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Synthesis and Antibacterial Evaluation of Some Novel 1,3,4-oxadiazol Derivatives Incorporated with Quinoline Moiety
Synthesis and Antibacterial Evaluation of Some Novel 1,3,4-oxadiazol Derivatives Incorporated with Quinoline Moiety
Journal of the Korean Chemical Society. 2011. Aug, 55(4): 656-661
Copyright © 2011, The Korean Chemical Society
  • Received : February 13, 2011
  • Accepted : April 04, 2011
  • Published : August 20, 2011
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About the Authors
Priyanka G. Mandhane
Ratnadeep S. Joshi
Wajid Khan
Department of Microbiology, Maulana Azad College, Aurangabad-431 001, India
Charansingh H. Gill
chgill50@yahoo.com

Abstract
5-(3,4,5-Triethoxyphenyl)-1,3,4-oxadiazole-2-thiol 6 on treatment with substituted 3-(bromomethyl)-2 chloroquinoline or 2-( p -tolyloxy)-3-(bromomethyl)quinoline 4a-j afforded the corresponding 3-((5-(3,4,5-triethoxyphenyl -1,3,4-oxadiazol-2-ylthio)methyl)-2-chloroquinoline or 3-((5-(3,4,5-triethoxyphenyl)-1,3,4-oxadiazol-2-ylthio)methyl)-2-( p -tolyloxy quinoline 7a-j , in the presence of K 2 CO 3 and DMF under stirring at ambient temperature. All the synthesized compounds were further screened for their antibacterial activities. Some of our compounds showed excellent antibacterial activities against test organisms and reference standard.
Keywords
INTRODUCTION
Quinoline scaffold is prevalent in a variety of pharmacologically active compounds as well as in naturally occurring products. 1 Quinoline-containing drugs are widely used in the treatment of malaria, 2 HIV-1 replication inhibitors, 3 antimicrobial and anti-tuberculosis drugs 4 and antihelmintic properties. 5 Beside this quinolines have also occupied a unique position in the design and synthesis of novel biologically active compounds since they are often used as anti-inflammatory, antiasthmatic, antibacterial, antihypertensive, antitumor, 6 , 7 antiproliferative, 8 anticancer 9 and antiparasitic agents. 10
In addition, gallic acid and its related compounds are widely distributed in fruits & plants. 11 , 12 It has been reported to have anticarcinogenic, antioxidative, antimutagenic, antiallergic and anti-inflammatory activities. 13 Gallic acid has been a building block of choice for different pharmaceutical leads due to the presence of this moiety in several bioactive natural products. 14 Hence, numerous derivatisations have been done and are reported as anticancer, 15 HIV-1 Integrase 16 and HIV-1RT inhibitors, 17 antioxidants, 18 antimalarials agents, 19 etc.
Literature review also revealed that 1,3,4-Oxadiazoles are an important class of heterocyclic compounds with a wide range of pharmaceutical and biological activities. Their synthesis and transformations have been of interest from a long time. They have revealed anti-inflammatory, anticonvulsant and analgesic activities. 20 , 21 They have also shown antibacterial, 22 antifungal 23 and muscle relaxant 24 properties.
Prompted by the above-mentioned biological properties of quinoline and oxadiazole it was contemplated to synthesize a novel series of quinoline incorporated oxadiazole and its derivatives ( 1 , 2 & 3 , 1 ). Antibacterial activities of the newly synthesized compounds are discussed in this paper.
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Characterization data for compounds7(a-j)
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Characterization data for compounds 7(a-j)
RESULT AND DISCUSSION
- Chemistry
In continuation on our research work to synthesize potent bioactive heterocycles. 25 Herein, we report the synthesis of a series of oxadiazole derivatives synthesized via 3-(bromomethyl)-2-chloroquinolines or 2-( p -tolyloxy)-(bromomethyl) quinolines 4a-j which were synthesized by reduction of substituted 2-chloroquinoline-3-carbaldehyde or 2-( p -tolyloxy)quinoline-3-carbaldehyde 2a-j in presence of catalytic amount of NaBH 4 and methanol giving (2-chloroquinolin-3yl)methanol or (2-( p -tolyloxy)quinolin- 3yl)methanol 3a-j , which was further brominated with PBr 3 in presence of DCM under ice cold condition to afford 4a-j ( 1 ).
