Religious Aspects and Medicinal Uses of Salvadora persica (Miswak)
Mehwish Iqbal in Complementary and Alternative Medicinal Approaches for Enhancing Immunity, 2023
Almost all parts (twigs, bark, root, fruits, seed, stem and flowers) of Salvadora persica have been evaluated; a comprehensive investigation of plant chemicals showed the presence of terpenes, carbohydrates, alkaloids, flavonoids, sterols, organosulphur compounds, glycosides and elemental sulfur, as well as small quantities of calcium, silica, fluoride, phosphorus and ascorbic acid (Aumeeruddy et al., 2018). Roots are loaded with benzyl isothiocyanate and salvadourea, which reveals antiviral activity against harmful viruses of the oral cavity such as HSV (herpes simplex virus) (Farag et al., 2021). Moreover, a great alkaloids content such as trimethylamine and salvadoricine was present in the roots (Al Lafi & Ababneh, 1995). Furthermore, pyrrole, pyrrolidine and piperidine derivatives have been separated from the twigs of SP, which are nitrogen-holding compounds (Galletti et al., 1993). Extracts of stems, twigs, and roots have been stated to consist of great quantities of salvadourea (Khalil, 2006). A number of alkaloids, for instance, trigonelline, theobromine and caffeine, were also present in the bark (Farag et al., 2017).
Disposition and Metabolism of Drugs of Dependence
S.J. Mulé, Henry Brill in Chemical and Biological Aspects of Drug Dependence, 2019
Approximately 4% of methadone is excreted free in urine and 5% in feces of man given 20 mg orally and in the rat.264 Biliary excretion is an important route for the elimination of methadone and its metabolites.264N-demethylation is an important metabolic pathway for methadone in vitro107 and in vivo.265 Evidence has also been produced for the formation of primary and secondary amine metabolites266 and for N-methylation to a quaternary ammonium compound in vitro to the extent of 15% by guinea pig liver slices.267N-demethylation of methadone to a secondary amine which spontaneously rearranged to form 1,5-dimethyl-3,3-diphenyl-2-ethylidene pyrrolidine (A) as a major metabolite in man has been reported.268 This metabolite was found particularly in bile. Lung tissue localized methadone to the greatest extent. Approximately 60% of the dose in man could be accounted for as methadone and pyrrolidine metabolite. Chromatographic evidence for three other unidentified metabolites has also been obtained.269 Evidence for further metabolism of the above pyrrolidine metabolite to 2-ethyl-5-methyl-3,3’-diphenyl-l-pyrroline (B) has recently been produced.270 These two metabolites have been isolated, characterized and synthesized and found to be pharmacologically inactive.270 In vitro conversion of methadone to its N-oxide has been shown to occur on incubation of methadone with 10,000 × g microsomal supernatant of male guinea pig liver homogenates.271
Drug Discovery: From Hits to Clinical Candidates
Divya Vohora in The Third Histamine Receptor, 2008
Eli Lilly & Co, Laboratoires Servier, Hoffman-La Roche, and Pfizer: Drug Design Efforts toward Novel H3 Receptor Antagonists Since 2003, researchers from Eli Lilly & Co have focused their medicinal chemistry program on novel N-benzoyl 2-(pyrrolidin-1-ylmethyl) pyrrolidine derivatives. Indeed, early claimed compound 137 displayed nanomolar potency (hH3 pKi 9.0) with adequate pharmacokinetic properties in rat (oral F = 59%) (Figure 5.18) [170, 171]. Interestingly, Lilly scientists further claimed novel potent H3 antagonists in which part of the spacer is modified and fused to the phenyl-core (138) [172] and for some others, the aminopropoxy linker is removed, as shown in claimed compound 139 [173]. In this case, a dramatic decrease in hH3R-binding affinity is noticed (pKi 7.1), but this modification proved that the N-benzoyl 2-(pyrrolidin-1-ylmethyl) pyrrolidine fragment could serve as a potent surrogate of the classic aminopropoxyphenyl framework. Further investigation from Lilly scientists led to novel potent H3 antagonists, as exemplified by claimed compound 140a-e (hH3 pKi 7.3-8.5) [174–177].
