The hepatitis C virus (HCV) nonstructural protein 3 (NS3) is both a protease, which cleaves viral and host proteins, and a helicase that separates nucleic acid strands, using ATP hydrolysis to fuel the reaction. Many antiviral drugs, and compounds in clinical trials, target the NS3 protease, but few helicase inhibitors that function as antivirals have been reported. This study focuses on the analysis of the mechanism by which ebselen (2-phenyl-1,2-benzisoselenazol-3-one), a compound previously shown to be a HCV antiviral agent, inhibits the NS3 helicase. Ebselen inhibited the abilities of NS3 to unwind nucleic acids, to bind nucleic acids, and to hydrolyze ATP, and about 1 μM ebselen was sufficient to inhibit each of these activities by 50%. However, ebselen had no effect on the activity of the NS3 protease, even at 100 times higher ebselen concentrations. At concentrations below 10 μM, the ability of ebselen to inhibit HCV helicase was reversible, but prolonged incubation of HCV helicase with higher ebselen concentrations led to irreversible inhibition and the formation of covalent adducts between ebselen and all 14 cysteines present in HCV helicase. Ebselen analogues with sulfur replacing the selenium were just as potent HCV helicase inhibitors as ebselen, but the length of the linker between the phenyl and benzisoselenazol rings was critical. Modifications of the phenyl ring also affected compound potency over 30-fold, and ebselen was a far more potent helicase inhibitor than other, structurally unrelated, thiol-modifying agents. Ebselen analogues were also more effective antiviral agents, and they were less toxic to hepatocytes than ebselen. Although the above structure–activity relationship studies suggest that ebselen targets a specific site on NS3, we were unable to confirm binding to either the NS3 ATP binding site or nucleic acid binding cleft by examining the effects of ebselen on NS3 proteins lacking key cysteines.
c Parasites in the genus Plasmodium cause disease throughout the tropic and subtropical regions of the world. P. falciparum, one of the deadliest species of the parasite, relies on glycolysis for the generation of ATP while it inhabits the mammalian red blood cell. The first step in glycolysis is catalyzed by hexokinase (HK). While the 55.3-kDa P. falciparum HK (PfHK) shares several biochemical characteristics with mammalian HKs, including being inhibited by its products, it has limited amino acid identity (ϳ26%) to the human HKs, suggesting that enzyme-specific therapeutics could be generated. To that end, interrogation of a selected small-molecule library of HK inhibitors has identified a class of PfHK inhibitors, isobenzothiazolinones, some of which have 50% inhibitory concentrations (IC 50 s) of <1 M. Inhibition was reversible by dilution but not by treatment with a reducing agent, suggesting that the basis for enzyme inactivation was not covalent association with the inhibitor. Lastly, six of these compounds and the related molecule ebselen inhibited P. falciparum growth in vitro (50% effective concentration [EC 50 ] of >0.6 and <6.8 M). These findings suggest that the chemotypes identified here could represent leads for future development of therapeutics against P. falciparum.
Several new inhibitors of dihydrofolate reductase (DHFR) have recently progressed into clinical development due to their potent anticancer and antibiotic properties. 1,2 For the treatment of bacterial diseases, DHFR inhibitors such as trimethoprim are often applied in combination with a sulfonamide (Bactrim, Septra). Representative clinical applications include the treatment of urinary tract infections, bronchial infections, and pneumonia. 2 Chromene 1 was recently reported to have submicromolar activities against pathogenic microorganisms such as Staphylococcus aureus and Pseudomonas carinii ( Figure 1). 3 Since only racemic 1 was evaluated for biological activity and the reported synthetic strategy was limited to the preparation of racemic products, we embarked on an enantioselective synthesis of this interesting lead structure.Chromenes have been obtained by the cyclization of allylic ethers using Grubbs' ruthenium catalyst. 4 An attractive aspect of this methodology is the use of a chiral ether of type 3 for the installation of the stereocenter at C(2) of chromene 2 (Scheme 1). 5 Allyl ether 3 could be obtained from a Mitsunobu displacement with phenol 4, and the vinyl substituent appeared to be readily derived by an organometallic coupling of a halogenated derivative of 5. In this paper, we report the successful realization of this strategy, albeit with less than the desired high enantioselectivity due to an unexpectedly facile chromene photoracemization process. Results and DiscussionThe polysubstituted o-bromophenol 7 was synthesized in two steps from commercially available 3-hydroxy-4,5-dimethoxybenzoic acid (6) according to Tanaka's protocol (Scheme 2). 6 Stille-coupling of 7 with tributylvinyltin provided styrene 4 in 81% yield. Subsequent Mitsunobu reaction 7 with carbinol (R)-8 in the presence of triethylamine 8 provided the allylic ether 9 in 66% yield. The propargyl alcohol 8 was prepared by Friedel-Crafts acylation 9 of bis(trimethylsilyl)acetylene with cyclopropanecarbonyl chloride followed by asymmetric reduction (1) Balasubramanian, B. N.; Kadow, J. F.; Kramer, R. A.; Vyas, D. Visser, M. S.; Weatherhead, G. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 8340. (5) For the use of kinetic resolution or chromatographic separation of chiral chromenes, see: (a) Vander Velde, S. L.; Jacobsen, E. N. J. Org. Chem. 1995, 60, 5380. (b) Loncartomaskovic, L.; Mintas, M.; Trotsch, T.; Mannschreck, A. Enantiomer 1997, 2, 459. Chiral chromene was also obtained from dehydrogenation of chromane and cyclization of an R, -unsaturated sulfoxide: (c) Stocker, A.; Netscher, T.; Rü ttimann, A.; Mü ller, R. K.; Schneider, H.; Todaro, L. J.; Derungs, G.; Woggon, W.-D.
To identify novel D 3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G proteincoupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
A simple and efficient method for the synthesis of anti-N-protected amino epoxides from carbamate-protected amino acids is described. The two key steps are the monobromination of a beta-ketoester and chelation-controlled reduction of a bromomethyl ketone intermediate. Good overall yields, high diastereoselectivity, and excellent functional group compatibility are characteristic.
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