THE SYNTHESIS OF QUINAZOLON-1,3,4-OXADIAZOLE ANALOGUES AND STUDIES OF THEIR ANTIMICROBIAL AND ANTIOXIDANT ACTIVITY

THE SYNTHESIS OF QUINAZOLON-1,3,4-OXADIAZOLE ANALOGUES AND STUDIES OF THEIR ANTIMICROBIAL AND ANTIOXIDANT ACTIVITY

V. S. Kulkarni ^{* 1}, D. S. Chavan ¹ and G. P. Senthil Kumar ²

Department of Pharmaceutical Chemistry ¹, Indira Institute of Pharmacy, Sadavali (Devrukh), Ratnagiri - 415804, Maharashtra, India.

Bharathi College of Pharmacy ², Bharathinagara - 571422, Karnataka, India.

ABSTRACT: A series of conjugation of two heterocycles 1, 3, 4-oxadiazole and quinazolone were synthesized and screened for antimicrobial as well as antioxidant activity. Compound4-(4-oxo-2-phenyl-quinazoline-3(4H)-yl)-benzohydrazide 3 on cyclization with different aromatic acids in the presence of phosphoryl chloride (POCl₃) give different 1, 3, 4-oxadiazole derivatives. Similarly, compound 3 on reaction with carbon disulphide (CS₂) gives substituted oxadiazole thione which on reaction with different halides in the presence of dimethylformamide (DMF) give oxadiazole thiones analogs 6a-6c. Structural assignments of these compounds have been made by elemental analysis, UV, IR, ¹H NMR, and mass spectral data. Synthesized analogs were screened for in-vitro growth inhibition activity against different strains of bacteria and fungi and compared with standard drugs ciprofloxacin and fluconazole. Compounds 4e and 4f have good activity against bacteria. All compounds have moderate activity against fungi. These compounds were screened for antioxidant activity by using radical scavenging DPPH assay by using ascorbic acid as a standard drug. Compounds 4e, 6a to 6c have good antioxidant activity.

1,3,4-oxadiazole, Quinazolone, Antimicrobial, Antioxidant

INTRODUCTION: Antimicrobial agents are the most significant weapons to fight against bacterial and fungal infection. But many commonly used antibiotics are becoming less effective against infections due to the emergence of microbial resistance. In case of infection, there is an occurrence of increasing fungal infection from day to day. These fungal infections continue to grow rapidly. Present antifungal agents do not satisfy the medical need, as well as some drugs like polyene antibiotics,  are most toxic.

So, antimicrobial agents are of interest for most researchers. Heterocyclic compounds like 1, 3, 4-oxadiazole and quinazoline nucleus possess a diversity of biological activity. 1, 3, 4-oxadiazole chemistry with a broad spectrum of medicinal value has got much significance in recent years.

The activities associated with oxadiazole nucleus are antimicrobial ^1-6, hepatoprotectives ⁷, anti-mitotic ⁸, anticancer ^{1, 9, 10}, anti-inflammatory ¹¹, anticonvulsant ^{12, 13}, analgesic ^{11, 14}, anti TB ^{15, 16}, diuretic ¹⁷, antihypertensive ¹⁸ and antidepressant ¹⁹. Quinazoline nucleus also possesses a variety of activities such as antimicrobial ^{20, 21}, anticancer ^{20, 22}, antiviral ²², antidiabetes ²³, anticonvulsant ²⁴, antituberculosis ²⁵, anti-inflammatory ²⁶ analgesics ^26, etc. Free radicals are generated in the human body which can damage proteins, lipids, DNA, and leads to carcinogenesis, toxicity and inflammation.

Antioxidant agents prevent oxidation of a biological substrate, lower oxidative stress, decrease DNA mutation and thus block loss of cell function. Given these findings, our interest increased to undertake the synthesis and biological evolution of substituted quinazoline-1,3,4-oxadiazole analogs hoping that these compounds might show certain antimicrobial and antioxidant activity.

The composition of all compounds was obtained by elemental analysis. IR, NMR and mass spectroscopy deduced structures. The entire newly synthesized compounds were screened for antimicrobial activity by cup plate method and antioxidant by diphenylpicrylhydrazide (DPPH) radical scavenging method.

