Synthesis and characterization of novel primaquine ureas with amino alcohols

Ovaj rad nastavak je višegodišnjih istraživanja derivata primakina kao antiproliferativnih lijekova u Zavodu za farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta. Temeljem rezultata tih istraživanja dizajnirane su kao potencijalni citostatici i antimalarici nove uree primakina koje u strukturi sadrže ciklički alifatski aminoalkohol ili fenol. U okviru ovog rada sintetizirana su benzotriazolskom metodom četiri nove uree primakina s aminoalkoholima 3a-d. Svim novosintetiziranim spojevima struktura je potvrđena uobičajenim analitičkim i spektroskopskim metodama (IR, 1H 13C NMR, MS), a krutim je produktima određena i temepratura tališta. Sva četiri spoja zadovoljavaju Lipinskijeva i Veberova pravila, a dobru oralnu bioraspoloživost predviđa im i alat SwissADME. Isti alat predviđa da su spojevi 3a-c supstrati P-glikoproteina, što može umanjiti njihov antitumorski učinak. Sintetiziranim će ureama u daljnjim istraživanjima biti ispitano antiproliferativno i antimalarijsko djelovanje.This paper is a continuation of many years of research into primaquine derivatives as antitumor drugs at the Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry. Based on the results of these studies, novel primaquine ureas containing a cyclic aliphatic or aromatic amino alcohol in the structure have been designed as potential cytostatics and antimalarials. Within this work, the benzotriazole method was used for the synthesis of four new primaquine ureas with amino alcohol moieties in their structures 3a-d. Structures of the newly prepared compounds were confirmed using conventional analytical and spectroscopic methods (IR, 1H and 13C NMR, MS). Melting points of the solid compounds were also determined. All four novel derivatives meet all of the Lipinski and Veber criteria for good oral bioavailability of potential drugs. SwissADME web tool predicts good oral bioavailability of all four derivatives, but it also predicts that compounds 3a-c are P-glycoprotein substrates, which could potentially limit their anticancer efficacy. Further studies will investigate antiproliferative and antimalarial activity of the synthesized primaquine derivatives