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Novel harmicines with improved potency against plasmodium
- 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.
- Subjects :
- Amide
PfHsp90
Stereochemistry
Pharmaceutical Science
P. berghei
Pharmacy
antiplasmodial activity
P. falciparum
01 natural sciences
Cinnamic acid
Analytical Chemistry
lcsh:QD241-441
03 medical and health sciences
chemistry.chemical_compound
harmine
cinnamic acid
amide
molecular dynamics simulations
Harmine
lcsh:Organic chemistry
Drug Discovery
HATU
Physical and Theoretical Chemistry
Binding site
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
010405 organic chemistry
Molecular dynamics simulations
Organic Chemistry
Biological activity
0104 chemical sciences
3. Good health
Amino acid
chemistry
Chemistry (miscellaneous)
Molecular Medicine
Antiplasmodial activity
Pyridinium
Subjects
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