MATERIAL AND METHODS: Melting points of compounds were determined using micro-controller based Melting point apparatus, CL 725/726 and were found uncorrected. The purity of compounds was checked by thin layer chromatography using silica gel G, F₂₅₄ precoated silica gel G (3 × 8 cm) as a stationary phase and various combinations of solvents as a mobile phase. These plates procured from E-merc, Darmstd. Theses resolved spots were visualized as brown colored spots by using iodine chamber. The IR spectra of synthesized compounds were recorded using KBr pellets in range of 4000-400 cm^-1 on Fourier transformer IR spectrometer (Shimadzu 8700). 1H NMR (400 MHz) spectra were recorded in chloroform-d and DMSO-d6 in Amx-400 MHz liquid state NMR spectrometer BRUKER. Chemical shifts (δ) are reported in parts per million with standard internal Tetramethylsilane (TMS) as well as mass spectra (JEOL GC mate Mass Spectrometer).

The chemicals and reagents used in the present project were of AR grade and LR grade, purchased from S.D. Fine Chem. Ltd., Merck, LOBA Chemicals, Mumbai, India. Required dry pyridine and dry ethanol are prepared as per procedure are given in the book, Practical of Organic Chemistry by Vogel. Pyridine is distilled using KOH, and dry ethanol is prepared using CaO_2.

The Experimental Work Comprises of:

1. Preparation of 2-phenyl-4-benzoxazinone ²⁶ (1).
2. Preparation of 4-(4-oxo-2-phenylquinazolin-3(4H)-yl) benzoyl chloride ²⁷ (2).
3. Preparation of 4-(4-oxo-2-phenylquinazolin-3(4H)-yl) benzohydrazide ^{26, 28}(3).
4. Cyclization to 1,3,4-oxadiazole ²⁹(4a-4i).
5. The synthesis of oxadiazole thiones ^{26, 30} (5).
6. The synthesis of oxadiazole thione derivatives ³¹ (6).

Step 1: General procedure for the synthesis of 2-substituted-4-benzoxazinone (1): To a cold solution of anthranilic acid 0.1 moles (13.71 g) in pyridine 60 ml, p-amino benzoyl chloride 0.1 mole (15.55 g) was added. The mixture was stirred for half an hrs. Then poured into 250 ml of ice-cold water, then to it 2-3 drops of concentrated HCl was added. The resulting solid was recrystallized by ethanol. Yield: 95% M.P.: 120 ºC.

Step 2: General procedure for the synthesis of 4-(4-oxo-2-subs quinazoline-3(4H)-yl) benzoyl chloride (2): A mixture of compound (1) 0.05 mole (11.9 g) and p-amino benzoyl chloride 0.05 mole (7.78 g) in dry pyridine 50 ml was refluxed for 8 h. The resultant solution was cooled and poured into ice-cold water 100 ml containing 5 ml concentration HCl. Solid which was separated, washed with water and recrystallized by ethanol. Yield: 70.53%. M.P.: 168 ºC.

Step 3: General procedure for the synthesis of 4-(4-oxo-2-subs quinazoline-3(4H)-yl) benzohydra-zide (3): To compound 2 (3.76 g, 0.01 mol) in 1,4-dioxane added to hydrazine hydrate (0.011 mol, 1.6 g) in 10 ml of 0.1N NaOH. Reflux it for 6 h. The reaction mixture was poured to 1N HCl. Solid thus separated by filtration and recrystallized by ethanol. Yield: 68.00%. M.P.: 150-153 ºC.

Step 4: General procedure for cyclization to 1,3,4-oxadiazole (4a-4f): The compound 3 (0.01 mole) was dissolved in POCl₃ (5 ml) and different aromatic acids (0.01 mole) were added. The reaction mixture after refluxing for 4-8 h was cooled to room temperature and poured onto crushed ice. On neutralization of content with neutral 20% sodium bicarbonate solution, solid separated was filtered, washed with water and dried. Ethanol and DMF recrystallized the crude product.

Step 5: General procedure for the synthesis of oxadiazole thiones (5): To compound 3 (0.01 mole) in CS₂ (0.01 mole) was refluxed for 5 h. The resultant mixture was added to ice-cold water. Then solid separated was filtered and recrystallize by ethanol. Yield: 87.57 %. M.P.: 197 ºC.

Step 6: General procedure for the synthesis of oxadiazole thiones derivatives (6a-c): To the solution of oxadiazole thiones (5) 0.01 mole in DMF (5 ml), alkyl/aryl halides 0.01 mole is added. Then the excess of DMF was evaporated to get solid substance and recrystallized by ethanol.