On the other hand, 3,4,5-triethoxybenzohydrazide 5 was further reacted with carbon disulfide in presence of potassium hydroxide under reflux condition to afford 5-(3,4,5-triethoxyphenyl)-1,3,4-oxadiazole-2-thiol 6 ( 2 ). Finally 5-(3,4,5-triethoxyphenyl)-1,3,4-oxadiazole-2-thiol 6 was alkylated with substituted 3-(bromomethyl)-2-chloroquinoline or 2-( p -tolyloxy)-(bromomethyl)quinoline 4a-j to afford 3-((5-(3,4,5-triethoxyphenyl)-1,3,4-oxadiazol-2-ylthio)methyl)-2-chloroquinoline or 3-((5-(3,4,5-triethoxyphenyl)-1,3,4-oxadiazol-2-ylthio)methyl)-2-( p -tolyloxy) quinoline 7a-j in presence of K 2 CO 3 and DMF at ambient temperature stirring for 15-20 min.
- Spectral analysis
The structures of the synthesized compounds were confirmed by spectral analysis (IR, 1 H NMR and Mass). The IR spectrum of compound 2a showed a peak at 1722 cm -1 due to C=O stretch. In 1 H NMR spectrum it exhibited two singlets, one at δ 2.41 due to CH 3 proton, second at δ 10.65 due to CHO proton. Mass spectrum was consisted with assigned structure.
As estimated the 1 H NMR spectrum of compound 3a showed singlet at δ 3.71 due to the presence of OH proton, while another singlet at δ 10.65 due to CHO proton get disappeared due to reduction of aldehyde. Similarly, in the 1 H NMR spectrum of compound 4a the broad peak of OH disappeared due to bromination.
1 H NMR spectrum of compound 6 showed a highly deshielded singlet at δ 11.23 attributed to SH proton, which get disappeared in compound 7a due to the alkylation of compound 6 with compound 4a-j . The IR and mass spectral data of compound 4 , 6 and 7a were consisted with the assigned structure.
The antibacterial screening results revealed that most of the newly synthesized compounds exhibited promising antibacterial activities. Generally, the test compounds showed better activity against the Gram Negative bacteria ( 2 ). Out of the compounds tested, compounds 7d , 7i and 7j exhibited excellent antibacterial activity against the Gram Negative bacteria i.e. Salmonella typhi and Pseudomonus aeroginosa and moderate activity against gram positive bacteria i.e. Bacillus subtilis and Staphylococcus aureus as compared with the broad spectrum antibiotic Streptomycine and Ampicilline.
Minimal inhibitory concentrations (MIC μg/mL) of tested compounds7(a-j)
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Minimal inhibitory concentrations (MIC μg/mL) of tested compounds 7(a-j)
- Conclusion
In conclusion, we have synthesized some novel 1,3,4-oxadiazol derivatives incorporated with quinoline moiety and evaluate their in-vitro antibacterial activity. Out of the compounds tested, compounds 7d , 7i and 7j exhibited excellent antibacterial activity against the Gram Negative bacteria i.e. Salmonella typhi and Pseudomonas aeroginosa and moderate activity against gram positive bacteria i.e. Bacillus subtilis and Staphylococcus as compared with commercially available drug.
EXPERIMENTAL SECTION
All chemicals and solvents were purchased from Merck, Spectrochem and S.D. Fine-chem. (India). Melting points were determined in open capillaries on Kumar’s melting point apparatus (India) and are uncorrected. IR spectra were recorded on JASCO FT-IR 4100, Japan using KBr discs. 1 H-NMR spectra were recorded on a Varian as 400 MHz spectrometer in CDCl 3 /DMSO- d 6, chemical shifts (δ) are in ppm relative to TMS, and coupling constants ( J ) are expressed in hertz (Hz). Mass spectra were recorded on Single-Quadrupole Mass Detector 3100, Waters. Elemental analyses were performed on CHNS analyzer Flash 1112, Thermo Finnigan. The progress of the reactions was monitored by TLC on Merck silica plates. Multiplicities are shown as the abbreviations: s (singlet), brs (broad singlet), d (doublet), t (triplet), m (multiplet). Solvents were commercially available materials of reagent grade.
