- Synthesis and antischistosomal activity of linker- and thiophene-modified biaryl alkyl carboxylic acid derivatives
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Schistosomiasis is a neglected tropical disease caused by blood flukes of the genus Schistosoma and causes severe morbidity in infected patients. In 2018, 290.8 million people required treatment, and 200,000 deaths are reported per year. Treatment of this disease depends on a single drug, praziquantel (PZQ). However, in the past few years, reduced sensitivity of the parasites toward PZQ has been reported. Therefore, there is an urgent need for new drugs against this disease. In the past few years, we have focused on a new substance class called biaryl alkyl carboxylic acid derivatives, which showed promising antischistosomal activity in vitro. Structure–activity relationship (SAR) studies of the carboxylic acid moiety led to three promising carboxylic amides (morpholine, thiomorpholine, and methyl sulfonyl piperazine) with an antischistosomal activity down to 10 μM (morpholine derivative) and no cytotoxicity up to 100 μM. Here, we show our continued work on this substance class. We investigated, in extended SAR studies, whether modification of the linker and the thiophene ring could improve the antischistosomal activity. We found that the exchange of the alkyl linker by a pentadienyl or benzyl linker was tolerated and led to similar antischistosomal effects, whereas the exchange of the thiophene ring was not tolerated. Our data suggest that the thiophene ring is important for the antischistosomal activity of this compound class.
- Peter Ventura, Alejandra M.,Haeberlein, Simone,Konopka, Leonie,Obermann, Wiebke,Grünweller, Arnold,Grevelding, Christoph G.,Schlitzer, Martin
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- Asymmetric synthesis of (-)-naltrexone
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(-)-Naltrexone, an opioid antagonist used extensively for the management of drug abuse, is derived from naturally occurring opioids. Herein, we report the first asymmetric synthesis of (-)-naltrexone that does not proceed through thebaine. The synthesis starts with simple, achiral precursors with catalytic enantioselective Sharpless dihydroxylation employed to introduce the stereogenic centers. A Rh(i)-catalyzed C-H alkenylation and torquoselective electrocyclization cascade provides the hexahydro isoquinoline bicyclic framework that serves as the precursor to the morphinan core. The acidic conditions used for Grewe cyclization not only provide the morphinan framework, but also cause a hydride shift resulting in the introduction of the C-6 oxo functionality present in (-)-naltrexone. The C-14 hydroxyl group is installed by an efficient two-step sequence of Pd-mediated ketone to enone dehydrogenation followed by C-H allylic oxidation using Cu(ii) and O2, a method that has not previously been reported either for the synthesis or semi-synthesis of opioids. The longest linear sequence is 17 steps, and because the stereogenic centers in the product rely on Sharpless asymmetric dihydroxylation, the route could be used to access either enantiomer of the natural product, which have disparate biological activities. The route also may be applicable to the preparation of opioid derivatives that could not be easily prepared from the more fully elaborated and densely functionalized opioid natural products that have traditionally served as the starting inputs.
- Dongbang, Sun,Pedersen, Blaine,Ellman, Jonathan A.
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- Alkyl phosphonate preparing method
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The invention provides an alkyl phosphonate preparing method. The method comprises: performing an Arbuzov reaction on compound A and compound B in a continuous reaction apparatus, and continuously discharging the product obtained from the reaction from the continuous reaction apparatus during the reaction procedure, to obtain alkyl phosphonate. The reaction temperature in the reaction procedure is T1; either of compound A and compound B having a lower boiling point has a boiling point at a standard atmosphere pressure to be T2; T1 is higher than T2 by 10-40 DEG C; and the reaction pressure in the reaction procedure is 0.5-2.0 MPa. The preparing method in the invention may use halohydrocarbon having large steric hindrance and lower polarizability of carbon-halogen bond as compound A, thereby effectively expanding a selection range of substrate, and correspondingly expanding the types of alkyl phosphonate prepared by using the Arbuzov reaction.
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Paragraph 0092; 0093; 0094; 0095
(2017/10/07)
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