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  • Harmicines - harmine and cinnamic acid hybrids as novel antiplasmodial hits.

Harmicines - harmine and cinnamic acid hybrids as novel antiplasmodial hits.

European journal of medicinal chemistry (2019-12-08)
Ivana Perković, Silvana Raić-Malić, Diana Fontinha, Miguel Prudêncio, Lais Pessanha de Carvalho, Jana Held, Tana Tandarić, Robert Vianello, Branka Zorc, Zrinka Rajić
ABSTRACT

Harmicines constitute novel hybrid compounds that combine two agents with reported antiplasmodial properties, namely β-carboline harmine and a cinnamic acid derivative (CAD). Cu(I) catalyzed azide-alkyne cycloaddition was employed for the preparation of three classes of hybrid molecules: N-harmicines 6a-i, O-harmicines 7a-i and N,O-bis-harmicines 8a-g,i. In vitro antiplasmodial activities of harmicines against the erythrocytic stage of Plasmodium falciparum (chloroquine-sensitive Pf3D7 and chloroquine-resistant PfDd2 strains) and hepatic stage of P. berghei, as well as cytotoxicity against human liver hepatocellular carcinoma cell line (HepG2), were evaluated. Remarkably, most of the compounds exerted significant activities against both stages of the Plasmodium life cycle. The conjugation of various CADs to harmine resulted in the increased antiplasmodial activity relative to harmine. In general, O-harmicines 7 exhibited the highest activity against the erythrocytic stage of both P. falciparum strains, whereas N,O-bis harmicines 8 showed the most pronounced activity against P. berghei hepatic stages. For the latter compound, molecular dynamics simulations confirmed binding within the ATP binding site of PfHsp90, while the weaker binders, namely 6b and harmine, were found to be positioned away from this structural element. In addition, decomposition of the computed binding free energies into contributions from individual residues suggested guidelines for further derivatization of harmine towards more efficient compounds. Cytotoxicity screening revealed N-harmicines 6 as the least, and O-harmicines 7 as the most toxic compounds. Harmicines 6g, 8b and 6d exerted the most selective action towards Plasmodium over human cells, respectively. These results establish harmicines as hits for future optimisation and development of novel antiplasmodial agents.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
4-Chlorocinnamic acid, 99%
Sigma-Aldrich
4-Fluorocinnamic acid, 99%
Sigma-Aldrich
Harmine, 98%