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Toxicokinetics
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
The associated and dissociated structures of a base and an acid are illustrated in Figure 10.3 with aniline and benzoic acid, which possess strong basic and acidic characteristics, respectively. The structure of benzoic acid shows the carboxyl anion after dissociation. Since its pKa = 4, the Ka = 1 × 10−4, resulting in a higher dissociation constant and strong acidic properties. Similarly, aniline is a highly protonated species, with a pKb of 10 and corresponding Kb of 1 × 10−10 (pKa + pKb = 14; thus, although it is a base, the pKa of aniline can also be expressed as 4). The low dissociation constant of the base indicates that the H+ ions are closely held to the nitrogen and contribute to its strongly basic nature. Structures of aniline and benzoic acid.
Organic Chemicals
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Aromatic and heterocyclic amines are chemicals composed of single- and multiple-ring systems with an exocytic amino group. They do not occur in nature except for complex heterocyclines that are generated during pyrolysis. They are synthetics used in dye and drug manufacturing and as antioxidants.383 The typical monoarylamines and polyarylamines with carcinogenic potential include aniline and o-toluidine (sarcoma), o-anisidine and p-cresidine (bladder cancer), and phenacetin384 (Table 5.48). At high doses, anilines are carcinogenic, and through its metabolite phenylhydroxylamine, aniline is a powerful hematopoietic poison producing methemoglobinemia. o-Toluidine and 2,6-dimethylaniline are released from the local anesthetics prilocaine and lidocaine.385 High-level chronic abuse, but not ordinary intermittent drug use, of phenacetin has led to human bladder cancer.386 These aforementioned aromatic amines have been observed to trigger chemical sensitivity.
Nasal Cavity Cancer in Laboratory Animal Bioassays of Environmental Compounds
Published in D. V. M. Gerd Reznik, Sherman F. Stinson, Nasal Tumors in Animals and Man, 2017
Four structurally related substituted benzene comopunds tested by the NCI produced nasal cancers when fed to rats; amine and methoxy groups appeared to be important. 2-Methoxy aniline, 2-methoxy-5-methyl aniline, and 2,6-dimethylaniline were carcinogenic as was 1-methoxy-4-nitro-2,3,5,6-tetrachlorobenzene. Aniline, however, was not carcinogenic to the nasal epithelium,55 nor was 4-methoxy-2-methylaniline.56 It must be remembered that although reported incidences are low, these studies were done at a time when only gross examination of the nasal cavities was routinely done on NCI bioassays, making it very likely that early or small tumors were not detected. Two other methoxy- or ethoxy-substituted benzene compounds, phenacetin42 and trimethoxycinnamaldehyde,51 were also nasal carcinogens in rats.
Research progress of natural products and their derivatives against Alzheimer’s disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Jin-Ying Liu, Hong-Yan Guo, Zhe-Shan Quan, Qing-Kun Shen, Hong Cui, Xiaoting Li
Fonseca et al. modified the structure of coumarin and chromone, and evaluated their MAO-A and MAO-B inhibitory activities. The results showed that there was no significant difference between the two natural product derivatives in their activities. They had inhibitory effect on MAO-B and no significant activity on MAO-A. The MAO-B inhibitory activity of coumarin derivative 9 (IC50=5.07 nM), chromone derivative 10 (IC50=4.2 nM) and compound 11 (IC50=3.94 nM) is strong. The introduction of aniline has a good effect. The introduction of chlorine substituents at the same time can enhance the MAO-B inhibitory activity. The results of pharmacokinetics showed that compounds 9 and 10 had good binding power and selectivity through non-competitive inhibition23 (Figure 2, Table 1).
The effect of co-administration of berberine, resveratrol, and glibenclamide on xenobiotic metabolizing enzyme activities in diabetic rat liver
Published in Drug and Chemical Toxicology, 2022
Azra Bozcaarmutlu, Canan Sapmaz, Ömer Bozdoğan, Aysel Kükner, Leyla Kılınç, Salih Tunç Kaya, Oğulcan Talat Özarslan, Didem Ekşioğlu
CYP1A-associated ethoxyresorufin O-deethylase (EROD) and CYP2B-associated pentoxyresorufin O-depentylase (PROD) activities were measured in rat liver microsomes according to the method described by Burke and Mayer (1974), with some modifications. A typical reaction mixture contained 5.0 μM 7-ethoxyresorufin for EROD and 10.0 μM 7-pentoxyresorufin for PROD. CYP2E-associated aniline 4-hydroxylase (A4H) activities of rat liver microsomes were measured as described by Imai et al. (1966). A typical assay mixture contained 8.0 mM aniline. CYP3A-associated erythromycin N-demethylase (ERND) activities of rat liver microsomes were measured using the method of Nash (1953) as modified by Cochin and Axelrod (1959). A typical assay mixture contained 1.0 mM erythromycin. GST activities were measured as described by Habig et al. (1974). A typical reaction mixture contained 2.0 mM GSH and 1.0 mM CDNB. GR activities were measured in rat liver cytosols according to the procedure of Carlberg and Mannervik (1985). A typical reaction mixture contained 0.1 mM NADPH and 1.0 mM GSSG. Catalase activities of rat liver cytosols were determined according to the method of Aebi (1984). A typical reaction mixture contained 40 mM H2O2. The details of these procedures were given in our previous study (Sapmaz et al. 2020).
Preclinical metabolism and disposition of an orally bioavailable macrocyclic FXIa inhibitor
Published in Xenobiotica, 2021
Silvi A. Chacko, Wu Yang, Yufeng Wang, Yuan Tian, Yang Hong, Michael Wallace, Bonnie Wang, William R. Ewing, Joseph M. Luettgen, Yue-Zhong Shu, Lisa J. Christopher
As shown in Figure 5, methyl or small alkyl carbamates of aryl amines can undergo descarbamoylation to reveal a structure containing a substituted aniline. These aryl amines have become an emerging structural alert for potential mutagenicity concern, particularly if the resulting metabolite with an aniline pendant moiety is a prominent circulating metabolite in animal plasma. Strategies for risk identification and mitigation associated with the aniline release include: (1) conduct an early biotransformation survey of urethane bond stability and aniline metabolite formation in liver microsomes/S9 fortified with NADPH, (2) evaluate the structure-activity relationship (SAR) for non-cleavable carbamates or other alternative linkers, with mechanistic consideration to block P450-mediated hydrogen abstraction at the alpha (sp3) carbon (Ghosh and Brindisi 2015), and (3) for advanced discovery drug candidates, upon confirmation of the pendant aniline metabolite as a circulating species, evaluate it in an Ames bacterial reverse-mutation test.