Arylmethylamino steroids as antiparasitic agents

Abstract

In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC50 1–5 nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes. The steroid compounds show low cytotoxicity in mammalian cells and do not induce acute toxicity symptoms in mice. Moreover, 1o has a remarkable activity against the blood-feeding trematode parasite Schistosoma mansoni. The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation. This study identifies chemical scaffolds that are rapidly internalized into blood-feeding parasites.

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

“…C) Chemical structures of the most potent BACADs . D) Chemical structures of AASs 33 – 35 with antischistosomal activity …”

“…In addition, studies with adult S. mansoni confirmed that AASs exert fatal effects on morphology, physiology, and survival of female and male worms in vitro. This was achieved using concentrations similar to PZQ ( 9 ) …”

“…[123] D) Chemical structures of AASs 33-35 with antischistosomal activity. [130] bond with His292. The first series of inhibitors contained a3aminobenzohydroxamate or 3-amidobenzohydroxamate, respectively,a sacore scaffold (e.g., 22 and 23,F igure 4A).…”

“…This was achieved using concentrations similart oP ZQ (9). [130] Among 60 AAS derivatives, three compounds( 33-35,F igure 4D)s howed ad ecreasei np airing stability, eggp roduction, and viability. For antischistosomala ctivity,t he N-(2-hydroxy)benzylo rN-(3-hydroxynaphth-2-ylmethyl) moiety was essential.…”

“…Oocytes appearedt ob ed isorganized within the ovaries of treated females, and the sizes of the testicular lobes were reduced in treated males. [130] Although the exact mode of action is unclear,t he data obtained justifies furtherdevelopment of this class of compounds.…”