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Novel Harmicines with Improved Potency against Plasmodium

Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, HR-10 000 Zagreb, Croatia
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal
Institute of Tropical Medicine, University of Tübingen, Wilhelmstraße 27, 72074 Tübingen, Germany
Computational Organic Chemistry and Biochemistry Group, Rudjer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia
Author to whom correspondence should be addressed.
Academic Editor: Silvie Rimpelová
Molecules 2020, 25(19), 4376;
Received: 6 September 2020 / Revised: 17 September 2020 / Accepted: 22 September 2020 / Published: 23 September 2020
(This article belongs to the Special Issue Natural Product-Inspired Molecules: From Weed to Remedy)
Harmicines represent hybrid compounds composed of β-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 5af and O-harmicines 6ah 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. View Full-Text
Keywords: harmine; cinnamic acid; amide; antiplasmodial activity; PfHsp90; molecular dynamics simulations; P. berghei; P. falciparum harmine; cinnamic acid; amide; antiplasmodial activity; PfHsp90; molecular dynamics simulations; P. berghei; P. falciparum
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MDPI and ACS Style

Marinović, M.; Perković, I.; Fontinha, D.; Prudêncio, M.; Held, J.; Pessanha de Carvalho, L.; Tandarić, T.; Vianello, R.; Zorc, B.; Rajić, Z. Novel Harmicines with Improved Potency against Plasmodium. Molecules 2020, 25, 4376.

AMA Style

Marinović M, Perković I, Fontinha D, Prudêncio M, Held J, Pessanha de Carvalho L, Tandarić T, Vianello R, Zorc B, Rajić Z. Novel Harmicines with Improved Potency against Plasmodium. Molecules. 2020; 25(19):4376.

Chicago/Turabian Style

Marinović, Marina, Ivana Perković, Diana Fontinha, Miguel Prudêncio, Jana Held, Lais Pessanha de Carvalho, Tana Tandarić, Robert Vianello, Branka Zorc, and Zrinka Rajić. 2020. "Novel Harmicines with Improved Potency against Plasmodium" Molecules 25, no. 19: 4376.

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