Contemporary medicinal-chemistry strategies for discovery of blood coagulation factor Xa inhibitors
Published in Expert Opinion on Drug Discovery, 2019
Xia Hao, Xiaofang Zuo, Dongwei Kang, Jian Zhang, Yuning Song, Xinyong Liu, Peng Zhan
The scaffold hopping strategy was employed to explore the chemically diverse space of a weakly active aminothiazole FXa inhibitor 10 identified from a biased screen. Replacement of the central aminothiazole scaffold with a variety of nitrogen-bearing aromatic heterocycles afforded compounds with even higher binding affinity and promising functional activity in plasma clotting assays. Further improvement of functional activity was obtained by incorporating pyrrolidine as the central scaffold. The pyrrolidine moiety enabled modulation of the binding affinity, functional activity and in vitro PK properties by introducing a broad panel of ring substituents, and 113–115 were identified as potent inhibitors with good metabolic stability (Figure 9) [10].
A patent review of BRD4 inhibitors (2013-2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Tian Lu, Wenchao Lu, Cheng Luo
As shown in Figure 11, the pyrrole derivatives (compound 78–80) have been reported by Abbvie as potent BRD4 inhibitors. Among them, compound 78 inhibits BRD4 BD1 and BD2 with the IC50 values of 38 nM and 225 nM, respectively. It also showed promising anti-proliferation activity against MX-1 cell lines. Compound 79 is a selective BRD4-BD1 inhibitor with 10-fold selectivity over its homologues, and no detectable inhibition against BD2 [98]. Another close analogue compound 80 showed 80% TGI in MX-1 xenograft model with the dose of 100 mg/kg [99]. In 2017, Chen yadong et al. of China pharmaceutical university designed and synthesized a series of new structures containing pyrrolidine chemical scaffolds. All these compounds have excellent inhibitory activity against BRD4 protein in vitro detected by alphascreen [100]. Novartis AG also developed new pyrrolopyrrolone derivatives using as BRD4 inhibitors, Compounds 82 and 83 also showed significant inhibitory effect in MV4-11, THP-1, K-562 and other leukemia cells [101].
The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP): pharmacokinetic and pharmacodynamic clinical and forensic aspects
Published in Drug Metabolism Reviews, 2018
Leandro Nóbrega, Ricardo Jorge Dinis-Oliveira
Cathinone is a monoamine and the main psychoactive naturally occurring alkaloid found in the leaves of the Catha edulis plant, commonly known as khat (Marinetti and Antonides 2013; Watterson and Olive 2014). SC are phenylalkylamines cathinone analogs, and are often termed ‘bk-amphetamines’ or ‘β-keto amphetamines’ due to the presence of beta-ketone group at the β-position of the side chain (Prosser and Nelson 2012; Miller et al. 2017; Valento and Lebin 2017). Functional group substitutions to the core structure of the parent cathinone compound (Figure 1) have yielded a large number of SC on the street and cyber drug markets, which can be separated into four different chemical families based on the substitutions made (Figure 2) (Valente et al. 2014; Miller et al. 2017): (i) the most basic N-alkylated derivatives, which may present alkyl substitutions in the α-carbon of the side chain (e.g. 4-methy-lethcathinone) and/or in the benzyl ring (e.g. mephedrone); (ii) the methylenedioxy benzyl ring derivatives (e.g. methylone), which are structurally similar to 3,4-methylenedioxyamphetamines (e.g. ecstasy or MDMA); (iii) the N-pyrrolidine derivatives (e.g. α-PVP) and; (iv) the synthetic cathinone family that has both the 3,4-methylenedioxy ring substitution and the N-pyrrolidinyl moiety (e.g. 3,4-methylenedioxy-α-pyrrolidinovalerophenone or 3,4-methylenedioxypyrovalerone or MDPV). Many of these derivatives suffer only slight changes to their structure aiming to bypass the legislation regarding NPS. In the US and Europe, bupropion is the only SC that has a medical application for treatment of depression and smoking-cessation aid (Miller et al. 2017).
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