# 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  
[PERSON] et al. proposed a method for the preparation of 2-aryl-1,3,4-oxadiazol substituted at position 5 with a \(p\)-bromophenylaminomethyl group by using mercury oxide in the presence of iodine. The use of \(p\)-bromoaniline and ethyl chloroacetate yields ethyl \(N\)-(\(p\)-bromophenyl) acetate (**14**). Then, the ester produced may be converted to the corresponding hydrazide (**15**) using hydrazine hydrate. Subsequent treatment with a range of aryl aldehydes results in formation of the appropriate hydrazone (**16a-j**) which undergo cyclization under the influence of mercury oxide and iodine (Scheme 3). The advantage of this method is that there is no need to heat the reaction mixture. The substrates are completely converted after 48 h. The final products may be purified by recrystallization from DMF:ethanol in a 1:1 volume ratio. A series of 1,3_A_-oxadiazol derivatives (**17a-j**) may be thus obtained with yields of 50-65% [100]. Aniline derivatives containing 1,3,4-oxadiazol moieties have been tested for antibacterial activity against _Staphylococcus aureus_, _Bacillus subtilis_, _Pseudomonas aeruginosa_ and _Escherichia coli_ using _Amoxicillin_ as a standard drug. In the studies of antifungal activity, all compounds were compared with the popular antifungal agent, Ketoconazole. In addition, biological activity was tested for anti-inflammatory effects. The described 1,3,4-oxadiazol  
Figure 6: Compounds based on 1,3,4-oxadiazol used in medicine: Furamizole [97], Raltegravir [98], Nesapidil [99], Zibotentan [95], Thiodazosin [97]. derivatives showed good antibacterial and anti-inflammatory activity, and moderate antifungal activity. Derivatives **17e**, **17f**, and **17h** showed better antibacterial activity, while compounds **17b**, **17c**, **17d**, and **17g** showed better antifungal activity [100]. [PERSON] et al. developed a synthetic path yielding the corresponding propan-3-one derivatives containing a 1,3_A_-oxadiazol core (Scheme 4). The essential cyclization step consisted of carrying out the reaction between the carboxylic acid derivative (**20**) and aromatic acid hydrazide (**19a-n**) in the presence of phosphoryl oxchloride (POCl\({}_{3}\)). In the first step, a hydrazide is formed, which then undergoes a cyclization reaction with a cyclodehydrate such as POCl\({}_{3}\). The reaction mixture was heated to reflux for several hours. Final compounds (**21a-n**) were purified by recrystallization from methanol with yields varying from 54 to 66%. The preceding stages included the formation of acid hydrazide (**19a-n**) according to a standard procedure consisting of esterification of carboxylic acids and hydraziss. The second reagent, carboxylic acid derivative (**20**), was prepared via electrophilic substitution reaction from bromobenzene and maleic anhydride [101]. All 2-[3-(4-bromophenyl)]propan-3-one]-5-phenyl-1,3_A_-oxadiazol (**21a-n**) derivatives products were tested for their anti-inflammatory effect. Their activity was checked in vivo in rats by inducing paw swelling with carrageenan. The obtained results were compared with the standard drug used in the treatment of this type of disease, _Indomethacin_. The 2-[3-(4-bromophenyl)]propan-3-one]-5-phenyl-1,3_A_-oxadiazol derivatives (**21a-n**) all showed an anti-inflammatory effect ranging from about 33 to 62%. Derivatives **21c** and **21i** showed the strongest activity, with efficiencies of 59.5% and 61.9%, respectively. This effect was comparable to that of Indomethacin, which showed an activity of 64.3% at the same dose (20 mg/kg body weight). These studies confirmed that the presence of 3,4-dimethoxyyl, 4-chlorophenyl or the 5-position substitution of the oxadiazole ring improves the anti-inflammatory activity. Some of the derivatives have also been tested for their analgesic effect based on commercially used _Acetylsalicylic acid_.