Synthesis of 2-chloroquinoline-3-carbaldehyde (1a): The compound 1a was prepared as per procedure reported in the literature. 2 m.p: 148 ℃ IR-(KBr): 2739, 1710, 1605 and 755 (cm -1 ); 1 H NMR-(DMSO- d 6): δ 10.36 (s, 1H), 8.57 (s, 1H), 8.06 (d, 1H), 7.92 (m, 2H), 7.75 (dd, 1H); MS: m/z 192.3 (M+); Anal. Calcd for C 10 H 6 ClNO: C, 62.68; H, 3.16; N, 7.31; O, 8.35; found C, 62.74; H, 3.21; N, 7.20; O, 8.31.
Synthesis of 2-(p-tolyloxy)quinoline-3-carbaldehyde (2a): To a mixture of p -cresol (0.031 mmol, 3.38 gms) and K 2 CO 3 (0.068 mmol, 9.51 gms) in DMF, compound 1a (0.031 mmol, 6 gms) was added and the reaction mixture was stirred at 85-90 ℃ for 5 hrs. The completion of the reaction was monitored by TLC. After completion, water (50 ml) was poured in the reaction mixture & the solid thus obtained was filtered off & recrystallized from ethyl acetate. 2a m.p: 129℃, IR-(KBr): 2945, 2750, 1720, 1600 and 1225 (cm -1 ); 1 H NMR-(DMSO- d 6): δ 10.65 (s, 1H), 8.71 (s, 1H), 7.88 (d, 1H), 7.74 (d, 1H), 7.71 (m, 1H), 7.45 (m, 1H), 7.39 (d, 2H), 7.19 (d, 2H), 2.41 (s, 3H); MS: m/z 264.1 (M+); Anal. Calcd for C 17 H 13 NO 2 : C, 77.55; H, 4.98; N, 5.32; O, 12.15; found C, 77.63; H, 5.01; N, 5.21; O, 12.09.
Synthesis of (2-chloroquinolin-3-yl)methanol (3a): To the mixture of compound 2a in methanol, sodium borohydride was added portion wise, & the mixture was stirred at room temperature for 15-20 min. The completion of the reaction was monitored by TLC & reaction mass was concentrated under vacuum. The reaction mass was poured into ice cold water and the solid thus obtained was filtered & recrystallized from ethyl acetate.
Compounds 3a: m.p: 134 ℃ IR-(KBr): 2945, 2750, 1722, 1600 and 1125 (cm -1 ); 1 H NMR-(DMSO- d 6 ): δ 8.21 (s, 1H), 8.18 (dd, 1H), 7.91 (m, 1H), 7.82 (dd, 1H), 7.51 (dd, 1H), 4.96 (s, 2H), 3.75 (s, 1H); MS: m/z 193.9 (M+); Anal. Calcd for C 10 H 8 ClNO: C, 62.03; H, 4.16; N, 7.23; O, 8.26; found C, 62.21; H, 4.19; N, 7.18; O, 8.21.
Compounds 3f: IR-(KBr): 3427, 2920, 1720, 1520 and 1225 (cm -1 ); 1 H NMR-(DMSO- d6 ): δ 8.05 (s, 1H), 7.62 (d, 1H), 7.48 (d, 2H), 7.41 (d, 1H), 7.25 (dd, 2H), 7.23 (d, 2H), 4.74 (s, 2H), 4.01 (s, 1H), 3.51 (s, 1H), 2.46 (s, 3H); MS: m/z 266.1 (M+); Anal. Calcd for C 17 H 15 NO 2 : C, 76.96; H, 5.70; N, 5.28; O, 12.06; found C, 77.13; H, 5.75; N, 5.17; O, 12.01.
