Browsing by Author "Smith, Leonard A."
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ItemA matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A(Bioorganic & Medicinal Chemistry Letters, 2017-02-01) Harrell, William A. Jr.; Vieira, Rebecca C.; Ensel, Susan M.; Montgomery, Vicki; Guernieri, Rebecca; Eccard, Vanessa S.; Campbell, Yvette; Roxas-Duncan, Virginia; Cardellina, John H. II; Webb, Robert P.; Smith, Leonard A.; ChemistryOur initial discovery of 8-hydroxyquinoline inhibitors of BoNT/A and separation/testing of enantiomers of one of the more active leads indicated considerable flexibility in the binding site. We designed a limited study to investigate this flexibility and probe structure-activity relationships; utilizing the Betti reaction, a 36 compound matrix of quinolinol BoNT/A LC inhibitors was developed using three 8-hydroxyquinolines, three heteroaromatic amines, and four substituted benzaldehydes. This study has revealed some of the most effective quinolinol-based BoNT/A inhibitors to date, with 7 compounds displaying IC50 values ⩽1μM and 11 effective at ⩽2μM in an ex vivo assay. ItemUtilizing Ayurvedic literature for the identification of novel phytochemical inhibitors of botulinum neurotoxin A(Journal of Ethnopharmacology, 2017-02-02) Yalamanchili, Chinni; Manda, Vamshi K.; Chittiboyina, Amar G.; Guernieri, Rebecca L.; Harrell, William A. Jr.; Webb, Robert P.; Smith, Leonard A.; Khan, Ikhlas A.; ChemistryEthnopharmacological relevance Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the identification of new drugs. Our aim is to identify novel phytochemicals for the inhibition of bacterial exotoxin, botulinum neurotoxin A (BoNT/A) based on Ayurvedic literature. BoNT/A is released by Clostridium species, which when ingested, inhibits the release of acetylcholine by concentrating at the neuromuscular junction and causes flaccid paralysis, resulting in a condition termed as botulism, and may also lead to death due to respiratory arrest. Results From the docking scores and structural diversity, nine compounds including acoric acid 1, three flavonoids, three coumarins derivatives, one kava lactone were selected and screened using an in vitro HPLC-based protease assay. The bioassay results showed that several compounds possess BoNT/A LC inhibition of 50–60% when compared to positive controls NSC 84094 and CB7967495 (80–95%). Conclusion Further testing of the active compounds identified from Ayurvedic literature and structure-activity studies of acoric acid 1 using more sensitive bioassays is under way. The identification of acoric acid 1, a novel scaffold against BoNT/A, exemplifies the utility of Ayurvedic literature for the discovery of novel drug leads.