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Rhubarb
Published in Mahendra Rai, Shandesh Bhattarai, Chistiane M. Feitosa, Ethnopharmacology of Wild Plants, 2021
Gan B. Bajracharya, Richa K. Gupta
Indole alkaloids, (+)-3-cyanomethyl-3-hydroxyindole (258) and its glycoside 3-cyanomethyl-3-hydroxyoxindole-N-β-D-glucoside (259), were isolated from R. maximowicizii seeds (Komakine et al. 2005). They inhibited the production of IL-10 induced by lipopolysaccharide.
Medical management of endometriosis
Published in Seema Chopra, Endometriosis, 2020
Dienogest (DNG) is structural derivative of the norethindrone family, having a cyanomethyl group at the C-17 position. There is enough evidence supporting a 2 mg daily dose of dienogest in endometriosis-associated dysmenorrhea and pelvic and premenstrual pain in various randomized and other clinical studies [16–19]. An equivalent efficacy to GnRH analogues with better safety and low incidence of hypoestrogenic symptoms was confirmed in another studies. It has positive effect on quality of life and on pelvic pain when given as pre- or postoperative therapy [20–22]. Long-term use has shown a favorable efficacy with progressive decrease in bleeding irregularities and pelvic pain. The positive effect on pain was seen even after 6 months of discontinuation of treatment. Dienogest used in patients with deep infiltrating endometriosis has shown a decrease in the size of implants after a period of 10–12 months of use and immediate relief in symptoms [23,24]. This can be considered as an alternative to surgery in bladder endometriosis in reducing pain and other urinary symptoms [25]. Similar to other progestins, irregular bleeding is common but decreases over a period of time and resolves after stoppage of treatment [26]. The only drawback for use of dienogest is its cost.
Metallic poisons *
Published in Bev-Lorraine True, Robert H. Dreisbach, Dreisbach’s HANDBOOK of POISONING, 2001
Bev-Lorraine True, Robert H. Dreisbach
The fatal dose of mercuric salts such as mercuric chloride (corrosive sublimate) is 1 g. Ingested metallic mercury is ordinarily not toxic, since it is not absorbed. However, metallic mercury retained in the lung or injected intravenously can produce toxicity, although often it does not. Mercury vapor is in the monatomic state and is lipophilic. It is transferred to brain cells, where it is oxidized to Hg2+ to produce toxic effects. Inhaled mercury vapor causes acute pneumonitis. Mercurous chloride, ammoniated mercury, mercury protoiodide, and organic antiseptic mercurials such as acetomeroctol, merbromin, mercocresol, nitromersol, phenylmercuric salts and esters, and thimerosal (Merthiolate) are not likely to cause acute poisoning because they are poorly absorbed. The single fatal dose of these compounds is 2–4 times the fatal dose of soluble inorganic mercury salts. The mercurial diuretics (mersalyl, meralluride, mercurophylline, mercumatilin, mercaptomerin, chlormerodrin, and merethoxylline) are almost as toxic as mercuric chloride in experimental animals when mercury content is compared. The exposure limit for mercury or mercury compounds is 0.05 mg/m3 as mercury. Alkyl mercury compounds such as methyl mercury chloride, methyl mercury cyanide, methyl mercury hydroxide, methyl mercury pentachlorophenate, methyl mercury toluene sulfonate, ethyl mercury chloride (Ceresan), ethyl mercury phosphate, and ethyl mercury toluene sulfonate are more toxic than mercuric chloride, and the exposure limit is 0.01 mg of mercury per cubic meter. Other organic mercury compounds, such as hydroxymercuriphenol and cyanomethyl-mercuri-guanidine, are as toxic as an equivalent amount of mercury in mercuric chloride.
The piperazine scaffold for novel drug discovery efforts: the evidence to date
Published in Expert Opinion on Drug Discovery, 2022
Maria Novella Romanelli, Dina Manetti, Laura Braconi, Silvia Dei, Alessio Gabellini, Elisabetta Teodori
It is interesting to notice that a piperazinyl-acrylamide moiety is present also in MRTX849 (28, Figure 2A) [38], another KRASG12C inhibitor undergoing clinical trials. In this molecule, the piperazine ring has been decorated with a cyanomethyl group. The modification was suggested by the X-ray structure of the complex between this protein and an analogue synthesized during the optimization process, with the aim of improving the binding of the inhibitor by displacing a nearby water molecule binding to Gly10. The optimal position for the decoration was adjacent to the acryloylamide moiety; indeed, the CN group was found to establish an H-bond with the same residue (Figure 2B right). As for 10, the piperazine ring is in a twist-boat conformation and the C-substituent is in a pseudoaxial arrangement.
Further validation of strecker-type α-aminonitriles as a new class of potent human carbonic anhydrase II inhibitors: hit expansion within the public domain using differential scanning fluorimetry leads to chemotype refinement
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mikhail Krasavin, Stanislav Kalinin, Sergey Zozulya, Anastasia Griniukova, Petro Borysko, Andrea Angeli, Claudiu T. Supuran
Testing of an expanded, 800-compound set of analogues of the earlier described Strecker-type α-aminonitriles in thermal shift assay against bovine carbonic anhydrase (bCA) led not only to further validation of this new class of inhibitors but also to refinement of the active chemotype, which became possible after biochemical testing of 47 selected TSA hits for hCA II inhibition in stopped-flow CO2 hydration assay. The active chemotype can be defined as N1-(cyanomethyl)piperazine bearing two other substituents (hydrophilic and hydrophobic) on the opposite sides of the piperazine core. Such a dichotomy of the newly identified pharmacophore appears to be in line with the known bipolar character of the enzyme’s active site. Further studies are underway to investigate the validity of this hypothesis.
Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design
Published in Expert Opinion on Drug Discovery, 2022
Kashif Haider, Anku Sharma, M Shahar Yar, Prasanna Anjaneyulu Yakkala, Syed Shafi, Ahmed Kamal
The structure–activity relationship (SAR) study of the compounds comprising of tetrahydro pyridazo pyrimidine as the main scaffold reveals that the naphthol ring without any substituent (compound 1) improves the metabolic stability of the compound. Similarly, the substitution of piperazine with water displacing groups such as cyanomethyl in compound 1 enhances the electrophilic character at β-carbon of acrylamide warhead that leads to the increase in potency of compound 2 [26]. The substitution of a chloro group at the 8th position of the naphthol ring in compound 2 provides better pharmacokinetic and pharmacodynamic properties in case of compound 3 [27].