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Novel harmicines with improved potency against plasmodium

Authors :
Ivana Perković
Zrinka Rajić
Jana Held
Robert Vianello
Branka Zorc
Marina Marinović
Diana Fontinha
Miguel Prudêncio
Lais Pessanha de Carvalho
Tana Tandarić
Repositório da Universidade de Lisboa
Source :
Repositório Científico de Acesso Aberto de Portugal, Repositório Científico de Acesso Aberto de Portugal (RCAAP), instacron:RCAAP, Molecules, Volume 25, Issue 19, Molecules, Vol 25, Iss 4376, p 4376 (2020)
Publication Year :
2020
Publisher :
MDPI, 2020.

Abstract

Harmicines represent hybrid compounds composed of &beta<br />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&ndash<br />f and O-harmicines 6a&ndash<br />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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Repositório Científico de Acesso Aberto de Portugal, Repositório Científico de Acesso Aberto de Portugal (RCAAP), instacron:RCAAP, Molecules, Volume 25, Issue 19, Molecules, Vol 25, Iss 4376, p 4376 (2020)
Accession number :
edsair.doi.dedup.....fd5222086219271d5970f2f366419ff7