title: Synthesis and toxicity assessment of 3-oxobutanamides against human lymphocytes and isolated mitochondria.
abstract: To reduce costly late-phase compound scrubbing, there has been an increased focus on assessing compounds within in vitro assays that predict properties of human safety liabilities, before preclinical in vivo studies. The aim of our study was to answer the questions that whether the toxicity risk of a series of 3-oxobutanamide derivatives could be predicted by using of human lymphocytes and their isolated mitochondria. Using biochemical and flow cytometry assessments, we demonstrated that exposure of lymphocytes and isolated mitochondria to five 3-oxobutanamide derivatives (1-5) did not exhibit remarkable toxicity at low concentrations (50-500μM) but toxicity could be observed at high concentrations (1000 and 2000μM), particularly for N-(5-(4-bromophenyl)-3-isoxazolyl)-3-oxobutanamide (4) and N-(2-benzothiazolyl)-3-oxo butanamide (5). Compounds 4, 5 and partly N-(5-methyl-3-isoxazol yl)-3-oxo butanamide (1) also showed a marked cellular and mitochondrial toxicity while compound 5 displayed superior toxicity. Compound 5 induced cytotoxicity on human blood lymphocytes which was associated with the generation of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP) collapse, lysosomal membrane injury, lipid peroxidation and depletion of glutathione. Our results suggested that among assessed compounds, increased toxicity of compound 5 compared to other compounds could be likely attributed to the presence of bromine substituent in 5. Finally our findings proposed that using of antioxidants and mitochondrial/lysosomal protective agents could be beneficial in decreasing the toxicity of 5.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Science, Ardabil, Iran.
authors.forename: Nima
authors.initials: N
authors.lastname: Razzaghi-Asl
authors.affiliation: Research Center for Health, Safety and Environment (RCHSE), Department of Occupational Health Engineering, Alborz University of Medical Sciences, Karaj, Iran.
authors.forename: Enaytollah
authors.initials: E
authors.lastname: Seydi
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Science, Ardabil, Iran.
authors.forename: Radin
authors.initials: R
authors.lastname: Alikhani
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Science, Ardabil, Iran.
authors.forename: Saba
authors.initials: S
authors.lastname: Rezvani
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Science, Shiraz, Iran.
authors.forename: Ramin
authors.initials: R
authors.lastname: Miri
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Ardabil University of Medical Science, Ardabil, Iran. Electronic address: salimikd@yahoo.com.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Salimi
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008933:Mitochondrial Swelling / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018675:Toxicity Tests
chemical_list: D006571:Heterocyclic Compounds; D006835:Hydrazones; D017382:Reactive Oxygen Species; D045304:Cytochromes c
keywords: 3-Oxobutanamide derivatives; Human lymphocytes; Isolated mitochondria; Predictive toxicology