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Synthesis, Cytotoxicity and Antimicrobial Evaluation of Some New 2-Aryl,5-Substituted 1,3,4-Oxadiazoles and 1,3,4-Thiadiazoles

  • Baby Ramana Mutchu
  • Vijay Kotra
  • Surendranatha Reddy Onteddu
  • S. N. Murthy Boddapati
  • Hari Babu Bollikolla
Short Communication
  • 65 Downloads

Abstract

The synthesis of 2-(5-methyl-2-nitrophenyl)-5-(substituted)-1,3,4-oxadiazoles (5a–e) and thiadiazoles (6a–e) was carried out by refluxing of N-(5-methyl-2-nitrobenzoyl)-2-substituted carbohydrazide with phosphorous oxychloride and Lawesson’s reagent respectively. The N-(5-methyl-2-nitrobenzoyl)-2-substituted carbohydrazides was synthesized by treating 2(5-methyl-2-nitrobenzohydrazide) with various aryl acids in the presence of HATU and DIPEA. Compounds 6a, 5c and 5d exhibited significant cytotoxic properties when compared to standard podophyllotoxin. Further, the compounds were also studied for their antibacterial activities.

Keywords

1,3,4-Oxadiazoles 1,3,4-Thiadiazoles Cytotoxic activity Antibacterial activity Lawesson’s reagent 

1 Introduction

The oxadiazole nucleus has emerged as one of the potential pharmacophores in medicinal chemistry [1, 2, 3, 4]. Substituted oxadiazoles and their analogs have also been used as precursors for synthesis of various biologically active molecules [5, 6, 7], and also showed various activities such as antibacterial [8, 9, 10], antimycobacterial [11], antifungal [12, 13], antiparasitic [14], anti-inflammatory [15], anti-allergy [16, 17], analgesic [18], anticonvulsant [19, 20], antihypoglycemic [21], insecticidal [22], anticancer properties [23, 24]. Moreover, the oxadiazoles have also been utilized as bioisosteres (surrogates) for carboxylic acids, esters and carboxamides [25]. The reviews [26, 27, 28, 29] on 1,3,4-thiadiazoles and 2-amino-1,3,4-thiadiazoles clearly indicated that the 1,3,4-thiadiazoles nucleus is similarly important as 1,3,4-oxadiazoles. Some of the prominent clinical drugs having 1,3,4-oxadiazole and thiadiazole units are shown in Fig. 1. Among various diseases cancer is a major health problem worldwide today. Improvements in treatment and prevention have lead to a decrease in cancer deaths, but the number of new diagnoses continues to rise. Chemotherapy is one of the most commonly used treatment options for cancer. Thus, it is urgent to develop novel chemotherapeutic agents for the treatment of cancer.
Fig. 1

Drugs with 1,3,4-oxadiazole and thiadiazole nucleus

The recent methodologies for preparation of 2,5-disubstituted-1,3,4-oxadiazoles include oxidative cyclization of aroyl/acyl hydrazones using catalytic Fe(III)/TEMPO [30], IBX/TEAB [31], catalytic Cu(OTf)2 [32], and stoichiometric molecular I2 [33]; cyclization of acylhydrazines using PPA or BF3·OEt2 and others [34, 35, 36]. The one-pot methodologies include synthesis from aryltetrazoles using DTBP/DCE, by dehydrative cyclization of ethyl carbazate and N-acylbenzotriazoles using Ph3P-I2 [37], and three-component reaction of isocyaniminotriphenyl-phosphorane, aldehyde, and benzoic acid under mild conditions [38]. Moreover, the valuable 2-amino-5-substituted oxadiazoles were generated through I2-mediated oxidative C–O/C–S bond formation of semicarbazones [39], eosin Y catalyzed oxidative heterocyclization of semicarbazones under visible-light photoredox catalysis using CBr4 as a bromine source, oxidative annulation of N-acyl hydrazines [40], tosyl chloride/pyridine-mediated cyclization of thiosemicarbazides [41]. Further, the methods which provide the 1,3,4-oxadiazole and thiadiazole nucleus from aryolthiosemicarbazide are oxidative desulfurization in the presence of iodobenzene/oxone [42] and EDC·HCl in DMSO or p-TsCl, triethylamine in N-methyl-2-pyrrolidone [43]. So, owing to the vast biological importance of 2,5-disubstituted-1,3,4-oxadiazoles [3, 9], 2,5-disubstituted-1,3,4-thiadiazoles [44, 45, 46, 47], and in continuation to our research on oxadiazoles [48, 49], in the present investigation we extended our work with new aryl moiety at second position in oxadiazole nucleus to generate a new series of 2-aryl-5-substituted-1,3,4-oxadiazoles and thiadiazoles as given in Scheme 1 and studied their cytotoxic and antibacterial properties.
Scheme 1

