Synthesis of 1, 3, 4-Oxadiazole of NSAIDs and their Biological Properties

 

Shankaraiah Malthum¹, Venkanna Banothu², Jaya Shree Anireddy^1*

¹Centre for Chemical Sciences and Technology, IST, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad 500085, Telangana State, India

²Center for Biotechnology, IST, JNTUH, Kukatpally, Hyderabad-500085, India

*CorrespondingAuthorE-mail:shankar.malthum@gmail.com

An efficient and inexpensive approach to the synthesis of 2-substituted 1, 3, 4- oxadiazoles from arylhydrazides and orthoester is reported using catalytic PTSA. The optimized reaction is performed using catalytic PTSA in EtOH and is complete within 1 h for non aromaticorthoesters and 2-30 h for aromatic orthoesters. The reaction permits both electron releasing and electron withdrawing groups on the arylhydrazide substrate. Most products formed in high yield and require only minimal purification. The reaction proceeded smoothly and cleanly under mild reaction conditions and no side reactions were observed. The structures of the products were confirmed by IR, 1H NMR, 13C NMR, mass spectroscopy, and elemental analysis. Compared with early reports, the current reactions proceed in shorter time and require less of the orthoester.

 

 

 

INTRODUCTION:

The oxadiazole structure is an important structural motif for the development of variety of potent drugs.¹ Compound which is having an oxadiazole moiety is known to possess a broad spectrum of biological activities including anticancer,² antifungal,^3,4 antibacterial,⁵ antimicrobial,^6,7 anti-inflammatory,^8,9 anticonvulsant,^10,11 analgesic,¹² inhibitors of HIV integrase¹³ and angiogenesis.¹⁴ The five-member heterocyclic compounds; particularly nitrogen and oxygen heterocycles oxadiazoles have been successfully tested against several diseases and therefore received special attention in pharmaceutical chemistry due to their diverse medicinal potential. Substituted 1,3,4-oxadiazole derivatives have demonstrated a broad spectrum of biological properties in both pharmaceutical and agrochemical fields.^15,16

 

Therefore, 1,3,4-oxadiazoles have attracted the researchers all over the world to work in this area of new drug development. Consequently, much attention has been paid to the synthesis of the 1,3,4-oxadiazole skeleton, through either the dehydrative cyclization of 1,2-diacylhydrazines¹⁷ or oxidative cyclization of N-acylhydrazones.¹⁸ Recently, some pioneering approaches for their synthesis have been explored.¹⁹ In 2014, Xu et.al reported a Pd catalyzed oxidative annulation for the synthesis of 2-amino-1,3,4-oxadiazoles through sequential isocyanide insertions into N−H and O−H bonds of hydrazides.^19a Subsequently, Lindhardt and Skrydstrup et al. demonstrated a three component approach to 1,3,4-oxadiazoles via a Pd-catalyzed carbonylative assembly of aryl bromides with hydrazides.^19b An improvement in the synthesis of oxadiazole derivatives is therefore highly desirable. In continuation of the synthesis of these compounds, we report an efficient preparation of 2-aryl derivatives of 1, 3, 4-oxadiazoles by using PTSA as a catalyst.

 

 

RESULTS AND DISCUSSION:

Chemistry:

The present work aims to investigate the synthesis of substituted 1, 3, 4-oxadiazoles from NSAIDs and to establish the structure of the products by chemical and spectral methods. The substituted acids of NSAIDs were used as a versatile starting material for the synthesis of 1, 3,4-oxadiazoles involving the formation of corresponding esters and hydrazides. Ethyl esters were synthesized from acids of NSAIDs by means of Fischer esterification which were further reacted with hydrazine hydrate in presence of ethanol to get corresponding hydrazide derivative. A mixture of the respective hydrazide and triethyl orthoformate was heated under reflux for 2.30 h and cooled. The crystals that separated after the mixture was cooled were filtered off, washed with ether, and dried. Mono substituted derivatives of oxadiazole can be obtained directly from acid hydrazides and triethoxymethane. 1, 3, 4-Oxadiazoles (4) were synthesized by refluxing hydrazides (3) in an excess of triethyl orthoformate (Scheme). The target compounds crystallized from the reaction mixture after cooling. In their ¹H NMR spectra the signals characteristic for the NHNH₂ fragment of the initial hydrazines are absent, while the proton signal of the CH=N fragment in the oxadiazole moiety is observed in lower field (around 8.36 ppm).

