Synthesis and characterization of amides of primaquine and cinnamic acid derivatives

Primakin je važan antimalarijski lijek iz skupine 8-aminokinolina. Osim antimalarijskog, otkrivena je i citostatska aktivnost njegovih derivata. Cimetna kiselina je prirodna kiselina, čiji su derivati pokazali širok spektar djelovanja, uključujući i citostatsku aktivnost. Također, cimetna je kiselina pokazala svojstvo povećanja antitumorske aktivnosti ishodnog spoja. Cilj ovog rada bio je sintetizirati amide primakina i tri derivata cimetne kiseline. Korištene su dvije metode, benzotriazolska (metoda A) i sinteza amida preko acilnog klorida (metoda B). Metoda A uključuje sintezu benzotriazolida (2a-c) reakcijom klorida 1-benzotriazolkarboksilne kiseline (BtcCl, 1) i odgovarajućeg derivata cimetne kiseline. Konačni produkti, amidi (4a-c) dobiveni su reakcijom benzotriazolida (2a-c) i primakina. Prvi korak metode B je prevođenje cimetne kiseline u odgovarajući acilni klorid (3a-c) pomoću tionil klorida. Dobiveni acilni kloridi (3a-c) korišteni su u idućem reakcijskom koraku bez izolacije. U reakciji s primakinom dobiveni su konačni produkti, amidi (4a-c). Metoda A pokazala se bržom, dok se iskorištenja nisu bitnije razlikovala u metodama. Strukture svih amida potvrđene su uobičajenim spektroskopskim metodama (IR, 1H i 13C NMR, MS) te je svim čvrstim produktima određeno talište. Sintetiziranim derivatima u daljnjim će istraživanjima biti ispitano antitumorsko djelovanje.Primaquine is an important 8-aminoquinoline antimalarial drug. Apart from antimalarial, its derivatives have shown cytostatic activity. Cinnamic acid is naturally occurring carboxylic acid, whose derivatives have wide range of biological activity, including cytostatic. In addition, cinnamic acid has ability to boost antitumor activity of the primary compound. The purpose of this research was to prepare amides of primaquine and three cinnamic acid derivatives. Two different methods were used. In the method A, the auxiliary compound benzotriazole in form of 1-benzotriazolecarboxylic acid chloride (BtcCl, 1) was used for the preparation of reactive compounds benzotriazolides (2a-c), which gave corresponding amides (4a-c) in the reaction with primaquine. In the method B, cinnamic acid derivatives were firstly converted into corresponding acyl chlorides (3a-c) with thionyl chloride. Prepared acyl chlorides (3a-c) were used in the following reaction step without isolation. In the reaction with primaquine, amides (4a-c) were obtained. The reaction times in the method A were shorter than in the method B. However, yields were similar in both methods. Structures of synthesized amides were confirmed by the usual spectroscopic methods (IR, 1H and13C NMR, MS) and for every solid compound its melting point was determined. Antitumor activity of synthesized primaquine derivatives will be tested in further analysis