# 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
Compounds **21b**, **21c**, **21e**, **21f** and **21i** showed analgesic activity ranging from about 44 to 71%, while _Acetylsalicylic acid_ showed an analgesic activity of 63.2%. An analysis showed that the most effective were the derivatives containing halogen substituents attached to the 5 position of the oxadiazole ring [101]. The synthesis of 1,3,4-oxadiazoles proposed by [PERSON] et al., leading to the preparation of extended _Iburopfen_ derivatives, is based on a cyclization reaction starting from carobithioamide derivatives (**24a-f**). The reactants used in this case were iodine dissolved in potassium iodide solution (Scheme 5). For this purpose, the carobithioamide derivatives (**24a-f**) prepared in advance from acid hydrazide (**23**) and the appropriate isothiamate were suspended in ethanol and dissolved with the addition of aqueous sodium hydroxide. Iodine in a 5% potassium iodide solution was then gradually added to the mixture until the iodine color was maintained at room temperature. In the next step, the mixture was heated to reflux for about 5 h. The advantages of this method of obtaining 1,3,4-oxadiazol derivatives are undoubtedly the lack of the need to use hazardous cyclodehydration compounds and the high yield of the final products. Ibuprofen derivatives containing 1,3,4-oxadiazole groups as solids were purified by recrystallization from ethanol. The desired final structures (**25a-f**) were obtained with yields of 72-85% [49]. The obtained products in the form of 5-[2-(4-isobutylphenyl)ethyl]-2-(aryl)-1,3,4-oxadiazol derivatives (**25a-f**) were tested for their anti-inflammatory activity. A carrageenan solution was injected into groups of six rats. One of the groups was treated as a control. The remaining rats were treated with the tested pre-therapy at doses of 70 mg/kg body weight. The reference point of the test substances was standard _Iburopfen_, which showed an anti-inflammatory effect of 92% four hours after administration. Derivative **25a** showed the strongest activity (86%). This compound was also tested for application as a painkiller, obtaining the desired activity at a level of 73%. The _Iburopfen_ standard showed an analgesic effect equal to 83.5% [49]. [PERSON] et al. proposed the preparation of 1,3,4-oxadiazole derivatives connected to a coumarin core via a methylenoxy linker (Scheme 6). The starting coumarin fragment was prepared from resorcinol (**26**) and ethyl acetoacetate (**27**). Then, it was treated with ethyl bromoacetate, yielding an extended coumarin-bearing ester, which was converted to the appropriate hydrazide (**30**) under the influence of hydrazine hydrate. Such hydrazidesunderwent cyclization in the presence of carbon disulfide and ethanol. The process of obtaining oxadiazole (**31**) was carried out in the presence of a base such as sodium hydroxide. The reaction mixture was heated to reflux overnight with stirring. Due to the use of a base during the synthesis, the mixture then had to be acidified with HCl solution. The obtained precipitate products were purified by recrystallization from ethanol. The advantage of using CS\({}_{2}\) as a cyclizing reagent is undoubtedly the high yield of 1,3,4-oxadiazole derivatives, i.e., 71-81% [102]. **Scheme 5. ** Synthesis of 5-[2-(4-_i_obutylphenyl)ethyl]-2-(aryl)-1,3,4-oxadiazole derivatives [49]. **Scheme 6. ** Preparation of coumarin derivatives containing 1,3,4-oxadiazole core [102]. The obtained derivatives were tested against the four isoforms of carbonic anhydrase hCA. In comparative tests, _Acetazolamide_ was used as the standard drug. None of the compounds obtained showed the potential to inhibit the cytosolic isoforms hCA I or hCA II. Significant blocking against the hCA XII transmembrane isoform was shown in all the molecules obtained, while against hCA IX, the inhibition was variable. Consequently, coumarin-oxadiazole hybrids were found to be selective inhibitors of two carbonic anhydrase enzymes directly related to tumors.