Projects of the Faculty of Pharmacy and Biochemistry
Harmine derivatives as potential antimalarial agents
| Status | project.status.4 |
|---|---|
| Acronym | CLICKforMALARIA |
| Summary | Malaria is a deadly mosquito-borne tropical and subtropical disease, caused by parazite of the genus Plasmodium. The most severe form of the disease is caused by P. falciparum. There is neither available vaccine for malaria, nor reliable vector control. In addition, Plasmodium is steadily developing resistance to the existing therapy, which urges the discovery of novel drugs with new mechanisms of action. Alkaloids of -carboline type are present in the medicinal plants Peganum harmala and Eurycoma longifolia, which have been used in the traditional Oriental medicine for the treatment of cancer and malaria. The active ingredients were identified as harmine, harmaline, harmalol and harman. In vitro and in vivo studies have proven harmine's antimalarial activity. Its possible mechanism of action is selective inhibition of P. falciparum heat shock protein 90, which is crucial for the parazite development and may play a major role in drug resistance. In the proposed project we decided to focus on the design and synthesis of a compound library (harmizoles), comprising harmine and 1) cinnamic acid moiety (harmicines), 2) known antimalarial drugs: chloroquine or mefloquine (harmiquines) and 3) ferrocene scaffold (harmocenes). The proposed hybrid drugs combine elements of the potent antimalarial alkaloide harmine with those from the established drugs (chloroquine and mefloquine) or compounds which enhance antimalarial acitvity (cinnamic acid and ferrocene). Standard methods of synthetic organic chemistry, as well as modern approaches, such as click chemistry and microwave assisted synthesis will be employed. Click chemistry approach will result in incorporating 1H-1,2,3-triazole scaffolds, which proved to be useful in the synthesis of various biologically active compounds. It will also enable versatility: a small number of alkyne and azide building blocks will be multiply combined to generate compound library, i.e. harmizoles. Antimalarial activity of the prepared compounds will be evaluated in vitro on both intra-erythrocytic and hepatic stage of the malaria parasite, as well as cytotoxycity against human cell lines. In addition, we will evaluate metabolic stability and determine metabolites of the active compounds using human liver microsomes and recombinant CYP450 enzymes. The proposed project is multidisciplinary and significant in the fields of medicinal chemistry (innovative and novel compounds will be generated) and biomedicine (antimalarial activity of the new compounds will be evaluated; a detailed biotransformation study of the active compounds will be conducted. As a final result, we will provide new candidate therapeutics against drug-resistant malaria parasite. The most active compounds will offer a valuable starting point for future development of innovative medicines. |
| Line of financing |
Croatian Science Foundation |
| Duration | 01.04.2018. - 30.06.2023. |
| Budget amount | Budget amount is not defined |
| Lead | - |
| Results |