• General procedure for the synthesis of p-amino benzoyl chloride: Firstly p-amino benzoyl chloride was synthesized. 1 g of PABA was dissolved into methanol to it 2.5 ml of thionyl chloride (excess) added dropwise and shook for 20 min and kept at reflux for 2 hrs. Then solid thus separated was filtered and recrystallize by ethanol.

SCHEME 1: THE SYNTHESIS OF 1,3,4 OXADIAZOLE DERIVATIVES

TABLE 1: 3- {[2- (SUBSTITUTED-PHENYL)- 1,3,4-OXADIAZOL-2-YL] PHENYL}-3H-2-PHENYL-QUINAZOL-4-ONE (4A-4F)

TABLE 2: 2- PHENYL- 3- [4- (5-SUBSTITUTED-THIOXO-4,5-DIHYDRO-1,3,4-OXADIAZOL-2-YL) PHENYL] QUINAZOLONE (6A-6C)

4a: 3- [4- (5-phenyl-1,3,4-oxadiazol-2yl) phenyl] 3H- 2- phenyl- quinazolin- 4(3H)- one:   Brown coloured solid, soluble in DMSO, Molecular formula: C₂₈H₁₈N₄O₂. Molecular weight: 442, yield: 76.72%, M.P.: 255 ºC, solvent system TLC: Chloroform: Ethyl Acetate (1:0.1), R_f value: 0.90, IR (KBr, cm^-1): 2466.75 (C-H Str. for aromatic), 1712.28 (C=O Str. for quinazoline), 1609.05 (C=C Str. for aromatic), 1503.66 (C-N Str.), ¹H-NMR (DMSO-d₆): 7.2 -8.3 m(18-H, Ar-H), Mass spectra: 442.56 [M⁺], 419.35, 372.89, 320.00, 276.55, 209.99, 155.44, 75.33. Elemental analysis % found (% calculated): C 76.13 (76.01); H 4.23 (4.07); N 12.89 (12.66).

4b: 3-{4-[5-(4-chlorophenyl)- 1, 3, 4-oxadiazol-2-yl] phenyl} 2- phenyl- quinazolin- 4(3H)- one: Brown coloured solid, soluble in DMSO, Molecular formula: C₂₈H₁₇N₄O₂Cl. Molecular weight: 477.5, yield: 76%, M.P.: 182 ºC solvent system TLC: Ethyl Acetate, R_f value: 0.93, IR (KBr,cm^-1): 2561.75 (C-H Str. for aromatic), 1714.48 (C=O Str. for quinazoline), 1608.48 (C=N Str. for aromatic), 1509.65 (C=C Str.), 759.99 (C-Cl Str.), 1295.68 (Str. for C-O), ¹H-NMR (DMSO-d₆): 7.1 -8.2 m (17-H, Ar-H), Mass spectra: 477.91 [M+1], 429.24, 371.78, 325.01, 276.59, 234.65, 209.48, 193.09, 91.33. Elemental analysis % found (% calculated): C 76-98 (76.92); H 4.51 (4.27); N 12.01 (11.96).

4c: 3- {4-[5-(2-chlorophenyl)- 1, 3, 4-oxadiazol-2-yl] phenyl} 2- phenyl-quinazolin- 4(3H)- one: Yellow solid compound, soluble in DMSO, Molecular formula: C₂₈H₁₇N₄O₂Cl. Molecular weight: 477.5, yield: 69%, M.P.: 113 ºC solvent system TLC: Ethyl Acetate, R_f value: 0.89, IR (KBr, cm^-1): 2569.75 (C-H Str. for aromatic), 1724.48 (C=O Str. for quinazoline), 1608.48 (C=N Str. for aromatic), 1509.65 (C=C Str.), 759.99 (C-Cl Str.), 1295.68 (Str. for C-O), ¹H-NMR (DMSO-d₆): 7.3-8.1 m (17-H, Ar-H), Mass spectra: 477.59 [M+1], 428.24, 370.78, 328.11, 276.59, 237.85, 209.48, 194.19, 91.41. Elemental analysis % found (% calculated): C 76-98 (76.92); H 4.51 (4.27); N 12.01 (11.96).

