Chemopreventive Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Ergothioneine (Figure 12.35) is an unusual naturally occurring amino acid with significant antioxidant activity. Structurally, it is identical to the amino acid histidine (in the betaine or zwitterion form) except for the addition of a thiol group at the C2-position of the 5-membered imidazole ring. It was discovered in 1909 in the sclerotia of Claviceps purpurea (the ergot fungus) which gave rise to its name, and was subsequently found in semen, blood, and various mammalian tissues such as the kidneys and liver. Its structure was determined much later in 1911, and it was not synthesized until 1951. It is claimed to be an “antioxidant vitamin” with cancer chemopreventive and cardiovascular properties, and is available worldwide as a dietary supplement. Structures of the two canonical forms of ergothioneine, the thione and thiol species. The thione form is the most stable species in solution, which means that the C2-sulfur atom of ergothioneine is less nucleophilic compared to other cellular thiols such as glutathione.
Giardia lamblia
Peter D. Walzer, Robert M. Genta in Parasitic Infections in the Compromised Host, 2020
Side effects and toxicity associated with imidazole drugs occur infrequently and appear to be more common with high-dose therapy. The most common side effects are gastrointestinal and include nausea, abdominal cramps, vomiting, and diarrhea. Constitutional symptoms including anorexia and headache and dermatological side effects, in particular, urticaria, flushing, and pruritis, also have been reported. Metronidazole should be used with caution in persons with central nervous system disease, since dizziness, vertigo, incoordination, and ataxia may be associated with the drug. Because neutropenia has been reported in some patients receiving the drug, metronidazole is contraindicated in persons with a history of blood dyscrasia. Imidazole derivatives also are contraindicated in persons consuming alcohol, since they can induce a disulfiram-like reaction with alcohol.
Skin infections
Ronald Marks, Richard Motley in Common Skin Diseases, 2019
This common infection is due to a yeast pathogen (Candida albicans) that resides in the gastrointestinal tract as a commensal. It is a not infrequent cause of vulvovaginitis in pregnant women, in women taking oral contraceptives and in those taking broad-spectrum antibiotics for acne. It is also responsible for some cases of stomatitis in infants and the cause of infection of the gastrointestinal tract and elsewhere in immunosuppressed people. It may contribute to the clinical picture in the intertrigo seen in the body folds of the obese and in the napkin area in infancy. Treatment with the imidazole preparations, topical and systemic, is effective. Oral and vaginal moniliasis responds to preparations of nystatin and to the imidazoles. Severe Candida infections may be treated with systemic fluconazole.
Acanthamoeba Keratitis: an update on amebicidal and cysticidal drug screening methodologies and potential treatment with azole drugs
Published in Expert Review of Anti-infective Therapy, 2021
Brian Shing, Mina Balen, James H. McKerrow, Anjan Debnath
Azoles are a class of antifungal agents originally developed to target sterol 14a demethylase (CYP51) and inhibit ergosterol biosynthesis [124]. Since Acanthamoeba spp. encode for CYP51 with 31–35% sequence identity to fungal CYP51, antifungal azoles have been considered and evaluated for treating Acanthamoeba keratitis [125]. Clinically, several azoles have been evaluated in very limited clinical cases for treating Acanthamoeba keratitis. These include imidazole (clotrimazole, miconazole, and ketoconazole) and triazole (itraconazole, fluconazole, and voriconazole) class antifungal azoles (Table 2). Several azoles have been identified and suggested to have potent amebicidal and cysticidal properties against Acanthamoeba spp., suggesting new treatments for Acanthamoeba keratitis [126]. Azoles are attractive for Acanthamoeba keratitis treatment as they are generally well tolerated [125]. However, considerations into the method of administration, ophthalmic formulation, and adjunctive surgical preparations have to be made as topically applied imidazoles poorly penetrate the corneal epithelium [127–131].
G4 DNA present at human telomeric DNA contributes toward reduced sensitivity to γ-radiation induced oxidative damage, but not bulky adduct formation
Published in International Journal of Radiation Biology, 2021
Ujjayinee Ray, Shivangi Sharma, Indu Kapoor, Susmita Kumari, Vidya Gopalakrishnan, Supriya V. Vartak, Nitu Kumari, Umesh Varshney, Sathees C. Raghavan
N-terminally His-tagged Msm_UvrB (84.5 kDa) and Msm_UvrC (79.3 kDa) proteins were expressed and purified with minor modifications. Bacterial cells were cultured in 500 ml LBT Kan up to log phase followed by induction with 0.08% acetamide at 25 °C for 14–16 h. Cells were harvested, chilled by incubating on ice for 20 min and resuspended in buffer A (50 mM Tris–HCl (pH 8.0), 500 mM NaCl, 1 mM DTT, 20% glycerol and 10 mM imidazole), as described previously (Thakur et al. 2016). Following sonication and centrifugation, the clarified extract was loaded onto Ni-NTA column (Novagen, Madison, WI). Further, protein was eluted with increasing concentration of imidazole (20–400 mM). Eluted fractions were analyzed on 8% SDS-PAGE, followed by Coomassie brilliant blue (CBB) staining. Enriched fractions were pooled and dialyzed against dialysis buffer (1× PBS containing 1 mM β-mercaptoethanol, 20% glycerol) for 6 h at 4 °C and aliquots were stored in −80 °C.
Evaluation of two in silico programs for predicting mutagenicity and carcinogenicity potential for 4-methylimidazole (4-MeI) and known metabolites
Published in Toxicology Mechanisms and Methods, 2020
Angela S. Howard, Neepa Choksi
Neither the CASE Ultra models nor the Toxtree mutagenicity model (AMES assay) identified structural alerts that were associated with mutagenic activity. All the CASE Ultra models (expert rule-based and statistical-based) identified the compounds of interest as either ‘known negative’ or ‘negative’. Several in vitro studies are consistent with the prediction that 4-MeI was not a mutagen or genotoxicant. For example, studies by Beevers and Adamson (2016) and Chan et al. (2004; NTP 2007) showed that 4-MeI was not mutagenic in S. typhimurium TA97, TA98, TA100, TA102, TA1535 or TA1537 in the absence or presence of S9. 4-MeI also failed to induce formation of micronucleated erythrocytes after intraperitoneal injection or oral exposure (Chan et al. 2004; National Toxicology Program 2007). Voogd and colleagues (1979) evaluated a series of nitroimidazoles and imidazoles to assess mutagenic potential. Results suggested that the imidazole feature itself does not induce direct mutagenic activity. Thus, the models’ predictions are consistent with the in vitro and in vivo studies available in the literature.
Related Knowledge Centers
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- Histamine
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- Nitroimidazole
- Organic Compound
- Nitrogen
- Arene Substitution Pattern