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Harmicines − harmine and cinnamic acid hybrids as novel antiplasmodial hits


Perković, Ivana; Raić-Malić, Silvana; Fontinha, Diana; Prudêncio, Miguel; Pessanha de Carvalho, Lais; Held, Jana; Tandarić, Tana; Vianello, Robert; Zorc, Branka; Rajić, Zrinka
Harmicines − harmine and cinnamic acid hybrids as novel antiplasmodial hits // European journal of medicinal chemistry, 187 (2019), 111927, 16 doi:10.1016/j.ejmech.2019.111927 (međunarodna recenzija, članak, znanstveni)


Naslov
Harmicines − harmine and cinnamic acid hybrids as novel antiplasmodial hits

Autori
Perković, Ivana ; Raić-Malić, Silvana ; Fontinha, Diana ; Prudêncio, Miguel ; Pessanha de Carvalho, Lais ; Held, Jana ; Tandarić, Tana ; Vianello, Robert ; Zorc, Branka ; Rajić, Zrinka

Izvornik
European journal of medicinal chemistry (0223-5234) 187 (2019); 111927, 16

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Harmine ; cinnamic acid ; triazole ; azide-alkyne cycloaddition ; antiplasmodial activity ; PfHsp90 ; molecular dynamics ; P. berghei ; P. falciparum

Sažetak
Harmicines constitute novel hybrid compounds that combine two agents with reported antiplasmodial properties, namely beta- 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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Farmacija



POVEZANOST RADA


Projekt / tema
HRZZ-UIP-2017-05-5160 - Derivati harmina kao potencijalni antimalarici (Zrinka Rajić Džolić, )

Ustanove
Farmaceutsko-biokemijski fakultet, Zagreb,
Institut "Ruđer Bošković", Zagreb,
Fakultet kemijskog inženjerstva i tehnologije, Zagreb

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


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