Development of non-sedating benzodiazepines with in vivo antischistosomal activity.

The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad-spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970s. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) is not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them for in vitro antiparasitic activity. This identified five compounds that progressed to in vivo screening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index and point to the C3 position of the benzodiazepine ring system as a logical site for further structure-activity exploration to further optimize this chemical series.

Development of non-sedating antischistosomal benzodiazepines.

The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970's. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) are not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them for in vitro antiparasitic activity. This identified five compounds that progressed to in vivo screening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index, and point to the C3 position of the benzodiazepine ring system as a logical site for further structure-activity exploration to further optimize this chemical series.

Development of a Novel, Small-Molecule Brain-Penetrant Histone Deacetylase Inhibitor That Enhances Spatial Memory Formation in Mice.

Histone acetylation is a prominent epigenetic modification linked to the memory loss symptoms associated with neurodegenerative disease. The use of existing histone deacetylase inhibitor (HDACi) drugs for treatment is precluded by their weak blood-brain barrier (BBB) permeability and undesirable toxicity. Here, we address these shortcomings by developing a new class of disulfide-based compounds, inspired by the scaffold of the FDA-approved HDACi romidepsin (FK288). Our findings indicate that our novel compound MJM-1 increases the overall level of histone 3 (H3) acetylation in a prostate cancer cell line. In mice, MJM-1 injected intraperitoneally (i.p.) crossed the BBB and could be detected in the hippocampus, a brain region that mediates memory. Consistent with this finding, we found that the post-training i.p. administration of MJM-1 enhanced hippocampus-dependent spatial memory consolidation in male mice. Therefore, MJM-1 represents a potential lead for further optimization as a therapeutic strategy for ameliorating cognitive deficits in aging and neurodegenerative diseases.

Synthetic Scope of Brønsted Acid-Catalyzed Reactions of Carbonyl Compounds and Ethyl Diazoacetate.

The comprehensive study of the reactions of carbonyl compounds and ethyl diazoacetate in the presence of a Brønsted acid catalyst is described. In result, a broad range of 3-oxo-esters were synthesized from a variety of ketones and aliphatic aldehydes by 1,2-aryl/alkyl/hydride shift. Aryl-methyl ketones produced only aryl-migrated products, whereas other ketones yielded a mixture of products. For diaryl ketones, the identity of two inseparable migrated products was confirmed by two-dimensional NMR spectroscopy.

Total Synthesis of Tryprostatin B: Synthesis and Asymmetric Phase-Transfer-Catalyzed Reaction of Prenylated Gramine Salt.

A concise and efficient total synthesis of microtubule inhibitor tryprostatin B (1) is described. The key step is the preparation of a diprenylated gramine salt 9a. In this step, the prenyl group is incorporated at the 2-position of the indole moiety by direct lithiation of the Boc-protected gramine. We also developed and optimized the asymmetric phase-transfer-catalyzed reaction with salt 9a to provide the C2-prenyl tryptophan intermediate 2 resulting in 93% enantiomeric excess (ee) and 65% yield. The total synthesis of 1 is done in six steps with 35% overall yield.

A Concise Synthesis of Potential COX Inhibitor BRL-37959 and Analogs Involving Bismuth(III) Catalyzed Friedel-Crafts Acylation.

We report the development of a concise method of synthesizing possible cyclooxygenase (COX) inhibitor BRL-37959, which is believed to be a potent nonsteroidal anti-inflammatory drug (NSAID). The four-step synthesis greatly increased the efficiency of compound production from commercially available salicylaldehydes. The synthesis involved an optimized, bismuth(III) trifluoromethanesulfonate catalyzed benzoylation of a benzofuran ring.

Convenient method of synthesizing 3-ethoxycarbonyl indoles.

We have developed a convenient two-step procedure for the synthesis of 3-ethoxycarbonyl indoles from commercially available materials. The two-step procedure involves the synthesis of 2-aryl-3-hydroxypropenoic acid ester, followed by a catalytic reduction. This method is efficient, simple, and selective.

Acid-catalyzed reactions of aromatic aldehydes with ethyl diazoacetate: an investigation on the synthesis of 3-hydroxy-2-arylacrylic acid ethyl esters.

Several commercial Lewis acids, including those of the Bronsted type, specifically HBF(4).OEt(2), are able to catalyze the reaction between aromatic aldehydes and ethyl diazoacetate to produce 3-hydroxy-2-arylacrylic acid ethyl esters and 3-oxo-3-arylpropanoic acid ethyl esters. Reactions catalyzed by the iron Lewis acid [(eta(5)-C(5)H(5))Fe(+)(CO)(2)(THF)]BF(4)(-) (i.e., 1) have the best yields and greatest ratio of 3-hydroxy-2-arylacrylic acid ethyl ester. The product distribution of 1 is not affected in the presence of Proton Sponge, but is dependent on temperature and the nature of the substrate aldehyde, whereas the activity of HBF(4).OEt(2) is affected by the presence of Proton Sponge and is reactive at temperatures as low as -78 degrees C. Consequently, both 1 and HBF(4).OEt(2) are valuable catalysts in producing important 3-hydroxy-2-arylacrylic acid ethyl esters as precursors to biologically active compounds.

Catalytic Preparation of Aziridines with an Iron Lewis Acid.

The iron Lewis acid, [(eta(5)-C(5)H(5))Fe(CO)(2)(THF)](+)[BF(4)](-), was found to be an effective catalyst for the preparation of aziridines. This new method provides a facile, one-step route to predominantly cis-aziridines, with yields up to 95%, from compounds with a diazo functionality and a variety of substituted N-benzylidene imines with N-aryl or N-alkyl groups. The reaction mechanism is believed to proceed through an electrophilic iminium ion intermediate. To support this idea, the iron Lewis acid-imine complex [(eta(5)-C(5)H(5))Fe(CO)(2)(PhCH=NPh)](+)[BF(4)](-) was prepared, characterized, and reacted with different diazo compounds to provide the resultant cis-aziridines. Alternatively, it may be possible that the aziridines were derived from an electrophilic carbenoid intermediate, as is often proposed. Thus, the iron carbene [(eta(5)-C(5)H(5))Fe(CO)(2)(CHPh)](+)[SO(3)CF(3)](-) was prepared and treated with N-benzylideneaniline; however, the resultant aziridine was not formed.