4d: (2E)- 3- (4- {5-[4-(4-oxo-2-phenylquinazolin-3(4H)-2yl) phenyl]-1,3,4-oxadiazol-2-yl} phenyl) prop-2-enoic acid: Light brown solid compound, soluble in chloroform, 1,4-dioxane, Molecular formula: C₃₁H₂₀N₄O₄, Molecular weight: 512, yield: 75%, M.P.: 155 ºC solvent system TLC: Ethyl Acetate R_f value: 0.73, IR (KBr, cm^-1): 2579.15 (C-H Str. for aromatic), 1731.28 (C=O Str. for quinazoline), 1609.63 (C=N Str. for aromatic), 1519.10 (C=C Str.), 2759.99 (C-OH Str.), 1295.68 (Str. for C-O), 1630.27 (aliphatic C=C), 1720.09 (C=O for acidic), ¹H-NMR (DMSO-d₆): 8.9, 7.0 (d, J=1.8, J=1.5, 2H, CH=CH-), 7.25-8.00 (m, 18-H, Ar-H), Mass spectra:512.44 [M+1], 415.44, 372.18, 324.89, 271.10, 276.85, 209.19, 193.63, 59.19. Elemental analysis, % found (% calculated): C 70.59 (70.51); H 3.71(3.56); N 11.53 (11.25).

4e: 3- {[2-(p-aminophenyl)- 1,3,4-oxadiazol-2-yl] phenyl}- 3H- 2-phenyl- quinazol- 4- one: Yellow solid, soluble in DMSO, Molecular formula: C₂₈H₁₉N₅O₂, Molecular weight: 457, yield: 89%, M.P.: 195 ºC solvent system TLC: Benzene: Chloroform (9:1), R_f value: 0.48, IR (KBr, cm^-1): 3408.24 (Str. primary NH₂), 3133.59 (C-H Str. for aromatic), 1711.48 (C=O Str. for quinazoline), 1608.48 (C=N Str. for aromatic), 1509.65 (C=C Str.), 1295.06 (Str. for C-O), ¹H-NMR (CDCl₃-d): 8.3 (m,17-H, Ar-H), 3.3 (t, 2H, Ar-NH₂)  Mass spectra: 457.22 [M⁺], 419.72, 372.78, 320.00, 276.55, 209.02, 193.09, 77.24. Elemental analysis % found (% calculated): C 73.76 (73.36); H 4.70 (4.36); N 15.58 (15.28).

4f: 3- {[2-(p-chloromethyl)- 1,3,4-oxadiazol-2-yl] phenyl}- 3H- 2- phenyl- quinazol- 4- one: Yellow solid, soluble in DMSO, Molecular formula: C₂₃H₁₅N₄O₂Cl, Molecular weight: 414.5, yield: 70%, M.P.: 203 ºC solvent system TLC: Chloroform: Ethyl Acetate (9:1), R_f value: 0.85, IR (KBr,cm^-1): 3128.10 (C-H Str. for aromatic), 1701.40 (C=O Str. for quinazoline), 1613.29 (C=N Str. for aromatic), 1517.20 (C=C Str.), 1215.10 (Str. for C-O), 725.39 (str. for C-Cl), ¹H-NMR (DMSO₆-d₆): 7.3-8.2 (m,13-H, Ar-H), 3.8 (d,J=3.8, 2H, -CH₂-Cl) Mass spectra: 415.22 [M⁺], 365.19, 323.93, 271.45, 210.15, 190.23, 49.24. Elemental analysis % found (% calculated): C 66.89 (66.58); H 3.87 (3.51); N 14.17 (14.07).

5: 2- phenyl- 3- [4- (5-thioxo-5-dihydro- 1, 3, 4-oxadiazol-2-yl) phenyl] quinazolin- 4- one: Mol. Wt.: 398, Colorless solid, Soluble in DMSO, DMF, Mol. Formula: C₂₂H₁₄N₄O₂S, Yield: 87.57%, M.P.: 197 ºC, TLC: Ethyl Acetate: Glacial acetic acid (1:0.1). R_f value: 0.81, IR (KBr, cm^-1): 3750.45 (Str. for Sec amine), 3135.52 (C-H str. for aromatic), 1708.48 (C=O Str. for quinazoline), 1622.84 (C=C Str. for aromatic), 1509.84 (C=N Str.), 1135.78 (Str. for C-S), ¹H-NMR (DMSO₆-d₆): 7.1-8.5 (m,18-H, Ar-H), 4.3(d,1H,SH). Mass Spectra: 398.56 [M⁺], 371.30, 325.01, 276.59, 234.65, 209.48, 91.06, 43.31. Elemental analysis % found (% calculated): C 66.76 (66.33); H 3.59 (3.51); N 14.11 (14.07).