Synthesis of 3-(bromomethyl)-2-chloroquinoline (4a): Compound 3a was dissolved in DCM at 5 ℃, after 10-15 min. of stirring calculated amount of PBr 3 was added drop wise and the mixture was stirred at room temperature for 1 hr. The completion of the reaction was monitored by TLC. The DCM was removed under vacuum and the reaction mass was poured on ice cold water & the solution was neutralized by adding saturated solution of NaHCO 3 . The solid thus obtained was filtered and recrystallized from ethyl acetate.
Compound 4a: m.p: 179 ℃ IR-(KBr): 1670, 1630, 750 and 710 (cm -1 ); 1 H NMR-(CDCl 3 ): δ 8.25 (s, 1H), 8.16 (dd, 1H), 7.68 (dd, 1H), 7.40 (m, 1H), 7.52 (m, 1H), 4.47 (s, 2H); MS: m/z 257.4 (M+); Anal. Calcd for C 10 H 7 BrClN: C, 46.82; H, 2.75; N, 5.46; found C, 46.93; H, 2.81; N, 5.34.
Compound 4i: IR-(KBr): 2930, 1624, 1560, 1150 and 735 (cm -1 ); 1 H NMR-(CDCl 3 ): δ 8.05 (s, 1H), 7.61 (dd, 1H), 7.48 (s, 1H), 7.40 (dd, 1H), 7.23 (m, 2H), 7.16 (d, 2H), 4.74 (s, 2H), 2.46 (s, 3H), 2.38 (s, 3H); MS: m/z 343.1 (M+); Anal. Calcd for C 18 H 16 BrNO: C, 63.17; H, 4.71; N, 4.09; O, 4.68; found C, 63.31; H, 4.83; N, 3.96; O, 4.52.
Synthesis of 5-(3,4,5-triethoxyphenyl)-1,3,4-oxadiazole-2-thiol (6): To the compound 5 (0.01 mole) in ethanol 50 ml was added a solution of KOH (0.015 mole) in ethanol 20 ml, followed by the addition of CS 2 (20 ml). The reaction mixture was heated under reflux for 8hrs. Then it was concentrated, acidified with dilute hydrochloric acid & the resulting solid was collected, washed with water & recrystallized with ethyl acetate to afford the desired product. m.p: 203 ℃, IR-(KBr): 2870, 2580 and 1570 (cm -1 ); 1 H NMR-(CDCl3): δ 11.23 (s, 1H), 7.13 (s, 2H), 4.02 (m, 6H), 1.54 (t, 9H); MS: m/z 310.9 (M+); Anal. Calcd for C 14 H 18 N 2 O 4 S: C, 54.18; H, 5.85; N, 9.03; O, 20.62; found C, 54.31; H, 5.92; N, 8.91; O, 20.51.
Synthesis of 3-((5-(3,4,5-triethoxyphenyl)-1,3,4-oxadiazol-2-ylthio)methyl)-2-(p-tolyloxy) quinoline) (7a): To the mixture of 6 (1 eq.) and K 2 CO 3 (1.2 eq.) in DMF, 4a (1.2 eq.) was added and the reaction mixture was stirred at room temperature for 15-20 min. The completion of the reaction was monitored by TLC. After completion ice cold water was added to the reaction mass and the solid thus obtained was filtered off and recrystallized from ethyl acetate.
Compound 7a: IR-(KBr): 2890, 1680, 1180 and 1090 (cm -1 ); 1 H NMR-(CDCl 3 ): δ 8.27 (dd, 1H), 8.13 (s, 1H), 7.92 (dd,1H), 7.86 (dd, 1H), 7.61 (m, 1H), 6.69 (s, 2H), 4.35 (s, 2H), 3.95 (m, 6H), 1.54 (t, 9H); MS: m/z 486.8 (M+); Anal. Calcd for C 24 H 24 ClN 3 O 4 S: C, 59.31; H, 4.98; N, 8.65; S, 6.60; found C, 59.52; H, 5.03; N, 8.38; S, 6.54.
Compound 7c: IR-(KBr): 2922, 1660, 1310 and 1210 (cm -1 ); 1 H NMR-(CDCl 3 ): δ 8.21 (d, 1H), 8.10 (s, 1H), 7.87 (d, 1H), 7.45 (s, 1H), 6.71 (s, 2H), 4.32 (s, 2H) 4.01 (m, 6H), 3.95 (s, 3H), 1.57 (t, 9H); MS: m/z 515.9 (M+); Anal. Calcd for C 25 H 26 ClN 3 O 5 S: C, 58.19; H, 5.08; N, 8.14; S, 6.21; found C, 58.34; H, 5.16; N, 8.01; S, 6.13.
