Non-symmetrical furan-amidines as novel leads for the treatment of cancer and malaria

Abstract

NRH:quinone oxidoreductase 2 enzyme (NQO2) is a potential therapeutic target in cancer and neurodegenerative diseases, with roles in either chemoprevention or chemotherapy. Here we report the design, synthesis and evaluation of non-symmetrical furan-amidines and their analogues as novel selective NQO2 inhibitors with reduced adverse off-target effects, such as binding to DNA. A pathway for the synthesis of the non-symmetrical furan-amidines was established from the corresponding 1,4-diketones. The synthesized non-symmetrical furan-amidines and their analogues showed potent NQO2 inhibition activity with nano-molar IC50 values. The most active compounds were non-symmetrical furan-amidines with meta- and para-nitro substitution on the aromatic ring, with IC50 values of 15 nM. In contrast to the symmetric furan-amidines, which showed potent intercalation in the minor grooves of DNA, the synthesized non-symmetrical furan-amidines showed no affinity towards DNA, as demonstrated by DNA melting temperature experiments. In addition, Plasmodium parasites, which possess their own quinone oxidoreductase PfNDH2, were inhibited by the non-symmetrical furan-amidines, the most active possessing a para-fluoro substituent (IC50 9.6 nM). The high NQO2 inhibition activity and nanomolar antimalarial effect of some of these analogues suggest the lead compounds are worthy of further development and optimization as potential drugs for novel anti-cancer and antimalarial strategies.

Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway

“…In addition, we tested the compounds against a small panel of human cancer cell lines. In recent years, numerous reports have shown that compounds with antimalarial activity may represent potential anticancer agents, and vice versa [47–49]. The results obtained were compared to our previous findings on asexual P. falciparum and HEK293 cells [22] .…”

Evaluation of analogues of furan-amidines as inhibitors of NQO2

“…NQO2 is a potential target for cancer chemotherapy as its inhibition has therapeutic and/or preventative potential. In our laboratory, non-symmetrical furanamidine 1 (Figure 1) and para-substituted analogues were identified as novel lead inhibitors of NQO2 with both anti-cancer and anti-malarial activities [3]. Here, further modifications to these non-symmetrical furan-amidines have been evaluated.…”

“…Here, further modifications to these non-symmetrical furan-amidines have been evaluated. Some of the non-symmetrical furan-amidines [3] showed poor water solubility, therefore the furan ring of 1 was replaced by more water-soluble isosteric heterocycles, including imidazole and oxazole. The lead NQO2 furan inhibitor possesses the highly basic amidine group, which will potentially decrease its passive diffusion and oral bioavailability [4,5].…”

“…The syntheses of these analogues are illustrated in Schemes 5 and 6. It was anticipated that heating of ethyl benzimidate hydrochloride 30 (prepared by reaction of nitrile 31 with ethanol) [3] at reflux with ammonium chloride methanol/water would give the furan-amidine 1, however the isolated product was the methyl imidate 23 [16] (Scheme 5). The methyl imidate group is a much less basic isostere (pKa 6.2) [16] than the highly basic amidine group (pKa 11.8) [17].…”

Synthesis, characterization and DNA interactions of [Pt3(TPymT)Cl3], the trinuclear platinum(II) complex of the TPymT ligand

“…Pt 3 L 3+ shows the strongest effects, with a destabilisation of the polynucleotide double helix that brings about a T m decrease of about 4° C. <Figure 5near here> Melting temperature changes are not a direct measure of affinity but their extent allows to comment on the ability of the binding molecule to alter the stability of the double strand. In the case of intercalation of a small planar molecule between the base pairs a major stabilisation effect is observed (usually ∆Tm>10° C,[18]),…”