Syntheses, Characterization and Biological Evaluation of a Series of 2-Phenylamino-5-(2-Chlorophenyl)-1,3,4-Oxadiazole Derivatives

Syntheses, Characterization and Biological Evaluation of a Series of 2-Phenylamino-5-(2-Chlorophenyl)1,3,4-Oxadiazole Derivatives S. Kumar1 and P. K. Srivastava2 1 Department of Chemistry, Faculty of Science, Iswar Saran P G College, University of Allahabad Allahabad-211004, India 2 Department of Zoology, Faculty of Science, University of Allahabad, Allahabad-211002, India (Received: April 23, 2018; Accepted: April 18, 2019; Published (Web) June 30, 2019) ABSTRACT: Electrochemical synthesis of 2-phenylamino-5-(2-chlorophenyl)-1,3,4-oxadiazoles have been carried out in good yields at platinum electrode through the electrochemical oxidation of acyl thiosemicarbazide at room temperature in acetic acid. Two platinum electrodes in the form of square plates were used as working as well as counter electrode and saturated calomel electrode was used as reference electrode. The structure of the compounds was confirmed by IR, NMR, mass spectral and elemental analyses. The antibacterial activity of the derivatives was also assessed and compared with data against a series of Gram-positive Klebsiella pneumoniae, Escherichia coli and Gramnegative bacteria Streptococcus aureus and Bascillus subtilis. The antifungal activity was assessed against the fungal strain Aspergillus niger, Crysosporium pannical, Pellicularia solmanicolor and Candida albicans and compared against the standard antifungal drug Griesvofulvin. Key words: 1,3,4-Oxadiazoles, Arylthiosemicarbazide, Controlled potential electrolysis, Platinum electrode, Green chemistry. INTRODUCTION Various 1,3,4-oxadiazole derivatives were reported in the literature to have a broad spectrum of biological activities including such as antibacterial1,2, anti-HIV1, antifungal3,6, genotoxic3,6, antitubercular6, virucidal7, antimalarial8, insecticidal9, herbicidal10, analgesic11, anti-inflammatory12, muscle relaxants13,14, anticonvulsant15, sedative16, hypnotic16, anticancer17 and lipid peroxidation inhibitors. In the present investigation, a series of substituted 1,3,4oxadiazole derivatives were synthesized as potential antibacterial and antifungal agents by the electrooxidative synthesis. The oxadiazole ring systems have a long history of application in pharmaceutical and agrochemical industries due to their activity. On the study of literature it have been found that the methods for Correspondence to: S. Kumar E-mail: Dhaka Univ. J. Pharm. Sci. 18(1): 75-83, 2019 (June) DOI: https://doi.org/10.3329/dujps.v18i1.41894 synthesis of oxadiazoles19 2,5-disubstituted or 2amino-5-substituted-1,3,4-oxadiazoles include bromine oxidation of semicarbazide derivative and the cyclodesulfurisation of acylthiosemicarbazide derivative in the solution using I2/NaOH or 1,3-dicyclohexylcarbodimide (DCC) as well as mercury (II) acetate [Hg(OAc)2] or yellow mercury (II) oxide HgO.20-22 All these methods are usually carried out in various different synthetic steps and requires the heating at high temperature. The handling of these reagents is not only difficult but also very hazardous to the environment. The each stage of the reaction including extraction and purification of the products from the mixture required great precautions. Karen Evans23 have synthesized a similar cyclized product by the chemical method in which 2-amino-5substituted-1,3,4-oxadiazoles were prepared by rapid parallel synthesis in efficient one-pot preparation using resin-bound reagents. 76 The electrochemical oxidation reaction has several merits. These reactions do not require oxidizing reagents and can be performed at room temperature. Application of electricity as a non conventional energy source for activation of reactants in suitable solvents has now gained popularity over the usual homogeneous and heterogeneous reactions. It provides chemical processes with special attributes, such as enhanced reaction rate, higher yield of pure products, better selectivity and several ecofriendly advantages. During hit to lead efforts following a recent high throughput screening campaign, we initiated the electrolysis of semicarbazone for the synthesis of 2-amino-5-substituted-1,3,4-oxadiazoles at the platinum electrode as a green synthesis. Later on, it have been found out from the literature that the activity of the oxadiazoles can be enhanced if the amino group is also substituted by an alkyl, aryl or acyl group. Keeping this observation in view and in continuation of our research on the synthesis of heterocyclic compounds containing nitrogen and oxygen with expected biological activity, this paper presents the synthesis of several derivatives of 2phenylamino-5-(2-chlorophenyl)-1,3,4-oxadiazoles which contain phenyl moiety and the study of their antibacterial and antifungal activity. EXPERIMENTAL Physical measurements. Melting points were determined using open capillary tubes and were uncorrected. The purity of the synthesized compounds were ascertained by thin layer chromatography on Silica gel G 60 F254 plates from Merck and visualized by exposure to iodine vapor. Spectra were obtained as follows: Infra red (IR) spectra were recorded on a Shimadzu 8201 PC IR spectrophotometer (4000-400 cm-1) in KBr pellets and reported in cm-1. 1H NMR and 13C NMR spectra were measured at room temperature on Bruker DRX 300 MHz and 75 MHz FT spectrometer instruments, with tetramethylsilane (TMS) and CDCl3 or C6D6 and their chemical shifts are reported in  (parts per million). Carbon multiplities were assigned by DEPT Kumar and Srivastava techniques. Microanalysis for C, H, N was performed in the Elementar Vario EL III. General procedures for the synthesis of acylthiosemicarbazide (4a-4l). Arylisothiocyanate 3 was prepared directly from an arylamine. The sparingly soluble ammonium aryldiathiacarbamate was obtained by the reaction of an arylamine, CS2, and aqueous ammonia. Then aryldiathiacarbamate is decomposed by lead nitrate to produce arylisothiocyanate. The equimolar amount of arylhydrazine 2 and arylisothiocynate 3 were mixed in a small beaker with continuous stirring. After few minutes of stirring, the mixture was left overnight, which gave a solid compound arylthiosemicarbazide 4. (4a): IR/cm-1: 1015 (N-N), 1265 (C=S), 1449 (C=N + ArC=C), 1632 (C=O), 3068 (ArC-H); 1HNMR: δ 6.88-7.98 (m, 8H, ArH), 10.60-11.96 (s, 3H, NH); 13C-NMR: δ 116.1, 119, 126.4, 127.6, 128.6, 129.8, 133.4, 140.7, 143.06, 148.1, 159.5, 181.6; M/Z=305.5 [M+]. Calcd. for C14H12N3OSCl: C, 54.98; H, 3.92; N, 13.74; Cl, 11.62; S, 10.47. Found: C, 54.09; H, 3.61; N, 13.46; Cl, 11.22; S, 10.17. General procedure for the synthesis of 2-Nphenylamino-5-(2-chlorophenyl)-1,3,4-oxadiazol (1a-l). Arylthiosemicarbazide 4, 4a (1000 mg, 3.27 mmol) and LiClO4 (106 mg, 0.67 mmol) were dissolved in acetic acid (100 ml) to prepare the reaction mixture for electrolysis. Electrolysis. Preparative scale controlled potential electrolyses21-29 were performed at room temperature in 250 ml three-electrode cell assembly with platinum plate (1.0 cm x 1.0 (...truncated)