engleski

Synthesis of amide-type harmicens - harmine- ferrocene hybrids

Background Malaria is a life-threatening parasitic disease responsible for more than 400 000 annually. The greatest challenge in the chemotherapy of malaria is the development of effective treatments against drug-resistant Plasmodium strains. An attractive approach, extensively used in drug development, is molecular hybridization. Linking two or more bioactive molecules into one single hybrid provides the potential to enhance the efficacy of each bioactive molecule and to overcome the drug resistance. Aims β-Carboline alkaloid harmine is a promising antimalarial agent targeting P. falciparum heat- shock protein 90 (PfHsp90). Furthermore, the combination of the organometallic compound ferrocene and known antimalarials, such as chloroquine and dihydroartemisinin, has been proven to increase their efficacy. Therefore, we have decided to combine those two entities into one single molecule, i.e. prepare harmine- ferrocene hybrids. Methods Two β-carboline rings were synthesized by Pictet- Spengler reaction. Coupling reactions were performed by using standard coupling reagents, HATU/DIEA. Microwave- assisted reactions were performed in a microwave reactor (Discover SP, CEM). NMR spectra were recorded on a Bruker Avance III HD operating at 300 or 400 MHz for the 1H and 101 or 151 MHz for the 13C nuclei (Bruker). Mass spectra were recorded on HPLC- MS/MS instrument (Agilent Technologies) using electrospray ionization in positive mode. FTIR- ATR spectra were recorded using a Fourier- Transform Infrared Attenuated Total Reflection UATR Two Spectrometer (PerkinElmer). All chemicals and solvents were purchased from commercial sources. Results Here we present four novel amide-type harmicens, harmine and ferrocene hybrids, synthesized at C- 1, C-3, O-7 and N-9 positions of the β-carboline core, prepared by the reaction of harmine-based amines and ferrocene acetic acid.In order to establish structure diversity, the desired amines were prepared at four different positions of the harmine’s β-carboline core: 1, 3, 7 and 9. Synthesis of amines at C-1 and C-3 included several reaction steps. First, β-carboline rings were synthesised by Pictet-Spengler condensation of tryptamine (C-1) or tryptophan methyl ester (C-3) with a corresponding aldehyde (2, 2- dimethoxyacetaldehyde/acetaldehyde dimethyl acetal) in TFA/DCM, followed by aromatisation with KMO4 in DMF at rt (C-1) or in the microwave reactor using 10% Pd/C in EtOH (C-3). Subsequent removal of the acetal group at C-1 using AcOH/H2O generated the corresponding aldehyde. Ester (C-3) and aldehyde (C-1) were reduced with LiAlH4 in THF to alcohols, followed by azidation with ADMP/DBU and further catalytic hydrogenation to give rise to harmine-based amines 1 and 2. Amines 3 and 4, at O-7 and N-9, were synthesised by the alkylation of harmine or harmole with 2-(Boc- amino)ethyl bromide in presence of Cs2CO3 in DMF. Removal of the Boc-protecting group under acidic conditions (HCl/MeOH) resulted in the preparation of the corresponding amines. Finally, coupling reactions between harmine-based amines and ferrocene acetic acid were performed by using HATU and DIEA in DCM. The title compounds were purified by column chromatography, recrystallized from ethanol, triturated with diethyl ether and fully characterized by IR, 1H and 13C-NMR spectroscopy and MS. Conclusion Four novel amide- type harmicens 5-8 were successfully synthesized and characterized. Evaluation of harmicens antimalarial activity, on both erythrocytic and hepatic stages of the Plasmodium life cycle, as well as cytotoxicity against human cell lines is in progress.

malaria ; hybridization ; β-Carboline ; ferrocene, amide-type

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