Topical Products Applied to the Nail
Heather A.E. Benson, Michael S. Roberts, Vânia Rodrigues Leite-Silva, Kenneth A. Walters in Cosmetic Formulation, 2019
Amorolfine is regarded as a highly efficacious antifungal drug with activity against both dermatophytes and non-dermatophytes fungi (Kushwaha et al., 2015). The drug that belongs to the morpholine class acts by inhibiting the enzymes in the ergosterol biosynthetic pathway. The drug-induced enzyme inhibition hampers the cell multiplication that ultimately causes fungal cell death. Amorolfine nail lacquer (5% w/w) is applied once or twice weekly for a period of 6–12 months in the management of distal and lateral subungual onychomycosis. The product is approved for use in Europe but not in the United States and Canada (Kushwaha et al., 2015). However, the major side effects associated with amorolfine are irritation, burning sensations, pain and redness (Kushwaha et al., 2015 ; Shivakumar et al., 2012 ; Hafeez et al., 2014).
Introduction
Brijesh Kumar, Vikas Bajpai, Vikaskumar Gond, Subhashis Pal, Naibedya Chattopadhyay in Phytochemistry of Plants of Genus Cassia, 2021
In the seed extract of C. occidentalis chrysophanol, toxins, 1,4-oxazine derivative n-methyl morpholine has been isolated. Seeds also contain physcion, physciondianthron heterosides and physcion condensed as homodianthrone as well as a mixture of anthraquinones. 1-glucoside of physcion (0.018%) along with physcion (0.0068%) and two new anthraquinones like 1, 8-dihydroxy-2-methyl anthraquinone (0.0014%) and 1,4,5-trihydroxy-3-methyl-7-methoxy anthraquinone (0.0016%), chrysophanol free and as a glycoside were also found in seed samples. A new polysaccharide galactomannan consisting of d-galactose and d-mannose in the proportion of 1:3.1, as well as trace amount of d-xylose was also found in the C. occidentalis seeds. Maltose, lactose, sucrose and raffinose are also detected from seed. Some other compounds identified from the seeds of C. occidentalis are -1,8-dihydroxy-2-methyl anthraquinone, physcion, rhein, aloe-emodin, chrysophanol and steroidal glucosides. An analysis of flowers indicated the presence of anthraquinones, emodin, physcion and physcion-1-O-β-d-glucoside as well as the ubiquitous sterol β-sitosterol (Veerachari and Bopaiah, 2012).
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies in Clinical Tuberculosis, 2020
Oral bioavailability is approximately 100% and is not affected by food.203 The volume of distribution is 0.6 L/kg and protein binding is 31%. Biotransformation by non-enzymatic oxidation of the morpholine ring results in hydroxyethyl and aminoethoxyacetic acid metabolites which are conjugated with glycine and eliminated in the urine. A total of 30% of parent drug is eliminated unchanged in the urine.204 The t1/2 of LZD is 2.9 hours, Cmax is 10.3 μg/mL, and AUC 66.8 μg/mL × hour at a dose of 600 mg once daily.205 LZD is concentrated in epithelial lining fluid (4.1–8.4×) but not in alveolar cells (0.14–0.70×).206,207 Concentrations in lesions determined by ex vivo dialysis were 49% of serum.208 CSF exposure is 57% of plasma.209
Qualitative and quantitative prediction of human in vivo metabolic pathways in a human hepatocyte-murine stromal cell co-culture model
Published in Xenobiotica, 2018
Kenneth C. Cassidy, Ping Yi
Compound 4 contained a morpholine ring and urea in the chemical structure (Figure 4B). In the human 14C ADME study after 504 h postdose (the last collection interval), the total radioactive recovery was only 62% of the dose with a majority excreted in feces (61% of the dose), and only 2.1% of the dose recovered as unchanged parent. The major in vivo metabolites were an N, O-desethyl metabolite (4-M1), 4-M5 (oxidative N-dealkylation of the morpholine group) and a hydrolysis of the urea to a primary amine (4-M7). Several minor metabolites were also observed. Incubation of Compound 4 for 4 h in suspended cryopreserved hepatocytes poorly predicted in vivo metabolism. In fact, two of the major in vivo metabolites 4-M5 and 4-M7 were not detected in the suspension hepatocyte incubation (Table 5, Figure 4A). In contrast, the 168 h incubation in co-culture predicted two of the three major in vivo metabolites, e.g. 4-M1 and 4-M5. However, the urea hydrolysis product (4-M7) was not detected in the co-cultures or suspended hepatocytes, suggesting that the hydrolytic pathway was extra-hepatic, perhaps via intestinal microflora metabolism.
Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Rani Sasidharan, Bo Hyun Eom, Jeong Hyun Heo, Jong Eun Park, Mohamed A. Abdelgawad, Arafa Musa, Nicola Gambacorta, Orazio Nicolotti, Sreedharannair Leelabaiamma Manju, Bijo Mathew, Hoon Kim
Morpholine is a tetrahydro-1,4-oxazine with a saturated heterocyclic ring and provides a promising developmental starting point due to its biological profile with metabolic stability. The presence of a heteroatom like oxygen or nitrogen facilitates hydrogen bonding, and thus, interactions with enzymes, and the presence of electron-deficient atoms may also impart hydrophobic interactions with morpholine. From the synthetic perspective, various molecular scaffolds have been added to morpholine by replacing its secondary nitrogen11. Moclobemide (1) and reboxetine (2) (both antidepressants) provide examples of FDA-approved drugs containing the morpholine moiety (Figure 1). These drugs reversibly inhibit MAO-A and selectively inhibit norepinephrine reuptake in the central nervous system (CNS), and thus, block the human a4b2 nicotinic acetylcholine receptor. In addition, more than 20 drugs containing the morpholine moiety have been FDA approved; they include mycophenolate mofetil (an immunosuppressant), linezolid and finafloxacin (antibiotics), geftinib (an antineoplastic and epidermal growth factor inhibitor), rivaroxaban (an anticoagulant and factor Xa inhibitor), and eteplirsen, which is used to treat Duchenne muscular dystrophy12. Considering the importance of morpholine nucleus, it is worthwhile to design morpholine derived compounds of medicinal chemistry interest.
In vitro metabolism of alectinib, a novel potent ALK inhibitor, in human: contribution of CYP3A enzymes
Published in Xenobiotica, 2018
Toshito Nakagawa, Stephen Fowler, Kenji Takanashi, Kuresh Youdim, Tsuyoshi Yamauchi, Kosuke Kawashima, Mika Sato-Nakai, Li Yu, Masaki Ishigai
All metabolites identified in this study are considered to be oxidized at the morpholine ring to form M5 as a primary metabolism step. Many drugs have a morpholine moiety in their chemical structures, and oxidation at the morpholine ring commonly occurs as a few examples can be found (De Brabanter et al., 2013; Denissen et al., 1994; Volotinen et al., 2007). Due to the distribution of electron density, the α- or β-carbon of the morpholine is easily oxidatively metabolized to the carbinolamine or the lactol. As they are unstable and exist in equilibrium with the aldehyde, which undergoes oxidation to a stable acid metabolite or cleavage to an aminoethanol metabolite, it is not common to detect a hydroxy morpholine metabolite as a stable metabolite. Although the unstable metabolite was reported as a minor metabolite of linogliride detected only in dog urine (Wu & Mutter, 1995), the stable acid forms or the cleavage forms were reported in most cases (Denissen et al., 1994; McKillop et al., 2004a). A hydroxymorpholine metabolite of alectinib, M5, was also present at a very low concentration in hepatocyte incubates of all species investigated. The main metabolite was the cleaved aminoethanol, M4. M4 was further oxidatively dealkylated to form a minor secondary amine metabolite, M6. The stable acid metabolites, M1a and M1b, were also found, although the M1b formation was much higher than M1a. There are four possible isomers for M5, two positional isomers and the stereoisomers of each, which may have different specificity to metabolic enzymes and thus affect which stable forms become the major. It was unclear which isomer of M5 existed in the hepatocytes for two reasons: too little M5 was formed for a structural analysis by NMR, and standards could not be chemically synthesized because the products were unstable.
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