Synthesis of 2-aryl-5-substituted-1,3,4-oxadiazoles (5a–e) and thiadiazoles (6a–e)

Synthesis of compounds 5(a–e) and 6(a–e): As shown in Scheme 1, initially the 5-methyl-2-nitro-benzoic acid (1) was treated with ethanol in presence of sulphuric acid to obtain the ester 2 which was then treated with hydrazine hydrate to get the acyl hydrazide moiety (3). The acyl hydrazide thus obtained was treated with various aromatic carboxylic acids (a–e) in presence of HATU and DIPEA in THF solvent at room temperature for 13 h to get the key intermediate N-(5-methyl-2-nitrobenzoyl)-2-substituted carbohydrazide (4a–e). Finally, the carbohydrazide was treated separately with POCl3 and Lawesson’s reagents to get the desired 2-aryl-5-substituted-1,3,4-oxadiazoles (5a–e) and thiadiazoles (6a–e) in good yields, respectively.

The isolated yields of the final compounds were about 75–91% (Table 1). The yields of 2-aryl-5-substituted-1,3,4-thiadiazoles (6a–e) were low compared to oxadiazoles (5a–e). The 1,3,4-oxadiazoles 5b, 5d, and 5e with o-Nitro, m-methyl; 2-chloro-pyridine and pyridine substitutions respectively were obtained in greater than 90% yields. The compound 5a with 2-furan substitution was obtained in 85% yield and the remaining compounds 6a (thiadiazole with furan substitution), 5c (oxadiazole with thiophene substitution) and 6c (thiadiazole with thiophene substitution) were obtained about 75% yields. However, the thiadiazoles 6b, 6d, and 6e could not proceeded with good yields (< 10%, TLC) even though the temperature and time are increased and no proper reason was assessed. The obtained 2-aryl-5-substituted-1,3,4-oxadiazoles and thiadiazoles were well characterized by the spectral data.
Table 1

Synthesis and cytotoxicity results of 2-aryl- 5-substituted-1,3,4-oxadiazoles and thiadiazoles

The cytotoxic activities of 2-(5-methyl-2-nitrophenyl)-5-(substituted)-1,3,4-oxadiazoles (5a–e) and thiadiazoles (6a–e) were tested using brine shrimp lethality bioassay according to literature protocol [50] and the obtained data was validated using Finney probed analysis software. The cytotoxicity properties of the compounds were compared with the standard podophyllotoxin and results of the activities were provided in Table 1. The standard podophyllotoxin has the ED50 of 3.64 µg/mL. The compounds 6a, 5c and 5d exhibited significant cytotoxic properties (IC50 = 10–19.45 µg/mL) and 5e exhibited less significant activity. But the cytotoxic property of the compounds 5a, 5b, and 6c were not significant when compared to the standard drug. From the table it was observed that the 1,3,4-oxadiazole compound with thiophene substitution at 5th position (5c) or the 1,3,4-thiadiazole compound with furan substitution at 5th position (6a) were showed significant activity. Further, the symmetrical oxadiazole 5b was found to be less cytotoxic than the unsymmetrical compounds (6a, 5c, and 5d).

