The guanylhydrazone CNI-1493: an inhibitor with dual activity against malaria—inhibition of host cell pro-inflammatory cytokine release and parasitic deoxyhypusine synthase

Abstract

Malaria is still a major cause of death in the tropics. There is an urgent need for new anti-malarial drugs because drug-resistant plasmodia frequently occur. Over recent years, we elucidated the biosynthesis of hypusine, a novel amino acid contained in eukaryotic initiation factor 5A (eIF-5A) in Plasmodium. Hypusine biosynthesis involves catalysis of deoxyhypusine synthase (DHS) in the first step of post-translational modification. In a screen for new inhibitors of purified plasmodium DHS, CNI-1493, a novel selective pro-inflammatory cytokine inhibitor used in clinical phase II for the treatment of Crohn's disease, inhibited the enzyme of the parasite 3-fold at a concentration of 2 microM. In vitro experiments with 200 microM CNI-1493 in Plasmodium-infected erythrocytes, which lack nuclei and DHS protein, showed a parasite clearance within 2 days. This can presumably be attributed to an anti-proliferating effect because of the inhibition of DHS by the parasite. The determined IC50 of CNI-1493 was 135.79 microM after 72 h. In vivo application of this substance in Plasmodium berghei ANKA-infected C57BL/6 mice significantly reduced parasitemia after dosage of 1 mg/kg or 4 mg/kg/body weight and prevented death of mice with cerebral malaria. This effect was paralleled by a decrease in serum TNF levels of the mice. We suggest that the new mechanism of CNI-1493 is caused by a decrease in modified eIF-5A biosynthesis with a downstream effect on the TNF synthesis of the host. From the current data, we consider CNI-1493 to be a promising drug for anti-malarial therapy because of its combined action, i.e., the decrease in eIF-5A biosynthesis of the parasite and host cell TNF biosynthesis.

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase

“…Guanylhydrazones were selected because they contain one cationic site and therefore are appropriate to interact with the anionic region of the AChE active site and compete with acetylcholine. Several guanylhydrazones have been used as pharmacological agents for diverse diseases, such as cancer 25,26 , Chagas disease 27,28 , malaria and others 29 . These compounds were also studied by NMR and theoretical chemistry 30 .…”

New furin inhibitors based on weakly basic amidinohydrazones

“…11 Furthermore, CNI-1493, an anti-inflammatory and anti-parasitic compound that contains four amidinohydrazone groups, reached phase II clinical trials for the treatment of Crohn’s disease. 12–14 Very recently, in parallel to our work a related amidinohydrazone derived furin inhibitor 2 was identified by HTS. 15 …”

Quinoline-based antimalarial hybrid compounds

“…[172][173] In view of these characteristics, it was envisaged to link 4-aminoquinoline with N-acylhydrazone via an appropriate linker, resulting in hybrid molecules 94 ( Figure 46). Nucleophilic aromatic substitution of 4,7-dichloroquinoline with piperazine afforded 7-chloro-4-piperazin-1-ylquinoline, which was subsequently reacted with methyl acrylate under neat conditions.…”