Novel Harmicines with Improved Potency against Plasmodium

Abstract

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 5a–f and O-harmicines 6a–h 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.

Synthesis and Biological Evaluation of Harmirins, Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

“…The obtained 4-chlorocoumarins 6a-d were then converted to azides 7a-d using sodium azide. The harmine-based azides 2 and 3 and the harmine-based terminal alkynes 8-10 were prepared according to our previously published procedure [30][31][32].…”

“…Hydrobromic acid (47%) and sodium azide were purchased from Merck (Darmstadt, Germany), dichloromethane from Fischer Scientific (Loughborough, U.K.), diethyl ether from ITW Reagents (Darmstadt, Germany), and anhydrous sodium sulfate from Gram-Mol (Zagreb, Croatia). Azides 2 and 3, as well as alkynes compounds 8-10, were synthesized according to the previously published procedures [30][31][32]. 4-Chlorocoumarins 6a-d and 4-azidocoumarins 7a-d were synthesized according to the slightly modified previously published procedure [29].…”

Potentiometric Surfactant Sensor Based on 1,3-Dihexadecyl-1H-benzo[d]imidazol-3-ium for Anionic Surfactants in Detergents and Household Care Products

“…The nonbonded interactions were truncated at 11.0 Å. The binding free energies among components, ∆G BIND , were calculated using the established MM-PBSA protocol [19,20], all in line with our earlier reports on similar systems [21][22][23]. For that purpose, every second snapshot, 75.000 in total, collected from the entire MD trajectory, were utilized.…”

Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future

“…Using molecular dynamics simulations, the residues implicated in improving binding affinities for N,O-bis -harmicines were the methoxy group in 8b, which was stabilized by Asp79 [ 142 ]. As such, to utilize the triazole ring that was not contributing to PfHsp90 binding, a triazole was replaced by an amide bond, its bioisostere, to produce amide-type harmicides 5 and 6 [ 143 ]. These N -harmicines 5 and O- harmicides 6 compounds had higher antiplasmodial activity than the triazole-type harmicines.…”

“…These N -harmicines 5 and O- harmicides 6 compounds had higher antiplasmodial activity than the triazole-type harmicines. The most active compound against both chloroquine-sensitive and resistant strains, P. falciparum 3D7 (IC 50 040 nM) and Dd2 (IC 50 170 nM), respectively, was N- harmicine 5e [ 143 ]. Notably, both compounds 5b, and 5a showed the highest selectivity indices (ratio of IC 50 of the parasite cell line P. falciparum 3D7 compared to host cell line HepG2) with SI >700.…”