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.