In This Issue Cite This: ACS Med. Chem. Lett. 2018, 9, 952−952
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IDENTIFICATION OF A NOVEL BROAD-RANGE ANTISCHISTOSOMAL AGENT Schistosomiasis is a parasitic disease caused by worms of the genus Schistosoma and disproportionately affects people in the developing world. Current treatment options are limited, and drug-resistance presents an additional concern. In their Featured Letter, Rugel et al. (DOI: 10.1021/ acsmedchemlett.8b00257) report their work that led to the discovery of small molecules with broad-range antischistosomal activity. Using data from X-ray crystallography studies involving a sulfotransferase enzyme of three different Schistosoma species, the authors designed and synthesized novel derivatives of the existing antischistosomal drug oxamniquine. Initial worm killing assays against S. mansoni with 3-aminopyrrolidine and 3aminopiperidine analogs containing different heterocyclic ring cores and side chains produced encouraging results. This led the group to perform additional structure−activity relationship studies that also included 4-aminopiperidines to investigate the effects of benzyl substitutions. Compounds with appreciable activity against S. mansoni from these studies were then screened against S. hematobium and S. japonicum, resulting in the identification of compound 12a, which displayed activity against all three worm species. Future studies by the authors will focus on further optimization of 12a.
dominant cytosolic isoforms. The observed inhibition data and subsequent structural studies suggest famotidine as a lead for antibacterial compounds with a novel mechanism of action.
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DEVELOPMENT OF HYBRID PHOSPHOLIPID MIMICS AS AGONISTS FOR LIVER RECEPTOR HOMOLOGUE-1 The orphan nuclear receptor Liver Receptor Homologue-1 (LRH-1) maintains hepatic lipid and glucose metabolism and has emerged as a therapeutic target for metabolic disorders, such as type II diabetes and nonalcoholic fatty liver disease. Its physiological ligand is unknown, but in vitro experiments demonstrated that the receptor binds phospholipids and synthetic hexahydropentalene compounds. However, micromolar concentrations of these modulators are necessary for receptor activation, and their binding modes vastly differ. Jui and colleagues (DOI: 10.1021/acsmedchemlett.8b00361) investigated whether the binding features of these two ligand classes could be combined into a single scaffold in order to attain improved engagement with the ligand binding pocket. The authors developed various hybrid phospholipid mimics based on data obtained from structural studies and evaluated the resulting compounds for LRH-1 activity. Assay results revealed that efficacy was dependent upon linker length as compounds with longer alkyl linkers demonstrate greater activity. Subsequent optimization of the most active compound from this series resulted in a carboxylic acid hybrid identified as the most potent and efficacious LRH-1 agonist to date. Further work on these novel ligands is ongoing and focuses on various aspects, including mechanism of receptor activation.
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INHIBITION STUDIES WITH THE ANTIULCER AGENT FAMOTIDINE REVEAL ACTIVITY AGAINST HELIOBACTER PYLORI AND HUMAN CARBONIC ANHYDRASES Carbonic anhydrases are metallo-enzymes that facilitate the interconversion of carbon dioxide and water to bicarbonate and protons. There are 15 different human alpha-isoforms of carbonic anhydrases, which are expressed in various subcellular locations and tissues where they regulate acid−base homeostasis. In this issue, Supuran and colleagues (DOI: 10.1021/ acsmedchemlett.8b00334) disclose their investigation of the antiulcer agent famotidine as a carbonic anhydrase inhibitor. The authors screened all catalytically active human carbonic anhydrases against famotidine along with the standard sulfonamide inhibitor acetazolamide. This revealed a broad range of inhibition among the various isoforms with hCA II, VI, VII, and XII, displaying nanomolar inhibition by famotidine. The authors then expanded their investigation by performing inhibition studies with the two carbonic anhydrases found in the gastric pathogen H. pylori. Both famotidine and acetazolamide inhibited the enzymes, and famotidine exhibited greater activity against the H. pylori enzymes compared to the two human © 2018 American Chemical Society
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Published: October 11, 2018 952
DOI: 10.1021/acsmedchemlett.8b00446 ACS Med. Chem. Lett. 2018, 9, 952−952