6a: 3- {4-[5-(phenylsuphanyl)1, 3, 4-oxadiazol-2-yl]phenyl}2-phenyl-quinazolin-4-(3H)-one: Light brown solid, Soluble in  DMSO, Chloroform, Molecular Formula: C₂₈H₁₈N₄O₂S, Molecular Weight: 474, Yield: 92.5%, M.P.: 155 ºC, TLC: Chloroform: Glacial acetic acid (1: 0.1), R_f value: 0.83, IR (KBr,cm^-1): 2574.21 (C-H Str. for aromatic), 1718.48 (C=O Str. for quinazoline), 1652.14 (C=C Str. for aromatic), 1509.11 (C=N Str.), 1141.68 (C-S Str.) 7.4-8.3 (m,18-H, Ar-H), Elemental analysis % found (% calculated): C 70.94 (70.88); H 3.97 (3.79); N 11.89 (11.81).

6b: 3-(4-{5-[(4-chlorophenyl)sulphanyl]- 1, 3, 4-oxadiazol-2yl} phenyl) 2- phenyl-quinazolin-4(3H)-one: Colorless solid, soluble in DMSO, DMF, Molecular Formula: C₂₈H₁₇N₄O₂SCl, Molecular Weight: 508.5, Yield: 78.5%, M.P.: 159-161 ºC, TLC: Chloroform: Glacial acetic acid (1: 0.1), R_f value: 0.71, IR (KBr,cm^-1): 2574.21 (C-H Str. for aromatic), 1710.18 (C=O Str. for quinazoline), 1630.10 (C=C Str. for aromatic), 1501.78 (C=N Str.), 1151.28 (C-S Str.), 751.09 (C-Cl Str.), 7.1-8.3 (m,17-H, Ar-H IR (KBr,cm^-1): C 67.99 (67.96); H 3.61 (3.47); N 10.99 (10.81).

6c: 3-(4-{5-[(2-chlorophenyl)-sulphanyl]-1, 3, 4-oxadiazol-2yl} phenyl) 2- phenyl- quinazolin-4(3H)-one: Colorless solid, Soluble in DMSO, DMF, Molecular Formula: C₂₈H₁₇N₄O₂SCl, Molecular Weight: 508.5, Yield: 69.79%, M.P.: 149-152 ºC, TLC: Chloroform: Glacial acetic acid (1: 0.1), R_f value: 0.63, IR (KBr, cm^-1): 2571.20 (C-H Str. for aromatic), 1717.48 (C=O Str. for quinazoline), 1643.14 (C=C Str. for aromatic), 1503.45 (C=N Str.), 1051.56 (C-S Str.), 750.13 (C-Cl Str.), 7.2-8.1 (m,17-H, Ar-H), Elemental analysis % found (% calculated): C 68.01 (67.96); H 3.76 (3.47); N 0.89 (10.81).

Antimicrobial Activity: The newly synthesized compounds were tested in-vitro for their antibacterial activity against four microorganisms viz.  Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumonia at 200 and 300 µg/ml concentration using the ciprofloxacin reference standard and antifungal activity against two microorganisms Candida albicans and Asparagus niger at 100 and 200 µg/ml concentration using the Fluconazole as the reference standard. Zone of inhibition at different concentration was determined by the cup-plate method.

Stock solutions (10 mg/ml) of synthesized compounds were prepared by dissolving each compound in dimethylsulfoxide.  Using a standard procedure the subculture, base layer medium, agar medium, and peptone water were performed. Discs are having a measurement of 8 mm in diameter were punched from Whatman no. 1 filter paper. The test compounds were prepared in different concentrations using dimethylsulfoxide (DMSO). Solutions of the test compounds were prepared. Volumes of 0.05 ml and 0.1 ml of each compound were used for testing. The cups each of 9 mm diameter were made by scooping out medium with a sterilized cork borer in a Petri dish that was streaked with the organisms.

The solutions of each test compound (0.05 ml and 0.1 ml) were added separately in the cups and Petri dishes were subjected to incubate for 24 h at 37 °C. Standard drug ciprofloxacin was used at three concentrations namely 200 and 300 µg/ml for antibacterial activity. Parallel, to maintain the control group, 0.1 ml of DMSO was added, and this group did not exhibit any sign of inhibition. Zones of inhibition produced by each compound were measured (in mm) and the results of antibacterial studies are presented in Table 3.