Antibacterial activity of the synthesized 2-aryl-5-substituted-1,3,4-oxadiazoles and thiadiazoles was determined against Gram-positive bacteria (Bacillus megaterium MTCC 428, Enterococcus faecalis MTCC 439 and Streptococcus mutans MTCC 497) and Gram-negative bacteria (Escherichia coli MTCC 1687, Proteus vulgaris MTCC 426 and Pseudomonas aeruginosa MTCC 1688) in DMF by disc diffusion method on nutrient agar medium [51]. The results of antibacterial activity of 2-aryl-5-substituted-1,3,4-oxadiazoles (5a, 5b, 5c, 5d, 5e) and thiadiazoles (6a, 6c) were presented in Table 2.
Table 2

Antibacterial activity of 2-aryl- 5-substituted-1,3,4-oxadiazoles and thiadiazoles

S. no.

Test organism

Diameter of zone of inhibition (mm)

Positive control (tetracycline)

5a

6a

5b

5c

6c

5d

5e

1.

Bacillus megaterium MTCC 428

5

5

3

4

4

4

3

7

2.

Enterococcus faecalis MTCC 439

5

4

4

3

3

5

3

7

3.

Streptococcus mutans MTCC 497

4

3

3

3

3

4

3

8

4.

Escherichia coli MTCC 1687

6

3

3

0

3

6

4

8

5.

Proteus vulgaris MTCC 426

4

4

3

3

5

4

3

7

6.

Pseudomonas aeruginosa MTCC 1688

5

3

0

4

3

3

3

7

The compounds exhibited a wide range of antibacterial activity including both Gram positive and Gram-negative bacteria. Further, the compound 5a was found be more sensitive towards most tested organisms followed by 5d. The activity of compound 5d may be because of presence of chlorine atom on the pyridine ring. Zavyalova et al. [52] reported that thienopyridine and other pyridine derivatives possessed good antimicrobial i.e. antibacterial activity against gram positive bacteria S. aureus and are also efficient against gram negative E. coli, P. aeruginesa and P. vulgaris. Some nitrophenoxymethyl-1,3,4-thiadiazole derivatives synthesized by Shah et al. [53] were also showed good antimicrobial activity. The introduction of the nitro group significantly increased the antibacterial activity against S. aureus, the studied compounds exhibiting comparable activity to standard drugs, chloramphenicol and ampicillin. In the present study, the newer analogues of 2-aryl-5-disubstituted-1,3,4-oxadiazoles and thiadiazoles were also exhibited similar pattern of antibacterial activity.

In summary, the newly synthesized 2-(5-methyl-2-nitrophenyl)-5-(substituted)-1,3,4-oxadiazoles (5a–e) and thiadiazoles (6a–e) were exhibited prominent biological activities including anticancer and antimicrobial properties. The potent compounds (6a, 5c and 5d) will be studied for LC50 using in vivo studies along with other sets of developed oxadiazoles. At this point, we could highlight the findings of this initial study and this will not only direct us to synthesize similar compounds with greater biological activity, but also may have an influence on the synthesis of more compounds with broad range biological properties.

Notes

Acknowledgements

The authors are highly thankful to Acharya Nagarjuna University, Guntur, Andhra Pradesh, India for constant encouragement, and Laila Impex R&D Centre, Vijayawada, Andhra Pradesh, India for biological studies.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

42250_2018_34_MOESM1_ESM.pdf (3.2 mb)
Supplementary material 1 (PDF 3274 kb)

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Copyright information

© The Tunisian Chemical Society and Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of ChemistryAcharya Nagarjuna UniversityGunturIndia
  2. 2.Department of Pharmaceutical chemistryQuest International UniversityIpohMalaysia

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