Compound 7f: IR-(KBr): 2910, 1670, 1315 and 1275 (cm -1 ); 1 H NMR-(CDCl 3 ): δ 8.02 (dd, 1H), 7.92 (s, 1H), 7.81 (dd, 2H), 7.56 (m, 1H), 7.32 (d, 2H), 7.21 (d, 2H), 7.05 (s, 2H), 4.45 (s, 2H), 3.94 (m, 6H), 2.81 (s, 3H), 1.55 (t, 9H); MS: m/z 558.2 (M+); Anal. Calcd for C 31 H 31 N 3 O 5 S: C, 66.77; H, 5.60; N, 7.54; S, 5.75; found C, 66.86; H, 5.67; N, 7.43; S, 5.69.
Compound 7i: IR-(KBr): 2950, 1645, 1290 and 1150 (cm -1 ); 1 H NMR-(CDCl 3 ): δ 8.05 (d, 1H), 7.89 (s, 1H), 7.68 (d, 2H), 7.27 (d, 2H), 7.02 (d, 2H), 6.63 (s, 2H), 4.37 (s, 2H), 3.94 (m, 6H), 2.86 (s, 3H), 1.57 (t, 9H); MS: m/z 572.1 (M+); Anal. Calcd for C 32 H 33 N 3 O 5 S: C, 67.23; H, 5.82; N, 7.35; S, 5.61; found C, 67.41; H, 5.91; N, 7.25; S, 5.53.
- Antibacterial activity
The MICs of the chemical compounds assays were carried out as described by well-diffusion method. 26 Two Gram-positive (Staphylococcus aureus ATCC 25923 and Bacillus subtilis ATCC 6633) and two Gram-negative (Salmonella typhimurium (ATCC No, 23564) and Pseudomonas aeruginosa ATCC 27853) bacteria were used as quality control strains. Streptomycin and Ampicilline were used as standard antibacterial agent. The bacterial liquid cultures were prepared in fusion broth for their activity tests. The compounds were dissolved in DMSO at concentration of 1 mg/ml. Antibacterial activity of DMSO against the test organisms was investigated, and was found to be nil. Molten nutrient agar (15 cm 3 ), kept at 45 ℃, was then poured into the Petri dishes and allowed to solidify. Ten millimeter diameter holes were then punched carefully using a sterile cork borer and completely filled with the test solutions. The plates were incubated for 24 h at 37 ℃. After 24 h, the inhibition zone that appeared around the holes in each plate was measured. Antibacterial activity was determined by examining the minimal inhibitory concentration (MICs, μg/mL) of the tested compounds, which are recorded in ( 2 ).
Acknowledgements
The authors are thankful to to The Head, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, for his valuable support and laboratory facilities. And RSJ is thankful to University Grants Commission, New Delhi, for awarding the fellowship.
