Naslov
Design and synthesis of harmine and coumarin/quinoline hybrids bridged with 1, 2, 3-triazole

Autori
Raić-Malić, Silvana ; Perković, Ivana ; Rajić, Zrinka

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, ostalo

Skup
4th Drug Discovery Re-Invented Conference

Mjesto i datum
Nassau, Bahami, 21.02.2019. - 24.02.2019

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
harmine, malarina, quinoline, coumarin, hybrid drugs

Sažetak
Malaria, one of the neglected tropical diseases, is responsible for more than 430000 deaths and 210 million new cases annually. The cause of malaria, protozoal parasite of the genus Plasmodium, is developing resistance to the known drugs, which drives the need for the discovery and development of new antimalarials. One of the methods for finding new drug entities is to covalently combine two pharmacophores in one molecule, i.e. to prepare hybrid drugs. Thus, we decided to employ that concept in the present study, in which we have designed and prepared hybrids based on -carboline alkaloid harmine and coumarine or quinoline, linked with 1, 2, 3-triazole ring. It has been established that harmine and related b-carbolines exhibit antimalarial activity, possibly by inhibiting PfHSP90. On the other hand, coumarins are the most abundant naturally occurring secondary metabolites found in several plant families, microorganisms and a few animal species, while quinoline-containing antimalarial drugs, such as primaquine and chloroquine, are the mainstays of chemotherapy against malaria. In addition, coumarin and quinoline derivatives possess a broad spectrum of biological activities, including antimalarial, antibacterial and antifungal activity. 1H-1, 2, 3-triazole scaffold will be introduced by the means of Cu(I) catalyzed regioselective 1, 3-dipolar cycloaddition of terminal alkynes and organic azides („click“ reaction). It was chosen as a linker due to the high chemical stability and the ability to form hydrogen bonds with biomolecular targets. Triazoles are also recognized as bioisosters of amides. Harmine and 7-O-demethylated harmine (harmole) were converted to the corresponding alkynes 1, 6 and 7 by the means of propragylation, while 4-chlorocoumarine and 4, 7-dichloroquinoline were transformed to the appropriate azides 2 and 3, respectively. Finally, “click” reaction between an alkyne and an azide produced conjugates 4, 5 and 8-11. Evaluation of the antimalarial activity on both erythrocytic and hepatic stages is in progress.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija

POVEZANOST RADA