Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones

Abstract

Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified.

Ultrasound-Assisted Extraction of Antimalarial Compounds from the Bidara Laut (Strychnos ligustrina) Heartwood

“…Matthews (2015) stated that quinaprilat is the most effective compound inhibiting P. falciparum. Lande et al (2021) also discovered that the compound 3,4bis-cyclobut-3-ene-1,2-dione inhibit protein kinase plasmodial, which had a significant impact on the parasite malaria's life cycle (Arendse et al 2021). The findings of this study demonstrated that aqueous bidara laut heartwood extract from the maceration and UAE extraction methods could dissolve antimalarial alkaloid compounds.…”

Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis

“…Most derivatives showed submicromolar activity, and some displayed some selectivity against the human cell line THP-1. The most active compounds did not inhibit the plasmodial protein kinase PfGSK-3, so further studies are required to elucidate the mechanism of action of these compounds and to design derivatives with optimized aqueous solubility [ 71 ].…”

Functional inactivation of Plasmodium falciparum glycogen synthase kinase GSK3 modulates erythrocyte invasion and blocks gametocyte maturation

“…In previous studies, PfGSK3β was considered as likely essential in asexual stages of the parasite and investigated as a potential drug target for the development of antimalarial kinase inhibitors ( 10 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ).…”