title: 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.
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Soraya
authors: S
authors: Alnabulsi
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Elham
authors: E
authors: Santina
authors: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors: Ilaria
authors: I
authors: Russo
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Buthaina
authors: B
authors: Hussein
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK; CRUK-EPSRC Cancer Imaging Centre in Cambridge and Manchester, Manchester M20 3LJ, UK.
authors: Manikandan
authors: M
authors: Kadirvel
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Amy
authors: A
authors: Chadwick
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Elena V
authors: EV
authors: Bichenkova
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Richard A
authors: RA
authors: Bryce
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Karen
authors: K
authors: Nolan
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Constantinos
authors: C
authors: Demonacos
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK.
authors: Ian J
authors: IJ
authors: Stratford
authors: Manchester Pharmacy School, University of Manchester, Manchester M13 9PT, UK. Electronic address: Sally.Freeman@manchester.ac.uk.
authors: Sally
authors: S
authors: Freeman
mesh_terms: D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010961:Plasmodium / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000578:Amidines; D000962:Antimalarials; D000970:Antineoplastic Agents; D005663:Furans
keywords: Anticancer; Breast cancer; Infectious diseases; Malaria; NQO2 inhibitors; Non-symmetrical furan-amidines; Synthesis