| Abstract | se od antranilne kiseline I njezinih halogeniranih derivate te derivate 4-amino-7-klorokinolina. Kao poveznica
između dva farmakofora izabran je 1,3,4-oksadiazol, peteročlani heterociklički prsten stabilan na enzimsku i kemijsku
razgradnju.
Sinteza je započeta amidacijom derivata metilnih estera antranilne kiseline u odgovarajuće hidrazide (2a-e) u
reakciji s vodenom otopinom hidrazina. Metilni esteri 1a i 1b prethodno su priređeni iz odgovarajućih kiselinskih
derivata korištenjem tionil-klorida i metanola, dok su preostali esteri bili komercijalno dostupni. Hidrazidi su zatim
prevedeni u odgovarajuće 3-H-1,3,4-oksadiazol-2-onske derivate (3a-e) reakcijom s CDI. Drugi građevni element,
aminokinolinski derivat 4 priređen je reakcijom 4,7-diklorokinolina i etilendiamina. 1,4-Disupstituirani semikarbazidi
5a-e dobiveni su u reakciji kinolinskog derivata 4 i oksadiazola 3a-e. U zadnjem reakcijskom koraku, u reakciji
ciklizacije zatvoren je 1,3,4-oksadiazolni prsten te su dobiveni konačni produkti 6a-e.
Dobiveni spojevi karakterizirani su uobičajenim analitičkim i spektroskopskim tehnikama: 1H i 13C NMR i
MS. Čistoća im je utvrđena UPLC analizom te je kod svih sintetiziranih spojeva iznosila preko 95 %. Tališta
sintetiziranih spojeva određivana su diferencijalnom pretražnom kalorimetrijom.
Izračun fizičko-kemijskih deskriptora spojeva te njihovih farmakokinetičkih parametara napravljen je pomoću
besplatne web aplikacije SwissADME. Na temelju rezultata može se zaključiti da bi spojevi trebali imati
zadovoljavajuća svojstva topljivosti i permeabilnosti što ukazuje na dobru oralnu bioraspoloživost.
Ispitivanja biološkog djelovanja sintetiziranih spojeva izlaze iz okvira ovog rada te će biti provedena naknadno. |
| Abstract (english) | In the course of this paper, five novel hybrid compounds were synthesized and structurally characterized. Their
structures consisted of anthranilic acid and its halogenated derivatives, along with 7-chloro-4-aminoquinoline. 1,3,4-
oxadiazole, a five-membered heterocyclic ring resistant to chemical and enzymatic degradation, was used as a linker
between the two pharmacophores.
The synthesis began with the amidation of anthranilic acid methyl ester derivatives into their corresponding
hydrazides (2a-e), in a reaction with an aqueous solution of hydrazine. Methyl ester derivatives 1a and 1b were
previously obtained from the corresponding acid derivatives, using thionyl chloride and methanol, while the remaining
ester derivatives were comercially available. The hydrazides were then converted to the corresponding 3-H-1,3,4-
oxadiazol-2-one derivatives (3a-e) in a reaction with CDI. Another building block, the aminoquinoline derivative 4 was
obtained in the reaction between 4,7-dichloroquinoline and ethylenediamine. 1,4-disubstituted semicarbazides 5a-e were
obtained in the reaction between the aminoquinoline derivative 4 and the 3-H-1,3,4-oxadiazol-2-one derivatives 3a-e.
During the final reaction step, a 1,3,4-oxadiazole ring was enclosed in a cyclization reaction and the final products 6a-e
were obtained.
The synthesized compounds were characterized using standard analytical and spectroscopic techniques: 1H and
13C NMR and MS. Their purity was determined by UPLC analysis, all of which exceeded 95 %. Melting points of the
synthesized compounds were determined by differential scanning calorimetry.
The calculation of the compounds' physicochemical descriptors, along with their pharmacokinetical parameters
was performed using a free web tool called SwissADME. Based on the results, it can be concluded that the compounds
show satisfactory properties in terms of solubility and permeability, which indicates high oral bioavailability.
Biological screening of the synthesized compounds is beyond the scope of this paper, and will be performed in
the future. |
