Synthesis of Some Novel 1,3,4-Oxadiazole Derivatives and their Potential Biological Activity

Abstract

A new Mannich base of quinazolin-4-one derivatives possessing 1,3,4-oxadiazole ring have been synthesized by reacting 3-[4-(5-thioxo-4,5-dihydro-[1,3,4]oxadiazole-2-yl)-phenyl]-2-phenyl-3H-quinazolin-4-one (4) with different secondary amines and formaldehyde using N,N-dimethylformamide as the solvent to afford 3-[4-(4-substituted amino-4-ylmethyl-5-thioxo-4,5-dihydro-[1,3,4]oxadiazole-2-yl)-phenyl]-2-phenyl-3H-quinazolin-4-ones (5a-e). The structures of the newly synthesized compounds have been established by analytical and spectral methods. The compounds have also been screened for their biological activity. [PUBLICATION ABSTRACT]

Headnote

ABSTRACT:

A new Mannich base of quinazolin-4-one derivatives possessing 1,3,4-oxadiazole ring have been synthesized by reacting 3-[4-(5-thioxo-4,5-dihydro-[1,3,4]oxadiazole-2-yl)-phenyl]-2-phenyl-3H-quinazolin-4-one (4) with different secondary amines and formaldehyde using N,N-dimethylformamide as the solvent to afford 3-[4-(4-substituted amino4-ylmethyl-5-thioxo-4,5-dihydro-[1,3,4]oxadiazole-2-yl)-phenyl]-2-phenyl-3H-quinazolin-4-ones (5a-e). The structures of the newly synthesized compounds have been established by analytical and spectral methods. The compounds have also been screened for their biological activity.

KEYWORDS: Synthesis, Oxadiazole, Antibacterial and antifungal activity

INTRODUCTION:

Quinazolinone derivatives possess potent biological activity such as analgesic, antibacterial, antifungal and antitumor. Several patent claims have been made on quinazolines as intermediates for potential antimalerials. 2,3-Disubstituted4-(3H)-quinazoline intermediates have been found to be active against Plasmodium galliaceum and showed antiinflammatory action on experimental edemas in animals1-5.

On the other hand 1,3,4-oxadiazoles are known to have broad spectrum of biological activities6-10. In the light of these interesting biological active evidences, we thought it worthwhile to synthesize some new quinazolinone derivatives containing oxadiazole moiety with the objective of screening them for their biological activity.

RESULTS AND DISCUSSION:

4-Amino benzoic acid was esterified using ethanol and catalytic amount of sulphuric acid to give 4-amino benzoic acid ethyl ester11. 2-Amino benzoic acid was allow to react with benzoyl chloride in pyridine to give 2-phenyl-3,1benzoxazin-4-one12(1) which on heating with 4-amino benzoic acid ethyl ester in pyridine yielded 4-(4-oxo-2phenyl-4H-quinazolin-3-yl)-benzoic acid ethyl ester (2).

The compound (2) was then condensed with hydrazine hydrate in ethanol to afford 4-(4-oxo-2-phenyl-4Hquinazolin-3-yl) benzoic acid hydrazide (3) in good yields which on treatment with ethanolic potassium hydroxide and carbon disulphide furnished 3-[4-(5-thioxo-4,5-dihydro[1,3,4]oxadiazole-2-yl)-phenyl]-2-phenyl-3H-quinazolin-4one (4). The reaction of the compound (4) with different secondary amines and formaldehyde using N,Ndimethylformamide afforded Mannich base 3-[4-(4substituted amine-4-ylmethyl-5-thioxo-4,5-dihydro-[1,3,4] oxadiazole-2-yl)-phenyl]-2-phenyl-3H-quinazolin-4ones (5a-d) [SCHEME 1].