The cup plate method using potato-dextrose agar medium was used for screening of antifungal activity against fungal strains, including Asparagus niger and Candida albicans using Fluconazole as standard drug. The method stated in Indian Pharmacopoeia prepared the nutrient broth medium and other subculture. DMSO was used as the control, and no sign of zone of inhibition was observed. Zone of inhibition produced by each compound was measured in mm. The findings of antibacterial and antifungal evaluations are presented in Table 4.

Antioxidant Activity:

DPPH Method: The free radical scavenging activity of these compounds was measured using DPPH ²⁹. The test samples (10-100 µl) were mixed with 1.0 ml of DPPH solution and filled with methanol to make 4.0 ml. The absorbance of resulting solutions was measured at 517 nm using visible the spectrometer. Ascorbic acid is used as a reference compound. Lower absorbance of solutions indicates higher scavenging activity. Radical scavenging activity is expressed in the IC₅₀ (µg/ml) Table 5 after calculating inhibition percentage of free radical by samples using the following formula:

% inhibition = {(A control − A sample) / (A control)} × 100

A control = absorbance of DPPH alone

A sample = absorbance of DPPH along with different samples.

TABLE 3: ANTIBACTERIAL ACTIVITY FOR SUBSTITUTED OXADIAZOLE DERIVATIVES

TABLE 4: ANTIFUNGAL ACTIVITY FOR SUBSTITUTED OXADIAZOLE DERIVATIVES

TABLE 5: IC₅₀ VALUES FOR EVALUATED ANTIOXIDANT ASSAYS OF DIFFERENT DERIVATIVES

RESULT AND DISCUSSION: Compounds of interest 4a-4f were obtained using 4-(4-oxo-2-phenylquinazolin-3(4H)-yl) benzohydrazide 3 as starting material in reaction with different aryl acids in POCl₃ (reaction time varied from 5 to 8 hrs.) in four steps. Compound 5 was obtained using 4- (4-oxo- 2- phenylquinazolin- 3 (4H)- yl) benzo-hydrazide 3 as starting material in reaction with carbon disulphide for 5 h. The synthesis of oxadiazole thiones from the benzoxazinone is four step procedures.

Compounds 6a to 6c were obtained from compound 5 in reaction with different aryl-Cl groups in the presence of DMF.

Analytical and spectral data (IR, ¹H-NMR, MASS spectra) of all synthesized compounds were in full agreement with the proposed structure. IR of compounds was shown exact results. For compound 4e, it shows a peak at 3408 cm^-1 for the free amino group. For compound 5, it shows a peak at 1121 cm^-1 for (=S). For the C-Cl group of compound 4c, it shows a peak at 900 cm^-1. It also shows a peak for quinazoline moiety, i.e. 1711 (C=O), 1608.48 (C=C), 1509.65 (C=N). It is also showing peaks as oxadiazole molecule gives.

Mass spectra of compounds were taken. It gives molecular ion a peak nearly same i.e. 442.56 [M+] for 4a, 477.91[M+] for 4b, 457.22 [M+] for 4e and for 5, it shows 398.56 [M+]. The fragmentation pattern of the molecule indicates that it contains a quinazoline group as it shows a peak at 209.

Compound 5, 6a, 6b, 6c showed good activity; 4a, 4d, 4f, 4e showed moderate activity; compound 4b and 4c showed less activity against S. aureus. Compounds 4a, 4d, 6b showed good activity; 4b, 4c, 4e, 6a, 6c showed moderate activity; while compound 5 showed less activity towards P. aureogenosa. Compound 4d and 4c showed good activity, but compounds 4b, 6c, 6a, 6b showed less activity towards E. coli. Compounds 4d, 4e, 4f showed good activity while 4c, 6a, 6c showed less activity towards K. pneumonia.

In the case of antifungal activity, compound 4e showed good activity towards both strains while compounds 6b and (6c showed less activity. Compound 4a has moderate activity.

In the case of antioxidant activity compounds 6a, 6b and 6c showed better activity as compared to other derivatives.

CONCLUSION: In summary, novel conjugates between 1,3,4-oxadiazole and quinazolone were synthesized by a conventional method. Their antimicrobial and antioxidant activities were studied. The compound did not demonstrate any significant activity. Several derivatives showed slight or moderate activities. Transformation of hydrazides into 1,3,4-oxadiazole in side chain caused the dramatic loss of antiradical activity.

ACKNOWLEDGEMENT: The authors are thankful to Indira Institute of Pharmacy, Sadavali and Bharathi College of Pharmacy, Bharathinagara for providing chemicals and facilities to conduct research work.