 

Scheme 1.

 

Fig 1. Variety of Nonsteroidal anti-inflammatory drugs

 

Antibacterial activity:

The antibacterial evaluation was carried out by using agar cup-plate method. The microorganisms Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus were used for the antibacterial evaluation. A palette of two Gram-negative organisms and one Gram-positive organism of clinical isolates such as Escherichia coli (Gram-ve), Klebsiellapneumoniae(Gram-ve)andStaphylococcus aureus (Gram+ve) respectivelywere obtained from microbiology laboratory of Global Hospital, Hyderabad. Nutrient agar media were prepared and then inoculated with fresh prepared culture media. The inoculated media were poured into Petri dish and allowed to set. Cups were made by punching the agar surface with a sterile cork bore (8mm). Different test compounds at a concentration of 1.0mg/50μL were added to wells (8mm in diameter) punched on agar surface. Plates were incubated overnight at 37°C and diameter of inhibition zone (DIZ) around each well was measured in mm. Experiments were performed in triplicates. Antibacterial drug ciprofloxacin was used at a concentration of 1mg/50μL as positive reference to determine sensitivity of microorganisms tested. DMSO was used as a negative control. The series of compounds were tested to ascertain theirin vitro antibacterial activities by agar-well diffusion method^{20, 21} and the results are summarised in Table 1, Fig. 2.

 

Table 1: Antibacterial activities of the target compounds 4a-4e

S. No.	Compd.	Diameter of Zone of Inhibition (mm) at Concentration of 1.0mg/50µl
		Escherichia coli (Gram-ve)	Klebsiellapneumonia (Gram-ve)	Staphylococcus aureus(Gram+ve)
1	4a	20	15	16
2	4b	15	10	NI
3	4c	14	12	10
4	4d	12	13	NI
5	4e	16	9	NI
6	CPF	32 ± 0.2	35 ± 0.4	36 ± 0.3

NI: No Inhibition, CPF: Ciprofloxacin, Data are means (n=3) ± Standard deviation of three replicates.

 

Fig 2. Antibacterial activity of target compounds (4a-4e).

CONCLUSION:

Some novel 1, 3, 4-oxadiazoles of NSAIDs(4a-e) have been synthesized and evaluated for antibacterial activities. The results of antibacterial studies of newly synthesized compounds reveal that the compounds possess significant antibacterial activities. Compound 4aexhibited outstanding antibacterial activity against Escherichia coli (20mm), Klebsiella pneumonia (15mm), and Staphylococcus aureus(16 mm) compared to ciprofloxacin [CPF] (32mm, 35mm and 36mm respectively). Compound 4c showed moderate activities against E. coli (14mm) and K. pneumonia (12mm). All the other newly synthesized compounds showed either moderate activity or no activity against bacterial strains. The most potent properties of this new class of antibacterial substances deserve further investigation in order to clarify the mode of action at molecular level, responsible for the activity observed. More extensive study is also warranted to determine biological parameters to have a deeper insight into structure-activity relationship and to optimize the effectiveness of this series of molecules.

 

Experimental section:

The ¹H and ¹³C NMR spectra were obtained on a Varian Gemini spectrometer at 300 MHz (¹H) in CDCl₃ and 100 MHz (¹³C) in DMSO-d₆ with TMS as internal standard. The FT IR spectra were recorded on a Bruker spectrophotometer and reported in wave number (ν cm^-1) by using potassium bromide pellets. The mass spectra were determined on JEOL Sx102 mass spectrometer coupled with liquid chromatography system in Electrospray Time of Flight (TOF) mode. Silica gel plates Alugram Sil G/UV-254 were used for monitoring the reaction and the purity of the products. Melting points were determined in open capillary tubes on a Cintex meltingpoint apparatus and were uncorrected. Elemental analysis was carried out on the C, H, N Analyzer CE 440.