BIOLOGICAL ACTIVITY:

Antibacterial Activity:

All the newly synthesized quinazolin-4-ones (5a-d) were screened in vitro for their antibacterial activity against Staphylococcus aureus, Escherichia coli, Bacillus subtilis and Salmonella typhosa by the ditch-plate technique13 using concentrations of 2 and 5 mg/ml. Nutrient agar was employed as culture media and DMF was used as solvent control for antibacterial activity.

The compound (5a) and (5b) showed moderate activity against Escherichia coli and Staphylococcus aureus. The compound (5d) exhibited high activity against Escherichia coli and moderate activity against Staphylococcus aureus. The compounds (5c) possessed weak activity against both Escherichia coli and Staphylococcus aureus.

Antifungal acitivity:

The compounds (5a-d) synthesized were screened for their antifungal activity against Aspergillus niger, Candida albicans, Cryptococcus neoformans and Thielaviopsis paradoxa by paper-disc diffusion method14 at concentrations of 2 and 5 mg/ml. Nutrient agar was employed as culture media and DMF was used as solvent control for antifungal activity.

The compounds (5a), (5c) and (5d) showed marked activity against Aspergillus niger, Candida albicans and Cryptococcus neoformans. The compound (5b) showed moderate activity against Aspergillus niger, Cryptococcus neoformans and weak activity against Candida albicans and Thielaviopsis paradoxa.

MATERIAL AND METHODS:

Melting points were taken in open capillaries and are uncorrected. IR spectra (KBr in cm-1) were recorded on Jasco 410 plus FTIR spectrophotometer. 1H NMR spectra were recorded on a Varian 300 MHz NMR spectrophotometer using DMSO-d6 as solvent and TMS as internal standard (chemical shifts in δ ppm). Nitrogen content was determined by Perkin Elmer C, H, N analyser. The purity of the compounds was monitored by thin layer chromatography.

4-(4-Oxo-2-phenyl-4H-quinazolin-3-yl)-benzoic acid ethyl ester (2)

A mixture of 2-phenyl-3,1-benzoxazin-4-one (4.46 g, 0.02 mole) and 4-amino-benzoic acid ethyl ester 1 (3.63 g, 0.022 mole) in 100 cm3 pyridine was refluxed for about 10 hours. The reaction mixture was then allowed to cool to room temperature and left overnight. The crystalline solid obtained was filtered, washed with ethanol and recrystallized from pyridine, yield 80%, m.p. 160°C; IR (KBr) 1735 (C=O ester), 1670 (CO.N), 1616 (C=N), 1577, 1544, 1508, 1448 (C=C, aromatic), 1182 (C-O-C). 1H NMR (DMSO-d6) δ 1.22 (t, 3H, CH3), 4.11 (q, 2H, CH2), 6.9-8.4 (m, 13H, ArH). MS (m/z): 370 [M+1], 371, Anal. Calcd. for C23H18N2O3: C, 74.58, H, 4.90, N, 7.56, Found : C, 74.60, H, 4.93, N, 7.58 %.

4-(4-Oxo-2-phenyl-4H-quinazolin-3-yl)-benzoic acid hydrazide (3)

Compound 2 (3.70 g, 0.01 mole) and 2 cm3 (0.04 mole) of 99% hydrazine hydrate in 250 cm3 ethanol was refluxed for about 10 hours. The reaction mixture was then allowed to cool to room temperature. The separated white coloured crystalline solid was filtered, washed with ethanol and recrystallized from N,N-dimethylformamide, yield 82%, m.p. 195°C ; IR (KBr) 3315, 3272 (NH.NH2), 1674 (CO.N), 1613 (C=N), 1585, 1508, 1450 (C=C, aromatic). 1H NMR (DMSO-d6) δ 4.3 (s, 2H, NH2), 6.9-8.6 (m, 13H, ArH), 9.3 (s, 1H, NH). MS (m/z): 356 [M+1], 357, Anal. Calcd. for C21H16N4O2: C, 70.78, H, 4.53, N, 15.72, Found: C, 70.80, H, 4.55, N, 15.74 %.

