title: Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides.
abstract: A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb%=61.0±3.6) and 1,3,4-oxadiazole 10 (metHb%=52.4±0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure.
authors.affiliation: School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Daniel
authors.initials: D
authors.lastname: Conole
authors.affiliation: School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Beck
authors.affiliation: School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Morgan
authors.initials: M
authors.lastname: Jay-Smith
authors.affiliation: Department of Pharmacology & Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Tingle
authors.affiliation: Centre for Wildlife Management and Conservation, Lincoln University, Lincoln, New Zealand; Cawthron Institute, Nelson, New Zealand.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Eason
authors.affiliation: School of Chemical Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.affiliation: School of Chemical Sciences, University of Auckland, Auckland, New Zealand. Electronic address: d.rennison@auckland.ac.nz.
authors.forename: David
authors.initials: D
authors.lastname: Rennison
mesh_terms: D000818:Animals; D001566:Benzocaine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D005260:Female; D008297:Male; D008706:Methemoglobin / Q000096:biosynthesis; D008708:Methemoglobinemia / Q000378:metabolism*; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012378:Rodenticides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010069:Oxadiazoles; D012378:Rodenticides; D008706:Methemoglobin; D001566:Benzocaine
keywords: Benzocaine; Isostere; Methemoglobin; Methemoglobinemia; Rat toxicant; Rodenticide