Further investigation of harmicines as novel antiplasmodial agents: Synthesis, structure-activity relationship and insight into the mechanism of action

• Published in: European journal of medicinal chemistry 2021-11, Vol.224, p.113687-113687, Article 113687
• Main Authors: Marinović, Marina, Poje, Goran, Perković, Ivana, Fontinha, Diana, Prudêncio, Miguel, Held, Jana, Pessanha de Carvalho, Lais, Tandarić, Tana, Vianello, Robert, Rajić, Zrinka
• Format: Article
• Language: English
• Subjects: Antiplasmodial activity; Cinnamic acid; Harmine; Hybrid compounds; P. berghei; P. falciparum; P. berghei; P. falciparum; PfHsp90; β-Carboline
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.113687

The rise of the resistance of the malaria parasite to the currently approved therapy urges the discovery and development of new efficient agents. Previously we have demonstrated that harmicines, hybrid compounds composed from β-carboline alkaloid harmine and cinnamic acid derivatives, linked via either triazole or amide bond, exert significant antiplasmodial activity. In this paper, we report synthesis, antiplasmodial activity and cytotoxicity of expanded series of novel triazole- and amide-type harmicines. Structure-activity relationship analysis revealed that amide-type harmicines 27, prepared at N-9 of the β-carboline core, exhibit superior potency against both erythrocytic stage of P. falciparum and hepatic stages of P. berghei. Notably, harmicine 27a, m-(trifluoromethyl)cinnamic acid derivative, exhibited the most favourable selectivity index (SI = 1105). Molecular dynamics simulations revealed the ATP binding site of P. falciparum heat shock protein 90 as a druggable binding location, confirmed the usefulness of the harmine's N-9 substitution and identified favourable N–H … π interactions involving Lys45 and the aromatic phenyl unit in the attached cinnamic acid fragment as crucial for the enhanced biological activity. Thus, those compounds were identified as promising and valuable leads for further derivatization in the search of novel, more efficient antiplasmodial agents. [Display omitted] •Synthesis of amide- and triazole-type harmicines at C1, C3, O6 and N9 of β-carboline.•SAR analysis pointed to N9 as the most favourable position of the β-carboline ring substitution.•Harmicines 27 exert in vitro nanomolar activity against P. falciparum erythrocytic stage.•The most selective compound of all prepared harmicines was 27a.•Molecular dynamics simulations suggest binding of 27b within PfHsp90 ATP binding site.