3-[4-(5-thioxo-4,5-dihydro-[1,3,4]oxadiazole-2-yl)-phenyl]2-phenyl-3H-quinazolin-4-one(4)

Compound 3 (3.56 g, 0.01 mole) was added to a solution of potassium hydroxide (0.56 g, 0.01 mole) in absolute ethanol (40 cm3). Carbon disulphide (0.9 cm3, 0.015 mole) was added dropwise with continuous stirring over a period of half an hour. The reaction mixture was then refluxed until the evolution of hydrogen sulphide gas almost ceased. The solvent was removed under reduced pressure and the residue obtained was dissolved in water and acidified with dilute hydrochloric acid. The solid obtained was filtered, washed with water and recrystallized from ethanol, yield 70%, m.p. 192°C ; IR (KBr) 3290 (N-H str.), 1672 (CO.N str.), 1614 (C=N str.), 1576, 1562, 1508, 1488 (C=C, aromatic), 1175 (C-O-C, str.) 1110 (C=S str.); 1H NMR (DMSO-d6) δ 6.98.6 (m, 13H, ArH), 13.2 (s, 1H, NH). MS (m/z): 398 [M+1], 399, Anal. Calcd. for C22H14N4O2S: C, 66.32, H, 3.54 N, 14.06, Found : C, 66.33 H, 3.56, N, 14.08 %].

3-[4-(4-substituted amine-4-ylmethyl-5-thioxo-4,5dihydro-[1,3,4]oxadiazole-2-yl)-phenyl]-2-phenyl-3Hquinazolin-4-ones (5a-d)

3-[4-(5-thioxo-4,5-dihydro-[1,3,4]oxadiazole-2-yl)phenyl]-2-phenyl-3H-quinazolin-4-one 4 (2.39 g, 0.006 mole) was dissolved in 10 cm3 N,Ndimethylformamide. A slight excess of formaldehyde (0.5 cm3, 0.0067 mole) and appropriate secondary amines (0.006 mole) were added with vigorous stirring. The reaction mixture was stirred at room temp (30°C) for about 24 hours. The crystalline product obtained was filtered, washed with water and recystallized from DMF : ethanol (1:3).

3-[4-(4-Morpholin-4-ylmethyl-5-thioxo-4,5-dihydro[1,3,4]oxadiazole-2-yl)-phenyl]-2-phenyl-3H-quinazolin4-one(5a)

White-coloured solid, yield 64%, m.p. 182°C; IR (KBr) 1677 (CO.N str.), 1612 (C=N str.), 1579, 1558, 1508, 1448 (C=C, aromatic), 1180 (C-O-C), 1114 (C=S str.); 1H NMR (DMSO-d6) δ 2.6 (t, 4H, CH2.N.CH2), 3.65 (t, 4H, CH2.O.CH2), 4.7 (s, 2H, N.CH2.N ), 7.0-8.6 (m, 13H, ArH). MS (m/z): 497 [M+1], 498, Anal. Calcd. for C27H23N5O3S: C, 65.18, H, 4.66, N, 14.07. Found: C, 65.20, H, 4.68, N, 14.10 %.

3-[4-(4-Piperidin-1-ylmethyl-5-thioxo-4,5-dihydro[1,3,4]oxadiazole-2-yl)-phenyl]-2-Phenyl-3H-quinazolin4-one (5b)

Off white-coloured solid, yield 62%, m.p. 188°C; IR (KBr) 1670 (CO.N str.), 1611 (C=N str.), 1575, 1559, 1508, 1445 (C=C, aromatic), 1176 (C-O-C str.) 1115 (C=S str.); 1H NMR (DMSO-d6) δ 1.25-1.45 (m, 6H, CH2-CH2-CH2), 2.6 (t, 4H, CH2.N.CH2), 4.65 (s, 2H, N.CH2.N), 7.05-8.50 (m, 13H, ArH). MS (m/z): 495 [M+1], 496, Anal. Calcd. for C28H25N5O2S: C, 67.86, H, 5.08, N, 14.13. Found: C, 67.88%, H, 5.10%, N, 14.12%.