CONFLICT OF INTEREST: Nil

REFERENCES:

1. Sudesh K and Gururaja R: Facile the synthesis of some novel derivatives of 1,3,4-oxadiazole associated with quinolone moiety as cytotoxic and antibacterial agents. Organic Chemistry Current Research 2017; 6(2): 1-5.
2. Triloknadh S, Rao CV, Nagaraju B, Balaji H and Balaji M: Design and the synthesis of novel 1,3,4-oxadiazole and 1,2,4-triazolo[3,4-b]1,3,4-thiadiazole derivatives and their antimicrobial studies. European Journal of Biomedical and Pharmaceutical Sciences 2018; 5(7): 575-587.
3. Serkan L, Betul K, Begum N and Zafer A. The synthesis of oxadiazole-thiadiazole hybrids and their anticandidal activity. Molecules 2017; 22(11): 1-13.
4. Desai N, Dadiya A, Rajpara K and Rupoala Y: The synthesis and antimicrobial screening of 1,3,4-oxadiazole and clubbed thiophene derivatives. Journal of Saudi Chemical Society 2014; 18: 255-261.
5. Leyla Y, Emre F, Sinem T and Seref D: Antimicrobial activity evaluation of 1,3,4-oxadiazole derivatives. Acta Pharmaceutica Scientia 2017; 55(2): 45-54.
6. Rehman A, Siddiya A, Abbasi M, Rasnal S, Siddiqui S, Ahmed I and Afzal S: The synthesis of some new 5-substituted-2-((6-chloro-3,4-methylenedioxy-phenyl) methyl thio) 1,3,4- oxadiazole derivatives as suitable antibacterial agents. Bulletin of Faculty of Pharmacy, Cairo University 2015; 53(1): 37-43.
7. Bhaumik A and Eswaraiah C: Synthesis, characterization and evaluation of hepatocytes regenerator potentiality of some novel oxadiazole derivatives followed by molecular docking against nf-kb. International Journal of Pharmaceutical Science and Research 2017; 8(9): 3734-3750.
8. Rai KL and Linganna N: The synthesis of 2-amino-1,3,4-oxadiazole derivatives and screening for antimiotic IL Farmaco 2000; 55: 389-392.
9. Ahsan M: Rationale design, the synthesis and in-vitro anticancer activity of new 2,5-disubstituted-1,3,4-oxadiazole analogs. Chemistry Select 2016; 1(15): 4713-4720.
10. Selveraj K, Kalanthai K and Sadhasivam G: The synthesis, characterization and biological evaluation of novel 2,5-substituted-1,3,4-oxadiazole derivatives. Saudi Pharma-ceutical Journal 2017; 25: 337-345.
11. Rajwant K and Parminder K: The synthesis and pharmacological activities of 1,3,4-oxadiazole derivatives: a review. European Journal of Biomedical and Pharmaceutical Sciences 2018; 5(6): 1-14.
12. Tabatabai SA, Lashkari SB, Zarrindast M, Gholibeikian M and Shafie A: Design, the synthesis and anticonvulsant activity of 2-(2-Phenoxy) phenyl- 1,3,4-oxadiazole Derivatives. Iranian Journal of Pharmaceutical Research 2013; 12(S): 105-111.
13. Kumar A, Parveen BR and Vaishali: The synthesis, anticonvulsant and antimicrobial evaluation of some new 3-[5-(substituted-phenyl)-[1,3,4]oxadiazole-2-yl]-1-napthalen-2-yl-propan-1-one. International Journal of Research In Pharmacy and Chemistry 2017; 7(1): 85-91
14. Dewangan D, Nakhate KT, Tripathi DK, Kashyap P and Dhongde H: The synthesis, characterization and screening for analgesic and anti-inflammatory activities of 2, 5-disubstituted 1, 3, 4-oxadiazole derivatives. Medicinal Chemistry 2015; 14(2): 138-45.
15. Das R, G Shilakari Asthana, Suri KA, Mehta DK and Asthana A: The synthesis and assessment of the antitubercular and antimicrobial activity of some novel triazole and tetrazolo-fused 1, 3, 4-oxadiazole molecules containing pyrazine moiety. Journal of Sciences and Pharmaceutical Research 2015; 7(10): 806-811
16. Sajja Y, Vanguru S, Reddy H and Nagarapu VL: Design, the synthesis, and in-vitro antituberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,3,4-oxadiazole derivatives. Chemical Biology and Drug design 2017; 1-12.