References
Eicher T. , Hauptmann S. 2003 The chemistry of Heterocycles 2nd ed. Wiley-VCH Weinheim 316 -
Bray P. G. , Ward S. A. , O’Neill P. M. 2005 Curr. Top. Microbiol 3 295 -
Zouhiri F. , Danet M. , Be´rnard C. , Normand-Bayle M. , Mouscadet J. F. , Leh H. , Thomas C. M. , Mbemba G. , d’Angelo J. , Desmaele D. 2005 Tetrahedron Lett. 46 2201 -    DOI : 10.1016/j.tetlet.2005.02.033
Narender P. , Srinivas U. , Ravinder M. , Rao A. B. , Ramesh C. , Harakishore K. , Gangadasu B. , Murthy U. S. N. , Rao J. V. 2006 Bioorg. Med. Chem. 14 4600 -    DOI : 10.1016/j.bmc.2006.02.020
Rossiter S. , Péron J. M. , Whitfield P. J. , Jones K. 2005 Bioorg. Med. Chem. Lett. 15 4806 -    DOI : 10.1016/j.bmcl.2005.07.044
Maguire M. P. , Sheets K. R. , McVety K. , Spada A. P. , Zilberstein A. 1994 J. Med. Chem. 37 2129 -    DOI : 10.1021/jm00040a003
Gabriele B. , Mancuso R. , Salerno G. , Ruffolo G. , Plastina P. 2007 J. Org. Chem. 72 6873 -    DOI : 10.1021/jo071094z
Croisy-Delcey M. , Coroisy A. , Carrez D. , Huel C. , Chiaroni A. , Ducrot P. , Bisagni E. , Jin L. , Leclercq G. 2000 Bioorg. Med. Chem. 8 (ii) 2629 -    DOI : 10.1016/S0968-0896(00)00194-2
Dlugosz A. , Dus D. 1996 Farmaco 51 367 -
Abadi A. H. , Brun R. 2003 Arzneimforsch Drug Res 53 655 -
Niehaus J. U. , Gross G. G. 1997 Phytochemistry 45 1555 -    DOI : 10.1016/S0031-9422(97)00261-6
Kashiwada Y. , Nonaka G. , Nishioka I. , Chang J. J. , Lee K. H. 1992 J. Nat. Prod. 55 (8) 1033 -    DOI : 10.1021/np50086a002
Yasuda T. , Inaba A. , Ohmori M. , Endo T. , Kubo S. , Ohsawa K. 2000 J. Nat. Prod. 63 (10) 1444 -    DOI : 10.1021/np0000421
Cho S. J. , Tropsha A. , Suffness M. , Cheng Y. C. , Lee K. H. 1996 J. Med. Chem. 39 1383 -    DOI : 10.1021/jm9503052
Pettit G. R. , Lippert J. W. , Herald D. L. , Hamel E. , Pettit R. K. 2000 J. Nat. Prod. 63 (7) 969 -    DOI : 10.1021/np0000623
Carlson H. A. , Masukawa K. M. , Rubins K. , Bushman F. D. , Jorgensen W. L. , Lins R. D. , Briggs J. M. , McCammon J. A. 2000 J. Med. Chem. 43 (11) 2100 -    DOI : 10.1021/jm990322h
Tillekeratne L. M. V. , Sherette A. , Grossman P. , Hupe L. , Hupe D. , Hudson R. A. 2001 Bioorg. Med. Chem. Lett. 11 2763 -    DOI : 10.1016/S0960-894X(01)00577-7
Masuda T. , Matsumura H. , Oyama Y. , Takeda Y. , Jitoe A. , Kida A. , Hidaka K. 1998 J. Nat. Prod. 61 609 -    DOI : 10.1021/np970555g
Griffith R. , Chanphen R. , Leach S. P. , Keller P. A. 2002 Bioorg. Med. Chem. Lett. 12 (4) 539 -    DOI : 10.1016/S0960-894X(01)00811-3
Palaska E. , Sahin G. , Kelicen P. , Tugbadurlu N. , Altinok G. 2002 IL. Farmaco 57 101 -    DOI : 10.1016/S0014-827X(01)01176-4
Dogan H. , Daran A. , Rollas S. , Sener G. , Uysal M. K. , Gulen D. 2002 Bioorg. Med. Chem. 10 2893 -    DOI : 10.1016/S0968-0896(02)00143-8
Angelini I. , Angelini L. , Sparaco F. Brit. Patent 1,161,801, 1966/1969 , , 112937.
Brown P. , Best D. J. , Broom N. J. P. , Cassels R. , Bhanlon P. J. , Mitchell T. J. , Osborne N. F. , Wilson J. M. 1997 J. Med. Chem. 40 2563 -    DOI : 10.1021/jm960738k
Singh H. , Yadava L. D. S. , Chaudharg J. P. 1985 Acta. Chem. Hung. 11 118 -
Mandhane P. G. , Joshi R. S. , Nagargoje D. R. , Gill C. H. 2011 Phos. Sul. Sili. 186 (1) 149 - 158    DOI : 10.1080/10426507.2010.492363
Christine H. F. , Michael H. C. 1986 Antimicrob. Agents Chemother. 29 38 -