# Synthesis and Biological Activity of 1,3,4-Oxadiazoles Used in Medicine and Agriculture
## 5 Investigation of the Synthesis of New, Biologically Active 1,3,4-Oxadiazoles
The derivative **32b** appears to be the most promising compound and may be used in the future for the treatment of neoplastic diseases [102]. The synthesis of 2,5-bisphenyl-1,3,4-oxadiazoles proposed by [PERSON] et al. is based on the use of trifluoromethanesulfonic anhydride as the main reagent responsible for carrying out the cyclization of \(N\),\(N^{\prime}\)-diacylhydrazines (Scheme 7). The essential diacylhydrazines (**36**) were prepared from the substituted benzoic acid (**33**), which were esterified with methanol, then treated with hydrazine hydrate and finally coupled under the influence of TBTU and lutidine. The intermediate \(N\),\(N^{\prime}\)-diacylhydrazine (**36**) was dissolved in dichloromethane (DCM), and pyridine was used as the basic catalyst. The reaction mixture was stirred for approximately 3 h at 0 \({}^{\circ}\)C. The crude products were purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (9:1) as the mobile phase. The final products (**37**) were obtained with yields ranging from 77 to 86%. The undoubted advantage of this method is the relatively short reaction time of 3 h and avoiding the need to heat the reaction mixture [103]. The obtained derivatives were tested for antibacterial and antifungal activity against Gram-positive bacteria (_Bacillus cereus_, _Staphylococcus aureus_, _Staphylococcus aureus_ (MRSA), _Enterobacter aerogenes_ and _Mi-crococcus luteus_), Gram-negative bacteria (_Escherichia coli_, _Klebsiella pneumoniae_, _Proteus vulgaris_, _Salmonella typhimurium_, _Salmonella partyphi B_) and fungi (_Botrytis cinerea_, _Candida Krusei_, _Candida albicans_, _Fusarium moniliforme_, _Malassesia pachydermatis_, _Aspergillus niger_, _Fusarium solani_, _Colletotrichum gloesporioides_, _Aspergillus flavus_, _Candida parapsilosis_). The tests were performed using the disc diffusion method. Streptomycin, a standard antibacterial drug, was used as a reference for this purpose. The highest activity was observed for compound **5a**, which had two ortho bromo groups on two different aromatic rings directly attached to the 1,3,4-oxadiazole moiety. The remaining compounds showed moderate antibacterial activity. For antifungal studies, Ketoconazole, a standard drug for the treatment of disease caused by pathogenic fungi, was used as a reference compound. In this study, derivative **37a** also showed the strongest activity [103]. [PERSON] et al. developed an ultrasound-assisted method for the synthesis of 2-amino-1,3,4-oxadiazol derivatives substituted with aryl and methyl groups at position 5 (Scheme 8). The substrates for this type of reaction were various hydrazide derivatives (**38a-e**) bearing alkyl and aryl substituents and cyanogen bromine (**39**) added in an equimolar amount. It was also necessary to use a base--potassium bicarbonate. The presence of the base had a positive effect on the efficiency of the reaction by neutralizing the evolved hydrogen bromide, which could react with the hydrazide. Anhydrorous ethanol was used as a solvent. The reaction mixture was subjected to an ultrasonic bath at 50 \({}^{\circ}\)C. The formed oxadiazole derivatives were washed with water and dried to give pure final products. The undoubted advantage of using ultrasonic profiling is the reduction of the synthesis time to several hours and the high yield of the desired 1,3,4-oxadiazole derivatives (**40a-e**) [104]. The obtained 2-amino-1,3,4-oxadiazole derivatives were tested for their antioxidant activity. The tests were carried out against 2,2,-diphenyl-1-picrylhydrazyl (DPPPH). Effects were calculated as IC\({}_{50}\) values. _Ascorbic acid_ (_Vitamin_ C) IC\({}_{50}\) 0.022 mM was used as a reference substance. All obtained final products, except derivative **40d**, showed antioxidant activity. The strongest properties were exhibited by derivative **40c**; this was attributed to the presence of a nitro group, which is capable of withdrawing electrons and deactivating the phenyl ring [104]. [PERSON] et al.