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.

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Steroids are compounds widely available in nature and synthesized for therapeutic and medical purposes. Although several analytical techniques are available for the quantification of steroids, their analysis is challenging due to their low levels and complex matrices of the samples. The efficiency and quick separation of the HPLC combined with the sensitivity, selectivity, simplicity, and cost-efficiency of fluorescence, make HPLC coupled to fluorescence detection (HPLC-FLD) an ideal tool for routine measurement and detection of steroids. In this review, we covered HPLC-FLD methods reported in the literature for the steroids quantification in clinical, pharmaceutical, and environmental applications, focusing on the various approaches of fluorescent derivatization. The aspects related to analytical methodology including sample preparation, derivatization reagents, and chromatographic conditions will be discussed.

Inhibitors of the enzyme NQO2 (NRH: quinone oxidoreductase 2) are of potential use in cancer chemotherapy and malaria. We have previously reported that non-symmetrical furan amidines are potent inhibitors of NQO2 and here novel analogues are evaluated. The furan ring has been changed to other heterocycles (imidazole, N-methylimidazole, oxazole, thiophene) and the amidine group has been replaced with imidate, reversed amidine, N-arylamide and amidoxime to probe NQO2 activity, improve solubility and decrease basicity of the lead furan amidine. All compounds were fully characterised spectroscopically and the structure of the unexpected product N-hydroxy-4-(5-methyl-4-phenylfuran-2-yl)benzamidine was established by X-ray crystallography. The analogues were evaluated for inhibition of NQO2, which showed lower activity than the lead furan amidine. The observed structure-activity relationship for the furan-amidine series with NQO2 was rationalized by preliminary molecular docking and binding mode analysis. In addition, the oxazole-amidine analogue inhibited the growth of Plasmodium falciparum with an IC value of 0.3 μM.

Ketorolac, an NSAID, has low intrinsic permeation capacity through the skin. In this work, seven piperazinylalkyl ester prodrugs of ketorolac were synthesized to enhance its skin permeation. The chemical hydrolysis and the stability in human serum at 37°C were investigated in buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs were chemically more stable at pH 5.0 than at pH 7.4 with prodrug 8 being the most stable (t 1/2 = 119.75 h and 11.97 h at pH 5 and 7.4, respectively). The prodrugs' t 1/2 in human serum ranged from 0.79 to 3.92 min. The prodrugs' aqueous solubility was measured in buffer solution at pH 5.0 and 7.4 and Log P app was measured by partitioning between buffer solution (pH 5.0 and 7.4) and n-octanol. The prodrugs were more lipophilic than ketorolac at pH 7.4. Skin permeation of ketorolac and prodrug 8, the most stable chemically, through rat skin was studied at pH 5.0 and 7.4. Prodrug 8 enhanced permeation by 1.56-and 11.39-fold at pH 5 and 7.4, respectively. This is attributed to higher lipophilicity at pH 7.4 and higher aqueous solubility at pH 5 compared to ketorolac.

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