4075-59-6Relevant academic research and scientific papers
In vitro liver metabolism of aclidinium bromide in preclinical animal species and humans: Identification of the human enzymes involved in its oxidative metabolism
Albertí, Joan J.,Sentellas, Sònia,Salvà, Miquel
, p. 761 - 776 (2011)
The metabolism of aclidinium bromide, a novel long-acting antimuscarinic drug for the maintenance treatment of chronic obstructive pulmonary disorder, has been investigated in liver microsomes and hepatocytes of mice, rats, rabbits, dogs, and humans. Due to the rapid hydrolysis of this ester compound, two distinct radiolabeled forms of aclidinium were studied. The main biotransformation route of aclidinium was the hydrolytic cleavage of the ester moiety, resulting in the formation of the alcohol metabolite (M2, LAS34823) and carboxylic acid metabolite (m3, LAS34850), which mainly occurred non-enzymatically. By comparison, the oxidative metabolism was substantially lower and the metabolite profiles were similar across all five species examined. Aclidinium was metabolized oxidatively to four minor primary metabolites that were identified as monohydroxylated derivatives of aclidinium at the phenyl (M4) and glycolyl (m6 and m7) moieties of the molecule. The NADPH-dependent metabolite m4 involved the loss of one of the thiophene rings of aclidinium. Incubations with human recombinant P450 isoforms and inhibition studies with selective chemical inhibitors and antibodies of human P450 enzymes demonstrated that the oxidative metabolism of aclidinium is primarily mediated by CYP3A4 and CYP2D6. Additionally, up to eight secondary metabolites were also characterized, involving further hydrolysis, oxidation, or glucuronidation of the primary metabolites. Also, the liver oxidative metabolism of the alcohol metabolite (LAS34823) resulted in the production of one hydroxylated metabolite (M1) mediated by human CYP2D6, whereas the acid metabolite (LAS34850) was not metabolized enzymatically, although a minor non-enzymatic and NADPH-dependent reduction was observed.
Synthesis of α-Keto Acids via Oxidation of Alkenes Catalyzed by a Bifunctional Iron Nanocomposite
Song, Tao,Ma, Zhiming,Wang, Xiaoxue,Yang, Yong
supporting information, p. 5917 - 5921 (2021/07/31)
An efficient methodology for synthesis of α-keto acids via oxidation of alkenes using TBHP as oxidant catalyzed by a bifunctional iron nanocomposite has been established. A variety of alkenes with different functional groups were smoothly oxidized into their corresponding α-keto acids in up to 80% yield. Moreover, the bifunctional iron nanocomposite catalyst showed outstanding catalytic stability for successive recycles without appreciable loss of activity.
Novel peptidomimetic peptide deformylase (PDF) inhibitors of Mycobacterium tuberculosis
Gokhale, Kunal M.,Telvekar, Vikas N.
, p. 148 - 156 (2020/08/26)
Emergence of MDR-TB and XDR-TB led to the failure of available anti-tubercular drugs. In order to explore, identify and develop new anti-tubercular drugs, novel peptidomimetic series of Mtb–peptide deformylase (PDF) inhibitors was designed and synthesized. In vitro antimycobacterial potential of compounds was established by screening of compounds against Mycobacterium tuberculosis H37Rv strain using MABA. Among them, ester series of compounds 4a, 4b, 4c, 4d, and 4e were found most active, with compound 4c being highly active and exhibiting minimum inhibitory concentration of 6.25?μg/ml against M.?tb H37Rv strain. Additionally, the compounds were docked to determine the probable binding interactions and understand the mechanism of action of most active molecules on Mtb-peptide deformylase (PDF), which is involved in the mycobacterium protein synthesis.
Possible competitive modes of decarboxylation in the annulation reactions ofortho-substituted anilines and arylglyoxylates
Laha, Joydev K.,Panday, Surabhi,Tomar, Monika,Patel, Ketul V.
supporting information, p. 845 - 853 (2021/02/09)
Annulation reactions ofortho-substituted anilines and arylglyoxylates in the presence of K2S2O8at 80 °C under metal-free neutral conditions have been investigated, which extended a platform for the tandem synthesis of nitrogen heterocycles. While arylglyoxylic acids are known to undergo decarboxylation to form an acyl radical in the presence of K2S2O8and used in the Minisci acylation of electron-deficient (hetero)aromatics, their reactions with electron-richortho-substituted anilines to form nitrogen heterocycles have recently been studied. Depending upon the experimental conditions used in the reactions, the mechanism of the formation of heterocycles involving reactions of an acyl radical or aryl iminocarboxylic acids has been postulated. Given the subtle understanding of the mechanisms of annulation reactions of 2-substituted anilines and arylglyoxylates in the presence of K2S2O8, an extensive mechanistic investigation was undertaken. In the current study, the various mechanistic pathways including the generation of acyl, imidoyl, aminal, and N,O-hemiketal radicals have been postulated based on different possible decarboxylation modes. Some of the proposed intermediates are supported based on the available analytical data. The protocol uses a single, inexpensive reagent K2S2O8, which offers not only transition-metal-free conditions but also serves as the reagent for the key decarboxylation step. Taken together, this study complements the current development of the annulation reactions of 2-substituted anilines and arylglyoxylates in terms of synthesis and mechanistic understanding.
