ), 1605 ( C=N ), 1160 (C-O-C).; 1 HNMR (300 MHz, CDCl3, δ ppm ): 6.98-7.88 (m, 12H, aromatic ). ; MS: m/z 388 (M+ ).; Anal. Cacld. For C20H12N4O5 : C,61.86, H,3.11, N,14.43Found C,61.87, H,3.15, N,14.39. R-16- 2-(biphenyl-4-yl)-5-(3-nitrophenyl)-1,3,4-Oxadiazol IR (γ max cm-1): 2925( C-H ), 1607 ( C=N ), 1156 (C-O-C). ; 1 HNMR (300 MHz, CDCl3, δ ppm ): 7.12-7.71 (m, 13, aromatic ).; MS: m/z 343 (M+ ).; Anal. Cacld. For C20H12N3O3 : C,69.96, H,3.82, N,12.24 Found C,69.81, H,3.85, N,12.27. R-17- 2-(biphenyl-4-yl)-5-phenyl-1,3,4-Oxadiazol IR (γ max cm-1): 2935( C-H ), 1615 ( C=N ), 1150 (C-O-C). ; 1 HNMR (300 MHz, CDCl3, δ ppm ): 7.27-7.6 (m, 14, aromatic ).; MS: m/z 298 (M+ ).; Anal. Cacld. C20H14N2O For C,80.52, H,4.73, N,9.39 Found C,80.55, H,4.71, N9.37. R-18- 2-(5-(biphenyl-4-yl)-1,3,4-Oxadiazol-2-yl)phenol IR (γ max cm-1) 2930( C-H ), 1613 ( C=N ), 1238 (C-O-C). ; 1 HNMR (300 MHz, CDCl3, δ ppm ): 6.94-7.88 (m, 14, aromatic ), 4.9 (s,1H,OH). ; MS: m/z 314 (M+ ).; Anal. Cacld. C20H14N2O 2 For C, 76.42, H, 4.49, N,8.91 Found C, 76.56, H,4.50, N,8.89. RESULTS In the current study, totally newly synthesized Oxadiazoles derivatives were achieved with a versatile and efficient synthetic route. The yield of all synthesized compound were found to be a range of 65-80%. The titled compounds were characterized by physiochemical like m.p. & Rf value. The structures of the synthesized compounds were confirmed by elemental analysis, IR spectra and 1HNMR spectral analysis. The spectral data also supported the assigned structure by showing the characteristic absorption peak. Structure analysis and activity showed, some structure activity relationship can be extracted. The Structural requirements for antibacterial activity are different for substituted Oxadiazoles. The most active antibacterial compound R-14, R-11 and compounds R-17 showed the least antibacterial activity. The presence of electron deactivating groups on aromatic ring enhanced the antimicrobial of the compounds. DISCUSSION Antimicrobial ActivityAntimicrobial activities of the synthesized compounds against two Gram-positive bacteria (Staphylococcus aurous and Bacillus subtitles), two Gram-negative bacteria (Escherichia coli and Pseudomonas aeroginosa) were expressed as zone of inhibition values in mm12, 13. The zone of inhibition values were determined by cup plate agar diffusion method. Zone of inhibition values of the synthesized compounds and the standard drugs, Ofloxacin were compared at concentration of 100 µg/ml. The stock solutions of the compounds were prepared in dimethyl sulphoxide (DMSO) as solvent which was also used as control. The bacterial strains were obtained from Microbiology Department of CT Institute of Pharmaceutical Sciences, Jalandhar, Punjab, India. The compounds were screened for antibacterial activity against Staphylococcus aureus, Bacillus subtilis , Escherichia coli and Pseudomonas aeroginosa in Nutrient Agar medium. The petri plates were washed thoroughly and sterilized in hot air oven at 160°C for one hour. Sterile nutrient agar medium (15 ml) was poured into sterile petri dishes of 9 cm diameter and allowed to solidify. The petri plates were incubated at 37°C for 24 hours to check for sterility. The medium was seeded with the suspension of microorganism (1 ml) by spread plate method using sterilized triangular loop. Bores were made on the medium using sterilized stainless steel cylinder of 8 mm diameter to make cups or cavities. The solutions of test compounds (100 µg/ml in DMSO) were added serially in the cups or cavities with the help of micropipette (0.1 ml). A control having only DMSO in the cup was maintained in each plate. The petri plates were kept in refrigerator at 4°C for 1 hour, allowing diffusion to take place. These plates were incubated at 37°C for 24 hours and 28°C for 48 hours, for antibacterial activity respectively. The radius of zone of

