title: Evaluation of Antitrypanosomal Dihydroquinolines for Hepatotoxicity, Mutagenicity, and Methemoglobin Formation In Vitro.
abstract: N1-Benzylated dihydroquinolin-6-ols and their corresponding esters display exceptional activity against African trypanosomes in vitro, and administration of members of this class of compounds to trypanosome-infected mice results in cures in a first-stage African trypanosomiasis model. Since a quinone imine intermediate has been implicated in the antiparasitic mechanism of action of these compounds, evaluation of the hepatotoxic, mutagenic, and methemoglobin-promoting effects of these agents was performed. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate showed outstanding in vitro selectivity for Trypanosoma brucei compared to the HepG2, Hep3B, Huh7, and PLC5 hepatocyte cell lines. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-(2-methoxybenzyl)-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were not mutagenic when screened in the Ames assay, with or without metabolic activation. The latter 2 compounds promoted time- and dose-dependent formation of methemoglobin when incubated in whole human blood, but such levels were below those typically required to produce symptoms of methemoglobinemia in humans. Although compounds capable of quinone imine formation require careful evaluation, these in vitro studies indicate that antitrypanosomal dihydroquinolines merit further study as drug candidates against the neglected tropical disease human African trypanosomiasis.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA werbovetz.1@osu.edu.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
authors.affiliation: Toxicology and Pharmacokinetics, SRI International, Menlo Park, CA, USA.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Riccio
authors.affiliation: Toxicology and Pharmacokinetics, SRI International, Menlo Park, CA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Furimsky
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Julian V
authors.initials: JV
authors.lastname: Richard
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: He
authors.affiliation: Toxicology and Pharmacokinetics, SRI International, Menlo Park, CA, USA.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Iyer
authors.affiliation: Toxicology and Pharmacokinetics, SRI International, Menlo Park, CA, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Mirsalis
mesh_terms: D000085:Acetates / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D065767:Activation, Metabolic; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008706:Methemoglobin / Q000737:chemistry / Q000378:metabolism*; D009152:Mutagenicity Tests; D010084:Oxidation-Reduction; D011804:Quinolines / Q000009:adverse effects* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000009:adverse effects* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D014344:Trypanocidal Agents / Q000009:adverse effects* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000254:growth & development
chemical_list: C560079:1-benzyl-1,2-dihydro-2,2,4 -trimethylquinolin-6-ol; C560080:1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate; D000085:Acetates; D015507:Drugs, Investigational; D006454:Hemoglobins; C000626009:JR-I-78 compound; C000626008:OSU-75 compound; D011804:Quinolines; D011806:Quinolinium Compounds; D014344:Trypanocidal Agents; D008706:Methemoglobin
keywords: dihydroquinoline; drug discovery; human African trypanosomiasis; imine; quinone