Abstract
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.
Highlights
Malaria is a life-threatening parasitic disease that kills over 400,000 people each year, mainly children under 5 years of age in sub-Saharan Africa [1]
We report the synthesis of amide-type harmicines, their activity against both most active compound within the ATP binding site of P. falciparum heat shock protein 90 (Pf Hsp90) [15], erythrocytic and hepatic stages of Plasmodium infection, and their cytotoxicity
We evaluated the drug-like properties of the binding to Pf Hsp90 affects their activity
Summary
Malaria is a life-threatening parasitic disease that kills over 400,000 people each year, mainly children under 5 years of age in sub-Saharan Africa [1]. Five species of Plasmodium cause malaria in humans, and the most severe form of the disease is caused by P. falciparum, which is the most prevalent malaria parasite [2]. The complex life cycle of Plasmodium includes two hosts, Anopheles mosquitoes and mammals. In the latter, a clinically silent phase of hepatic infection obligatorily precedes a subsequent erythrocytic infection stage, responsible for the symptoms of malaria [3]. Since 2001, when the WHO recommended the use of artemisinin-based combination therapies (ACTs) for treating P. falciparum malaria, ACTs have become the mainstay of malaria therapy due to their high. Failure rates of P. falciparum treatments to the first-line ACTs were found to be above 10% in the Southeast Asia Region, and were as high as Molecules
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