3-[4-(4-Diethylaminomethyl-5-thioxo-4,5-dihydro[1,3,4]oxadiazole-2-yl)-phenyl]-2-phenyl-3H-quinazolin4-one(5c)

yield 71%, m.p. 158°C; IR (KBr) 1679 (CO.N str.), 1613 (C=N str.), 1575, 1555, 1508, 1448 (C=C, aromatic), 1116 (C=S str.); 1H NMR (DMSO-d6) δ 1.05 (t, 6H, -CH3), 2.65 (q, 4H, -CH2), 4.60 (s, 2H, N.CH2.N), 7.0-8.55 (m, 13H, ArH); MS (m/z): 483 [M+1], 484, Anal. Calcd. for C27H25N5O2S: C, 67.06, H, 5.21, N, 14.48. Found: C, 67.08, H, 5.25, N, 14.50 %.

3-[4-(4-Dimethylaminomethyl-5-thioxo-4,5-dihydro[1,3,4]oxadiazole-2-yl)-phenyl]-2-phenyl-3H-quinazolin4-one(5d)

yield 66%, m.p. 146°C; IR (KBr) 1677 (CO.N str.), 1612 (C=N str.), 1579, 1558, 1508, 1448 (C=C, aromatic), 1114 (C=S str.); 1H NMR (DMSO-d6) δ 2.25 (s, 6H, CH3.N.CH3), 4.55 (s, 2H, N.CH2.N ), 7.0-8.55 (m, 13H, ArH). MS (m/z): 455 [M+1], 456, Anal. Calcd. for C25H21N5O2S: C, 65.92, H, 4.65, N, 15.37. Found: C, 65.95, H, 4.65, N, 15.40 %.

ACKNOWLEDGEMENT:

The authors are thankful to The Institute of Science, Mumbai for 1H NMR spectra and Dr. (Mrs.) Vivien Amonkar, Head, Department of Microbiology, St. Xavier's College, Mumbai for providing biological activity.

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Received on 30.12.2012 Modified on 14.01.2013

Accepted on 19.01.2013 © AJRC All right reserved

Asian J. Research Chem. 6(2): February 2013; Page 97-100

References

REFERENCES:

1. J. C. Sheehan and G. D. Daves, J. Org. Chem., 29; 1964: 3599.

2. H. Heringer, Angew Chem., 76; 1964: 437.

3. M. S. Amine, A. M. F. Eissa, A. F. Shaaban, A. B. Sawy and R. El-sayed, Indian J. Heterocylic Chem., 7; 1998: 169.

4. W. L. F. Armarego, Adv. Heterocyclic Chem., 7; 1998: 1

5. Ch. Ravi Shankar, and V. Malla Reddy, J. Indian Chemical Soc., 60; 1983: 63.

6. P. F. Xu, H. Z. Hui, Z. Y. Zhang and R. L. Zheng, J. Chin. Chem. Soc., 51; 2004: 315.

7. V. J. Ram and A. J. Vlietinck, Heterocycl. Chem., 25; 1988: 253.

8. D. H. Boschelli, and C. D. Wright, J. Med. Chem., 36; 1993: 1802.

9. S. Bahadur and K. K. Pandey, J. Indian Chemical Soc., 57; 1980: 447.

10. G. Sahin, E. Palaska, M. Ekizoglu and M. Ozalp, IL Farmaco, 57; 2002: 539.

11. S. S. Tiwari and V. K. Pandey, J. Indian Chemical Soc., 52; 1975: 736.

12. Y. D. Kulkarni and S, H. Abdi, J. Indian Chemical Soc., 60; 1983: 504.

13. C. H. Collins and P. M. Lyne "Microbiological Methods" 3rd ed., Butterworths, London, 1970; pp. 424.

14. H. W. Seeley and P. J. Van Denmark, "Microbes in Action", W.H. Freeman and Co. USA, 1972.