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  • We report here the first

    2024-07-10

    We report here the first study on the inhibitory effects of the organic nitrates – on human erythrocyte GR. The previous reports by Becker et al., investigated other nitro derivatives (including arylizoalloxazines) by using Beutler’s method, monitoring GR inhibition. Data of show inhibition of hGR by compounds –. Compounds – behaved as strong inhibitors for GR, with values in the range of 11.7–44.3μM. -(1(),8(),)-8-hydroxycyclooct-4-enyl nitrate was relatively ineffective GR inhibitor (: 44.3μM), similarly to the structurally related compounds and (: 43.7μM). A second group of derivatives, including , and –, showed stronger inhibitory activity as compared to the previously mentioned organic nitrates, with values of 11.7–25.6μM, (). Thus, the nature of the groups in - and - to the cyclic OH moiety strongly influences GR inhibitory activity of the molecules. It is also interesting to note that hydroxybicyclo [2.2.1]heptan-2-yl nitrate derivatives – were much better hGR inhibitors as compared to the corresponding -(1(),2())-2-hydroxycyclohexyl nitrate () and -(1(),8(),)-8-hydroxycyclooct-4-enyl nitrate () from which they were prepared. Kinetic investigations (Lineweaver–Burke plots, data not shown) indicate that similarly to some Hydrocortisone and analgesic drugs,, , all the investigated organic nitrates act as noncompetitive inhibitors. These results suggest that protein sulphydryl groups are the target for inhibition by organic nitrates. The differences in the kinetics of inactivation of trypanothione reductase and glutathione reductase could reflect differences in the crystal structures of the disulphide-binding sites of the enzymes. The active site of trypanothione reductase is wider and possesses a hydrophobic and negatively charged region that accommodates the spermidine moiety of its substrate, whereas that of glutathione reductase is much narrower and contains a positively charged and hydrophilic region that interacts with the glycine carboxylates of glutathione disulphide. Molecular modelling studies show that in glutathione reductase, the disulphide-binding site is narrower, mainly due to Arg-A330, Arg-A20 and Asn-A100, whereas in trypanothione reductase, residues that are found at equivalent positions are hydrophobic and generally smaller. In both pockets, there is a His near to the phenyl ring of the drug which could serve to stabilise this aromatic moiety, while a Tyr close to the melaminyl ring may form electrostatic interactions with the considerable number of nitrogens. These additional noncovalent interactions could thus serve to stabilise the initial monothioarsane enzyme inhibitor complex., , Cunningham et al. demonstrated relatively weaker inhibitory activity of phenylarsenoxide and arsenite against both enzymes in their study. However, non-covalent interactions per se are insufficient to allow inhibition by analogues such as sodium melarsen or -[(4,6-diamino--triazin-2-yl)amino] benzoic acid ethyl ester that lack the trivalent arsenic atom. The most striking difference between glutathione reductase and trypanothione reductase is the 13-fold lower involving the time-dependent rearrangement to form the dithioarsane adduct. Comparison of the models of trypanothione reductase and glutathione reductase with the arsenical bound to the disulphide exchange thiol would suggest that the charge-transfer thiol is indeed less accessible in glutathione reductase due to the narrower active-site cleft.
    Introduction Secondary metabolites generated by microorganism or fungi are pharmaceutical compounds (Molitor et al., 2012; dos Santos et al., 2012). Fungi in the genus Fusarium produce various biologically active secondary metabolites, including cytotoxic fusarine (Ding et al., 2012), antibacterial beauvercin (Wang et al., 2011), antimalarial bostrycin (Trisuwan et al., 2010), and antifungal javanicin (Kornsakulkarn et al., 2011). In this paper we described the isolation and structure elucidation of metabolites from the soil fungus Fusarium solani PSU-RSPG37. The crude ethyl acetate extract from the culture broth of F. solani PSU-RSPG37 exhibited antimycobacterial, antimalaria, and cytotoxic activities. Investigation of the crude extract led to the isolation of two new pyrones, fusarpyrones A (1) and B (2) (Fig. 1), together with eight known compounds, anhydrofusarubin (3) (Shao et al., 2010), fusarubin (4) (Shao et al., 2010), 5-hydroxy-8-methoxy-2,4-dimethylnaphtho[1,2,b]furan-6,9-dione (5) (Kimura et al., 1988), 2,3-dihydro-5-hydroxy-8-methoxy-2,4-dimethylnaphtho[1,2,b]furan-6,9-dione (6) (Kimura et al., 1988), javanicin (7) (Kimura et al., 1988), fusalanipyrone (8) (Abraham and Arfmann, 1988), p-hydroxyacetophenone (Devkota et al., 2012), and tyrosol (Trisuwan et al., 2009). Their antimycobacterial, antimalaria, and cytotoxic activities were evaluated.