Visible-Light-Promoted Switchable Synthesis of C-3-Functionalized Quinoxalin-2(1H)-ones
Aganda, Kim Christopher C.,Hong, Boseok,Lee, Anna
supporting information, p. 1443 - 1448 (2021/01/26)
A visible-light-promoted synthesis of quinoxalin-2(1H)-ones has been developed using 9-mesityl-10-methylacridinium perchlorate as an organo-photocatalyst. The atmosphere-controlled method (Ar/air) enabled the selective synthesis of hydroxyl- and acyl-containing quinoxalin-2(1H)-ones under mild reaction conditions without the use of any metal catalysts or toxic reagents. A fluorescent labelling experiment showed that hydroxyl-containing quinoxalin-2(1H)-ones may have utility in various biological applications as potent fluorophores. (Figure presented.).
K2S2O8mediated synthesis of 5-Aryldipyrromethanes and meso-substituted A4-Tetraarylporphyrins
Laha, Joydev K.,Hunjan, Mandeep Kaur
, p. 664 - 673 (2021/06/03)
The synthesis of dipyrromethanes from pyrrole and arylglyoxylic acids in the presence of K2S2O8at 90 C is reported affording dipyrromethanes in very good yields. Unlike an excess pyrrole traditionally used in dipyrromethane synthesis, the current method uses a stoichiometric amount of pyrrole avoiding any use of Br?nsted or Lewis acid. A gram scale synthesis of 5-phenyldipyrromethane is also achieved demonstrating potential scale up of dipyrromethanes using this method feasible. Subsequently, dipyrromethanes were converted to A4tetraarylporphyrins also in the presence of K2S2O8at 90C. A direct synthesis of A4-tetraphenylporphyrin from excess pyrrole and phenylglyoxylic acid in the presence of K2S2O8 at 90C is also reported.
Hypervalent Iodine(III)-Promoted Radical Oxidative C-H Annulation of Arylamines with α-Keto Acids
Long, Lipeng,Wang, Jieyan,Gu, Liuqing,Yang, Shiguang,Qiao, Liang,Luo, Guotian,Chen, Zhengwang
supporting information, p. 12084 - 12092 (2021/08/24)
A novel catalyst-free radical oxidative C-H annulation reaction of arylamines with α-keto acids toward benzoxazin-2-ones synthesis under mild conditions was developed. This hypervalent iodine(III)-promoted process eliminated the use of a metal catalyst or additive with high levels of functional group tolerance. Hypervalent iodine(III) was both an oxidant and a radical initiator for this reaction. The synthetic utility of this method was confirmed by the synthesis of the natural product cephalandole A.
K2S2O8activation by glucose at room temperature for the synthesis and functionalization of heterocycles in water
Hunjan, Mandeep Kaur,Laha, Joydev K.
supporting information, p. 8437 - 8440 (2021/09/02)
While persulfate activation at room temperature using glucose has primarily been focused on kinetic studies of the sulfate radical anion, the utilization of this protocol in organic synthesis is rarely demonstrated. We reinvestigated selected K2S2O8-mediated known organic reactions that invariably require higher temperatures and an organic solvent. A diverse, mild functionalization and synthesis of heterocycles using the inexpensive oxidant K2S2O8 in water at room temperature is reported, demonstrating the sustainability and broad scope of the method. Unlike traditional methods used for persulfate activation, the current method uses naturally abundant glucose as a K2S2O8 activator, avoiding the use of higher temperature, UV light, transition metals or bases.
Minisci aroylation of N-heterocycles using choline persulfate in water under mild conditions
Hunjan, Mandeep Kaur,Laha, Joydev K.,Tinwala, Ummehani
, p. 22853 - 22859 (2021/12/24)
Metal persulfate mediated thermal oxidative organic transformations invariably require a higher temperature and frequently use an organic solvent. The objective of this work was to develop persulfate mediated oxidative transformations that can be performed nearly at room temperature using water as a solvent. This report describes modified Minisci aroylation of isoquinolines with arylglyoxylic acids using choline persulfate and its pre-composition (choline acetate and K2S2O8) in water at 40 °C. A few other nitrogen heterocycles were also utilized affording various aroylated products in good to excellent yields. Unlike metal persulfate that could produce metal salt byproducts, a key feature of the chemistry reported herein includes the use of environmentally benign choline persulfate containing biodegradable choline as a counter-cation, the Minisci reaction demonstrated at 40 °C in water as the only solvent, and unconventional activation of persulfate. This journal is
Aroylation of Electron-Rich Pyrroles under Minisci Reaction Conditions
Laha, Joydev K.,Kaur Hunjan, Mandeep,Hegde, Shalakha,Gupta, Anjali
supporting information, p. 1442 - 1447 (2020/02/22)
The development of Minisci acylation on electron-rich pyrroles under silver-free neutral conditions has been reported featuring the regioselective monoacylation of (NH)-free pyrroles. Unlike conventional Minisci conditions, the avoidance of any acid that could result in the polymerization of pyrroles was the key to success. The umpolung reactivity of the nucleophilic acyl radical, generated in situ from arylglyoxylic acid, could help explain the mechanism of product formation with electron-rich pyrroles. Alternatively, the nucleophilic substitution of the acyl radical on the electron-deficient pyrrole radical cation is proposed.
