Natural product-inspired aryl isonitriles as a new class of antimalarial compounds against drug-resistant parasites

Abstract

Malaria is a prevalent and deadly disease. The fast emerging of drug resistant malaria parasites makes the situation even worse. Thus, developing new chemical entities, preferably with novel mechanisms of action, is urgent and important. Inspired by the complex and scarce isonitrilecontaining terpene natural products, we evaluated a collection of easily prepared synthetic monoand bis-isonitrile compounds, most of which feature a simple, but rigid stilbene backbone. From this collection, potent antimalarial lead compounds against the Dd2 strain using a blood stage proliferation assay were identified. These compounds include 31 (EC 50 = 88 nM), 41 (EC 50 = 68 nM), and 43 (EC 50 = 27 nM). Preliminary SAR information showed that the isonitrile group is essential for the observed activity against the Dd2 strain and the bis-isonitrile compounds in general perform better than the corresponding mono-isonitrile compounds.

Marine organisms as potential sources of natural products for the prevention and treatment of malaria

“…They have weak antimalarial activity against the P. falciparum Columbian FcB1 strain (IC 50 = 6.6, 8.3, and 18 mM, respectively). 61 Netamines G-N ( [60][61][62][63][64][65][66][67] ) and tricyclic alkaloids were obtained from the Madagascar sponge Biemna laboutei (Desmacellidae). Netamine K showed antimalarial activity (IC 50 = 2.4 mM) against P. falciparum.…”

Medicinal Chemistry of Isocyanides

“…Author hypothesized that bis-isocyanides could interact with two different heme-iron due to the high density of heme in the parasitic environment. This rationale could explain why symmetrical diisocyanides are such potent compounds against Plasmodium falciparum …”

Can the isonitrile biosynthesis enzyme ScoE assist with the biosynthesis of isonitrile groups in drug molecules? A computational study

“…3,4 Some of these compounds have interesting medicinal properties and act as antifungal, antimalarial and antibacterial entities. [5][6][7] Understanding how nature synthesizes these natural products, therefore, is important. However, since most of these reaction processes happen fast, a computational analysis is needed to establish details of the reaction mechanism and the oxidants involved in the process.…”

“…There are several enzymes in nature responsible for the biosynthesis of isonitrile groups in natural compounds. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] One of those is a nonheme iron enzyme called ScoE, which uses dioxygen and a-ketoglutarate (aKG) as the co-substrate on an iron centre and converts a g-glycine subunit in a peptide chain to isonitrile through initial desaturation followed by decarboxylation. 14 Several crystal structures of ScoE have been reported and the active site structure of the most recent one as reported in the 6XN6 protein databank (pdb) file is shown in Fig.…”