The mechanism of the Pechmann condensation is still controversial despite the technological and biochemical importance of coumarins. Here, we present NMR evidence for a mechanism featuring the sequence of initial electrophilic aromatic substitution followed by transesterification and a final dehydration. This mechanism has been convincingly defined and supported by the temporal evolution of two key intermediates which could be purified and identified.

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Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [11C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [11C]-vorozole is binding to in the liver.

Synthesis of 7-Alkoxy-4-trifluoromethylcoumarins via the von Pechmann Reaction Catalyzed by Molecular Iodine. -(DEGROTE, J.; TYNDALL, S.; WONG, K. F.; VANALSTINE-PARRIS*, M.; Tetrahedron Lett. 55 (2014) 49, 6715-6717, http://dx.

Trichomoniasis is a sexually transmitted infection caused by the parasite, Trichomonas vaginalis. Infections are currently treated with 5‐nitroimidazole drugs, such as metronidazole and tinidazole. However, strains of the parasite with resistance to these drugs have emerged, indicating the need for new treatments with novel mechanisms. Since the parasite is unable to perform de novo synthesis of nucleobases, it must obtain them from its host using salvage pathway enzymes including adenosine/guanosine preferring nucleoside ribohydrolase (AGNH), an essential enzyme involved in the pyrimidine salvage pathway. We previously used fragment screening to identify ligand‐efficient fragment inhibitors of AGNH. Medicinal chemistry efforts were then focused on several fragment scaffolds including benzimidazoles and phenyl pyridines. IC50 values were determined using the same 1H NMR‐based activity assays as the fragment screens. The resulting structure‐activity relationships suggest that the fragment scaffolds interact primarily with the nucleobase regions of the active site rather than the ribose pocket. Collectively, the data define emerging structure‐activity relationships that suggest likely vectors and chemical modifications for improving inhibition potency while maintaining ligand efficiency. The data establishes a platform for ongoing medicinal chemistry development of compounds with nM potency that will provide the tools for in vitro target validation against both 5‐nitroimidazole‐sensitive and 5‐nitroimidazole‐resistant T. vaginalis strains.Support or Funding InformationResearch was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R15AI128585 to BJS and MAVP. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.