Solid phase synthesis of novel 1,3,4-oxadiazole derivatives and evaluation of their antimicrobial activity

Available online at www.worldscientificnews.com WSN 147 (2020) 35-44 EISSN 2392-2192 Solid phase synthesis of novel 1,3,4-oxadiazole derivatives and evaluation of their antimicrobial activity Shobhana A. Gadara1 and Kartik D. Ladva2 Department of Chemistry, Shree Manibhai Virani & Smt Navalben Virani Science College Autonomous, Kalawad Road, Rajkot - 360005, India 1,2 E-mail address: , ABSTRACT A series of 5-(N-Aryl/Arylalkyl)-2-(3-Chclorophenyl)-1,3,4-oxadiazole have been synthesized. The constitution of the products has been delineated by elemental analysis and spectral analyses. All the synthesized compounds were screened for their antibacterial activity against Staphylococcus aureus MTCC-96, Escherichia coli MTCC-443, B. subtilis MTCC-441, P. aeruginosa MTCC-1688, and antifungal activity against Aspergillus niger MTCC-282 and Penicillium SP.at different concentration and compared with standards drugs. The minimum inhibition concentration (MIC) of the compounds was studied by micro broth dilution method. Keywords: Aminoazole, 1,3,4-oxadiazole, in vitro antimicrobial assay, s-methylthioamide 1. INTRODUCTION The presence of two nitrogen and one oxygen heteroatoms in five membered rings Systems differentiate a unique class of compounds, the oxadiazole. Oxadiazoles belong to an imperative group of heterocyclic compounds having a toxophoric –N=C-O– linkage. 1,3,4Oxadiazole is a thermally static aromatic molecule [1]. They have drawn very usefulness to medicinal chemists from two decades due to its spacious diversity of activity, low toxicity and ( Received 18 June 2020; Accepted 09 July 2020; Date of Publication 10 July 2020 ) World Scientific News 147 (2020) 35-44 good Pharmacokinetic and Pharmacodynamics outlines [2]. This is because of massive number of applications of 1,3,4-oxadiazoles in the most distinct areas specially drug synthesis, dye stuff industry, heat resistant materials, heat resistant polymers and scintillates, change of the respective article before to 1965 are suitable [3]. Literature survey explain that the nitrogen and oxygen containing heterocyclic compounds crucial to antibacterial and antifungal drugs [4]. Among the various types of fivemember heterocyclic rings, the 1,3,4-oxadiazoles are the class of heterocyclic compounds with a wide range of pharmaceutical and biological action [5, 6]. The 1,3,4-oxadiazoles possessed various biological activity like antimicrobial [7-9], antifungal [10], antiproliferative [11], anticancer [12, 13], tyrosinase inhibitor [14] and Tiodazosin possessing oxadiazole nucleus are broadly used as antihypertensive [15]. Other biological properties related with 1,3,4-oxadiazole skeletal includes anti-inflammatory as well as analgesic activity [16-18]. In context to vast medicinal significance; a number of ways have been advanced for synthesizing 1,3,4oxadiazoles [19-21]. A number of synthetic methods under hard circumstances using various reagents viz. Cu(II) and phosphorous oxy-chloride have been established [22, 23]. The desired compounds were prepared by multi-step synthesis process. The creation of intermediates and their corresponding derivatives was proved by spectral characterization such as 1H NMR, 13C NMR, mass spectra, IR and elemental analysis. The compounds were reserved for their antimicrobial properties against a broad spectrum of gram-positive and gram-negative bacteria as well as fungi. 2. EXPERIMENTAL All research chemicals were purchased from Sigma-Aldrich Chemicals and used as received. Reactions were monitored by thin layer chromatography (TLC) on pre-coated silica gel GF254 plates (E-Merck Co) by using appropriate solvent systems. Melting points were determined in open capillaries and are uncorrected. Infrared (IR) spectra (KBr pellets) were recorded on a Shimadzu-FTIR-8400 spectrophotometer over frequencies ranging from 4000400 cm-1. The NMR Spectra (1HNMR & 13C NMR) were recorded on a Bruker Avance Spectrospin 400 MHz spectrometer using CDCl3 as solvents and TMS as an internal standard. Mass spectra were recorded on a Shimadzu GC-MS-QP-2010 spectrometer by using Electron Impact (EI) (0.7 kV) ionization source. The ion source temperature was 220 °C and interface temperature was 240 °C. -36- World Scientific News 147 (2020) 35-44 General procedure: A. Synthetic procedures for Intermediates  Synthesis of 3-chlorobenzothioamide (Int-1) To the stirred solution of 3-chlorobenzonitrile 1 (10 g, 0.072 mol) in DMF (100 mL), MgCl2.6H2O (36.89 g, 0.1817 mol) was added at 0-5 °C. The resultant solution stirred for 10 min, and then sodium hydrogensulphide (8.54 g, 0.1526 mol) was added portion wise in cooling. A mixture was stirred at room temperature for 1 h. After the completion of reaction, mixture was poured in to cold water. The separated product was filtered and washed with water and dried it in hot air oven (10.8 g, 87%).  Synthesis of methyl 3-chlorobenzimidothioate (Int-2) To a solution of 3-chlorobenzothioamide (Int-1) (10 g, 0.0582 mol) in diethyl ether (100 mL), methyl iodide (10.7 g, 0.0757 mmol) was added at 0 °C. This solution was stirred for 30 min at 0 °C then warmed to room temperature for 10 h. The resulting solid was filtered and washed with diethyl ether (20 mL) to obtain pure product (Int-2) (9.5 g, 90%). -37- World Scientific News 147 (2020) 35-44  Synthesis of ester of various benzoic acid (Int-3) To the stirred solution of various substituted benzoic acid (2 g, 0.01637 mol) in methanol (4 mL), concentrated sulfuric acid was added in a catalytic amount and the mixture was refluxed for 6 hr. After the completion of reaction, methanol was distilled out on rota-evaporator and water was added to the residue and extracted with ethyl acetate. Then ethyl acetate layer was washed with 5% sodium bicarbonate solution and followed by water. Ethyl acetate layer dried over sodium sulphate and filtered through cotton plug and distilled out ethyl acetate under vacuum to get solid product (Int-3) (1.7 g, 85%).  Synthesis of hydrazides (Int-4): To the stirred solution of various substituted ester of benzoic acid (Int-3) (1 g, 0.0073 mol) in methanol (4 mL), hydrazine hydrate was added and the mixture was refluxed for 4 hr. After completion of reaction, cool the reaction mass to 0-5 °C and filter the separated solid. Solid material washed with prechilled methanol to obtained pure product (Int-4) (0.8 g, 80%). B. General Synthetic procedure of Compounds (4a-4j)  General Procedure for preparation of 5-(N-Aryl/Arylalkyl)-2-(3-Chclorophenyl)1,3,4-oxadiazole (4a-4j) A mixture of methyl 3-chlorobenzimidothiate (Int-2) (3.26 mmol) and hydrazides (Int-4) (3.26 mmol) in DMF (40 mL) was heated at 120 °C for 3-4 h. After completion of the reaction, the mixture was poured in to ice cold water. The solid crude of 1,3,4-oxadiazole was obtained which was filtered and dried. The crude product was purified by column chromatography using ethylacetate and hexane as mobile phase. 2-(3-chclorophenyl)-5- (...truncated)