Uncovering new structural insights for antimalarial activity from cost-effective aculeatin-like derivatives

Abstract

A series of new aculeatin-like analogues were synthesized in two steps by combining two sets of building blocks. Many compounds showed inhibitory activities in vitro against Plasmodium falciparum and have helped to gain more insight into structure-activity relationships around the spirocyclohexadienone pharmacophoric scaffold. Plasmodium falciparum thioredoxin reductase (PfTrxR) has been investigated as a putative cellular target. Moreover, a new aculeatin-like scaffold without Michael acceptor properties, efficient at 0.86 μM against P. falciparum 3D7, was identified and raises the prospect of developing a new antimalarial agent.

Recent Advances in the Synthesis of Spiro‐β‐Lactams and Spiro‐δ‐Lactams

“…The synthesis of spirocyclohexadienone‐β‐lactams 100 with alkyl substituents from β‐keto amides 99 derived from 4‐aminophenol has been reported (Scheme 29). [46] The intramolecular lactamization occurs through a PIDA‐mediated oxidative process catalyzed by N , N ‐dimethyl‐4‐aminopyridine (DMAP) and copper sulfate. Spiro‐β‐lactams 100 were obtained in moderate to good yields (47–86%).…”

Methyl 8-oxo-2-phenyl-1-oxaspiro[4.5]deca-2,6,9-triene-3-carboxylate

“…This has been shown to increase their potential effectiveness as drugs (Winkler et al, 2015;Zheng et al, 2014). The title compound is a 5/6 spiro-ring fused system, in which the six-membered ring is a cyclohexadienone moiety where the carbonyl group and the two double bonds constitute a highly conjugated system, making it an efficient Michael acceptor.…”

“…Good evidence of the pharmacophoric properties of the cyclohexadienone moiety is the loss of antimalarial activity of aculeatin A when this group is reduced to the corresponding ketone analogue. Furthermore, construction of an aculeatin A analogue with two spirocyclohexadienone units led to improved antimalarial potency (Winkler et al, 2015).…”

Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery

“…This mechanistic behavior suggested the involvement of other plasmodial target apart from the classical Michael acceptors. These data suggest that the C-terminal redox center is the target for TrxR modification by (–)-aculeatin [31].…”