 

N-(2-(1,3,4-oxadiazol-2-yl)phenyl)-2,3-dimethylaniline (4a).

Light yellow crystals. Yield: 89%; IR (KBr, cm^-1) ν max: 3316, 3138, 2930, 1615, 1584, 1507, 1453, 1323, 1276, 746 cm^-1. 1HNMR (CDCl₃, 250 MHz): δH 2.23 (s, 3H, CH3), 2.33 (s, 3H, CH3), 6.77-6.88 (m, 2H, Ar-H), 7.05-7.31 (m, 4H, Ar-H), 7.87 (d, 3 JHH= 7.8 Hz, 1H, Ar-H), 8.45 (s, 1H, oxadiazole), 9.11 (s, 1H, NH). ¹³C NMR (DMSO-d₆, 100 MHz): δ (ppm): 165.6, 155.7, 142.6, 139.4, 138.8, 130.9, 130.4, 129.5, 126.8, 121.7, 120.3, 22.5, 20. 3. LC-MS (ESI, m/z):265.30 [M]⁺, 266.20 [M+H]⁺. Anal. Cald. for C₁₆H₁₅N₃O: C, 72.43; H, 5.70; N, 15.83. Found: C, 71.87; H, 5.63; N, 15.91.

 

 

 

2-(1-(6-methoxynaphthalen-2-yl)ethyl)-1,3,4-oxadiazole (4b):

White solid; Yield 98.3%; IR (KBr, cm^-1)υ_max: 3073.50 (C-H), 3032.74 (Ar=CH), 3033.67, 2860.61 (C-H), 1529.63, 1487.22 (Ar C=C), 1530.44 (C=N), 958.94 (C-H). ¹H NMR (CDCl₃,300 MHz) δ (ppm): 1.87 (d, 3H, J = 6 Hz, CH₃), 3.92 (s, 3H, -OCH₃), 4.53 (q, 1H, -CH), 7.09 (d, 1H, J =7.6 Hz, Ar-H), 7.15 (d, 1H, J =7.8 Hz, Ar-H), 7.25 (s, 1H, Ar-H), 7.37 (s, 1H, Ar-H), 7.67-7.73 (m, 2H, Ar-H), 8.32 (s, 1H, -CH=N). ¹³C NMR (DMSO-d₆, 100 MHz): δ (ppm): 167.6, 157.4, 153.5, 148.6, 134.5, 129.2, 127.4, 58.2, 41.5, 21.8.LC-MS (ESI, m/z):254.20 [M]⁺, 256.10 [M+H]⁺. Anal. Cald. for C₁₅H₁₄N₂O₂: C, 70.85; H, 5.55; N, 11.02. Found: C, 69.09; H, 5.95; N, 12.56.

 

2-(2-(4,5-diphenyloxazol-2-yl)ethyl)-1,3,4-oxadiazole (4c):

White solid; Yield 97.4%; IR (KBr, cm^-1)υ_max: 3073.50 (Ar=CH), 3032.74 (C-H), 3033.67, 2860.61 (C-H), 1529.63, 1487.22 (Ar C=C), 1529.44 (C=N), 958.94 (C-H). ¹H NMR (CDCl₃,300 MHz) δ (ppm): 3.62 (t, 4H, J = 6.3 Hz, -CH₂-CH₂), 7.48-7.54 (m, 6H, Ar-H), 7.84 (d, 2H, Ar-H), 8.15 (d, 2H, Ar-H), 8.33 (s, 1H, -CH=N). ¹³C NMR (DMSO-d₆, 100 MHz): δ (ppm): 163.4, 155.6, 154.5, 146.2, 137.7, 130.3, 128.5, 128.2, 33.8, 33. 2.LC-MS (ESI, m/z):317.30 [M]⁺, 318.30 [M+H]⁺. Anal. Cald. for C₁₉H₁₅N₃O₂: C, 71.91; H, 4.76; N, 13.24. Found: C, 69.82; H, 4.63; N, 12.98.