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Rakesh Kumar et al Der Pharmacia Lettre, 2013, 5 (1):366-370 _____________________________________________________________________________ inhibition (in mm) was observed around the cup or cavity after respective incubation was assured and measured in triplicate sets by using a scale. ( Table 2 ) Table 2: In vitro antimicrobial activity of the titled compounds (6a-6h). Compound R-11 R-12 R-13 R-14 R-15 R-16 R-17 R-18 Ofloxacin Standard

S.aureus 19 17 14 21 12 13 12 17 41

MIC in µg/ml and zone of inhibition P.aeruginosa K.pneumonia 17 18 16 17 13 16 19 19 11 13 14 15 13 11 16 15 38 39

E.Coli 19 15 17 20 12 12 11 17 37

CONCLUSION Oxadiazoles as useful templates for further development through modification or derivitization to design more potent biologically active compounds. The result of antimicrobial study indicated that the presence of halogen atom in aromatic ring enhanced the antibacterial activity. Various Oxadiazoles from biphenyl 4- carboxylic acid were prepared with the objective with developing their antimicrobial activity. Acknowledgement The author thankful Mr. Pranveer Singh (Chairman) Pranveer Singh Institute of Technology Kanpur and Central drug research Institute (CDRI) Lucknow For their valuable and continuous support throughout support this work. REFERENCES [1]. A.Walser, T. Flynn, C. Mason, J. Heterocyclic. Chem. 28 (1991) 1121-1125. [2]. N.F. Ewiss, A.A. Bahajaj, E.A. Elsherbini, j. Heterocyclic chem. 23 (1986) 1451-1458. [3]. A.R. Bhat, G.V.Bhat, G.G. Shenoy, J. Pharm. Pharmacol. 53 (2001) 267-272. [4] O.G. Todoulou, A.E. Papadaki-Valaraki, E.C.Flippatos, S.llkeda, E.De Clercq, Eur. J. Med. Chem.. 29 (1994) 127-131. [5]- B.S. Holla, R. Gonsalves, S. Shenoy, Eur. J. Med. Chem. 35 (2000) 267-271. ChemInform Abstract: Synthesis and Antibacterial Studies of a New Series of 1,2-Bis(1,3,4-oxadiazol-2-yl)ethanes and 1,2-Bis(4-amino-1,2,4triazol-3-yl)ethanes. [6]. F. Macaev, G. Rusu, S.Pogervnoi, A. Gudima, E. Stingasi, L.Vlad. et.al Bio org. Med. Chem. 13 (2005) 48424850. [7]. X.Z. Jou, L.H.Lai, G.Y.Jin, J.Agrc. Food.Chem.50 (2002) 3757-3760. [8 ]E. Palaska, G. Sahin, P.Kelicen, N.T. Durlu, G. Altinok, II Farmaco 57 (2002) 101-107.. [9] M.Amir, K. Shikha, Eur.J. Med. Chem. 39 (2004) 535-545. [10] A. Zargahi, A. Sayyed, M. Tabatabai, A. Faizi, P. Ahadian, V. Navavi, A. Zanganeh, Shafiee, Biorg. Med. Chem. 15 (2005) 1863-1865. [11] J.J, Bhat, B.R.Shah, H.P.Shah, P.B.Trivedi, N.K. Undavia, N.C. Desai, Indian j. chem. 33b (1994) 189-192. [12]. W.S. Harry, J.V.Paul, J.L.John, Culturing Microorganism Microbes in action. 4th ed.; New York: W.H. Freeman and Company; 1991, p. 37-61. [13]. J.G. Black, Growth and culturing the bacteria. 4th ed.; New Jersey: Prentice Hall; 1999, p. 155-163.

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