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Novel Harmicines with Improved Potency against Plasmodium

Marinović, Marina; Perković, Ivana; Fontinha, Diana; Prudêncio, Miguel; Held, Jana; Pessanha de Carvalho, Lais; Tandarić, Tana; Vianello, Robert; Zorc, Branka; Rajić, Zrinka (2020) Novel Harmicines with Improved Potency against Plasmodium. Molecules, 25 (19). ISSN 1420-3049

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Harmicines represent hybrid compounds composed of β-carboline alkaloid harmine and cinnamic acid derivatives (CADs). In this paper we report the synthesis of amide-type harmicines and the evaluation of their biological activity. N-harmicines 5a–f and O-harmicines 6a–h were prepared by a straightforward synthetic procedure, from harmine-based amines and CADs using standard coupling conditions, 1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo [4, 5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and N, N-diisopropylethylamine (DIEA). Amide-type harmicines exerted remarkable activity against the erythrocytic stage of P. falciparum, in low submicromolar concentrations, which was significantly more pronounced compared to their antiplasmodial activity against the hepatic stages of P. berghei. Furthermore, a cytotoxicity assay against the human liver hepatocellular carcinoma cell line (HepG2) revealed favorable selectivity indices of the most active harmicines. Molecular dynamics simulations demonstrated the binding of ligands within the ATP binding site of PfHsp90, while the calculated binding free energies confirmed higher activity of N-harmicines 5 over their O-substituted analogues 6. Amino acids predominantly affecting the binding were identified, which provided guidelines for the further derivatization of the harmine framework towards more efficient agents.

Item Type: Article
Uncontrolled Keywords: harmine ; cinnamic acid ; amide ; antiplasmodial activity ; PfHsp90 ; molecular dynamics simulations ; P. berghei ; P. falciparum
Divisions: Division of Organic Chemistry and Biochemistry
Project titleProject leaderProject codeProject type
Derivati harmina kao potencijalni antimalarici-CLICKforMALARIAZrinka Rajić DžolićUIP-2017-05-5160HRZZ
Depositing User: Robert Vianello
Date Deposited: 11 Nov 2020 16:05
DOI: 10.3390/molecules25194376

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