 

2-((1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)methyl)-1,3,4-oxadiazole (4d):

White solid; Yield 96.6%; IR (KBr, cm^-1)υ_max: 3338.23 (N-H), 3073.50 (Ar=CH), 3032.74 (C-H), 3033.67, 2860.61 (C-H), 1529.63, 1487.22 (Ar C=C), 1529.44 (C=N), 958.94 (C-H). ¹H NMR (CDCl₃,300 MHz) δ (ppm): 0.84 (t, 3H, J = 6.3 Hz, CH₃), 1.38 (t, 3H, J = 6.38 Hz, CH₃), 2.01 (q, 1H, J = 6.55 Hz, -CH₂), 2.19 (q, 1H, J = 6.58 Hz, -CH₂), 2.81 (t, 1H, J = 6.38 Hz, CH₂), 2.88 (m, 3H, CH₂-CH₂), 3.49 (q, 2H, -CH₂), 3.63 (s, 2H, -CH₂), 4.14 (t, 2H, -CH₂), 7.03-7.09 (m, 2H, Ar-H), 7.38 (d, 1H, J =7.8 Hz, Ar-H), 8.40 (s, 1H, -CH=N), 9.15 (s, 1H, -NH). ¹³C NMR (DMSO-d₆, 100 MHz): δ (ppm): 168.4, 158.4, 148.7, 145.6, 134.7, 127.4, 125.4, 117.3, 110.6, 43.4, 35.6, 23.4, 12.3.LC-MS (ESI, m/z):309.4 [M]⁺, 310.4 [M+H]⁺. Anal. Cald. for C₁₄H₁₂FN₃O₃: C, 73.76; H, 7.49; N, 13.58. Found: C, 72.98; H, 7.45; N, 12.85.

 

N-(2-(1,3,4-oxadiazole-2-yl)phenyl)-3-chloro-2-methylaniline (4e):

Light yellow solid; Yield 97.8%; IR (KBr, cm^-1)υ_max: 3334.23 (N-H), 3033.78 (Ar=CH), 2927.67, 2860.61 (C-H), 1529.63, 1487.22 (Ar C=C), 1583.44 (C=N), 858.94 (C-H). ¹H NMR (CDCl₃,300 MHz) δ (ppm): 2.33 (t, 3H, J = 6.3 Hz, CH₃), 4.20 (bs, 1H, -NH), 6.82 (d, 1H, J =7.8 Hz, Ar-H), 6.89 (d, 1H, J =7.5 Hz, Ar-H), 7.15 (d, 1H, J =7.8 Hz, Ar-H), 7.25-7.31 (m, 3H, Ar-H), 7.89 (d, 1H, J =7.6 Hz, Ar-H), 8.46 (s, 1H, -CH=N). ¹³C NMR (DMSO-d₆, 100 MHz): δ (ppm): 119.0, 119.3, 125.2, 125.9, 129.2, 134.2, 135.3, 139.7, 142.3, 154.6, 166.7. LC-MS (ESI, m/z): 285.1 [M]⁺, 286.0 [M+H]⁺. Anal. Cald. for C₁₅H₁₂ClN₃O: C, 63.05; H, 4.23; N, 14.71. Found: C, 62.98; H, 4.25; N, 14.66.

 

ACKNOWLEDGEMENT:

One of the authors (MSR) is thankful to University Grants Commission (UGC), New Delhi, Govt. of India for financial assistance in the form of a senior research fellowship. Authors MSR, JSA are thankful to TEQIP-II for aiding improved laboratory facilities.

 

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Received on 01.12.2017         Modified on 13.01.2018

Accepted on 20.01.2018         © AJRC All right reserved