17. Sudha BS, Shashikanth S, Khanum SA and Sriharsha SN: The synthesis and pharmacological screening of 5-(4-aroyl)-aryloxy-methyl-2-thio-1,3,4-oxadiazole. Indian Journal of Pharmaceutical Sciences 2003; 65(5): 465-470.
18. Naik RN, Patil SC and Satyanarayan SB: The synthesis and antioxidant, antibacterial, antihypertensive activities of 8-hydroxyquinoline appended with oxadiazole and triazole rings. Indo American Journal of Pharmaceutical Research 2014; 4(9): 3763-3772.
19. Tantray MA, Khan I, Hamid H, Alam MS, Dhulap A and Kalam A: The synthesis of benzimidazole-linked-1,3,4-oxadiazole carboxamides as GSK-3β Inhibitors with in-vivo antidepressant activity. Bioorganic Chemistry 2018; 77: 393-401.
20. Jafari E, Khajouei M, Hassanzadeh F and Hakimelahi G: Quinazolinone and quinazoline derivatives: Recent structures with potent antimicrobial and cytotoxic activities. Research in Pharmaceutical Sciences 2016; 11(1): 1-14.
21. Farag M and Jaiash DA: Design, the synthesis and biological evaluation of new quinazoline derivatives as antimicrobial and anti-fungal agents. Journal of Chemical and Pharmaceutical Research 2015; 712: 346-353.
22. Luo H, Hu D, Wu J, He M, Jin L, Yang S and Song B: Rapid the synthesis and antiviral activity of (quinazoline-4-ylamino) methyl-phosphonates through microwave irradiation. International Journal of Molecular Sciences 2012; 13: 6730-6746.
23. Mittapelli V and Padala SR: The synthesis and anti-diabetic activity of some 3- methylquinazolin-4(3H)-one derivatives. International Journal of ChemTech Research 2014; 6(14): 5647-5662.
24. Abuelizz HA, Dib RE, Marzouk M, Anouar EH, Maklad YN Attia H and Al-Salahi R: Molecular docking and anticonvulsant activity of newly synthesized quinazoline derivatives. Molecules 2017; 22(7): pii
25. Jignesh P, Ravala T, Akhajaa N, Dhaval M, JasparaaKruti N, Myangara N and Patel H: The synthesis and in-vitro antibacterial activity of new oxoethylthio-1,3,4-oxadiazole derivatives. Journal of Saudi Chemical Society 2014; 18(2): 101-106
26. Dhansay D, Vinay S, Kartik T, Tripathi K, Kashyap P and Dhongade H: The synthesis, characterization, and screening for analgesic and anti-inflammatory activities of new 1,3,4-oxadiazole derivatives linked to quinazoline-4-one Med Chem Res2016; 25(10): 2143-2154.
27. El-Mekabaty A: Chemistry of 4H-3,1-Benzoxazine-4-ones. International Journal of Modern Organic Chemistry 2013; 2(2): 81-121.
28. Kotaiah Y, Harikrishna N, Nagaraju K and Rao CV: The synthesis and antioxidant activity of 1, 3, 4-oxadiazole tagged thieno [2,3-d] pyrimidine derivatives. European Journal of Medicinal Chemistry 2012; 58: 340-5.
29. Ningaiah S, Bhadraiah UK, Doddaramappa SD, Keshavamurthy S and Javarasetty C: Novel pyrazole integrated 1,3,4-oxadiazoles-the synthesis, characterization and antimicrobial evaluation. Bioorganic & Medicinal Chemistry Letters 2014; 24(1): 245-8.
30. Baijika P, Marathakam A, Midhula C and Saheed KS: The synthesis and biological activities of 1,3,4-oxadiazole derivatives: a review of the literature. International Journal of Advance Research 2018; 6(1): 1114-1122.
31. Xu WM, Han FF, He M, Hu DY, He J, Yang S and Song BA: Inhibition of tobacco bacterial wilt with sulfone derivatives containing 1, 3, 4-oxadiazole moiety. Journal of Agricultural and Food Chemistry 2012; 60(4): 1036-41.
    

    ---

    How to cite this article:

    Kulkarni VS, Chavan DS and Kumar GPS: The synthesis of quinazolon-1,3,4-oxadiazole analogues and studies of their antimicrobial and antioxidant activity. Int J Pharm Sci & Res 2019; 10(3): 1477-84. doi: 10.13040/IJPSR.0975-8232.10(3).1477-84.

    ---

    All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---