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Monographs of fragrance chemicals and extracts that have caused contact allergy / allergic contact dermatitis
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Twenty-three patients had allergic contact dermatitis from a topical pharmaceutical preparation. The patients had positive patch test reactions to the cream base, but not to its individual ingredients, including the preservatives thymol and 1,3,5-trihydroxyethylhexahydrotriazine. It was found that thymol and a degradation product of the triazine formed a new contact allergen (‘compound allergy’). This chemical was identified by nuclear magnetic resonance spectroscopy and infrared spectroscopy as 3-(hydroxyethyl)-5-methyl-8-(2-methylethyl)-3,4-dihydro-2H-1,3-benzoxazine (7).
Phytopharmaceuticals in Cancer Treatment
Published in Prakash Srinivasan Timiri Shanmugam, Understanding Cancer Therapies, 2018
Prince Clarance, Paul Agastian
Sesquiterpene and eurochevalierine are considered as precursors in the biosynthesis of the potent benzoxazine natural product CJ-12662, a topoisomerase inhibitor. Eurochevalierine exhibits in vitro growth-inhibitory activity in various cancer cell lines. It appears that eurochevalierine represents a novel chemical scaffold for the development of anticancer agents effective against cancers unresponsive to traditional therapy with proapoptotic agents (Eamvijarn et al. 2012), because the ester bond linking the indole-containing portion of the molecule with the terpene residue is hydrolytically labile. Future studies will undoubtedly involve synthetic work aimed at resolving the minimum structural requirements in this scaffold (Evidente et al. 2014).
Levofloxacin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Levofloxacin (Levaquin, Iquix, Quixin) is a fluoroquinolone that is the optical S-(–) isomer of ofloxacin. It was originally developed by the Daiichi Seiyaku Pharmaceutical Co. Ltd. in Japan. Its chemical formula is (–)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de] [1,4]benzoxazine-6-carboxylic acid hemihydrate (Figure 104.1), and it has a molecular weight of 370 daltons. Ofloxacin is a racemic mixture of two optical isomers, but the S-isomer has antibacterial activity 32- to 128-fold greater than that of the R-isomer, and thus most of the antibacterial activity of ofloxacin is due to the S-isomer, which constitutes levofloxacin. Levofloxacin, like ofloxacin and other fluoroquinolones, is an inhibitor of the bacterial type II topoisomerases DNA gyrase and DNA topoisomerase IV. Levofloxacin was developed to take advantage of its increased antibacterial potency and a potentially improved toxicity profile (Davis and Bryson, 1994; Inage et al., 1992; Tanaka et al., 1992; Une et al., 1988).
Receptor-interacting protein kinase 1 (RIPK1) inhibitor: a review of the patent literature (2018-present)
Published in Expert Opinion on Therapeutic Patents, 2023
Lijuan Xu, Wannian Zhang, Chunlin Zhuang
Patent disclosures for type II RIPK1 inhibitors have increased significantly since 2018. Most of these new patents hybridize portions of type II inhibitor (binding to the ATP pocket) with portions of type III inhibitor (binding to the hydrophobic allosteric pocket near the ATP binding site). The portions of these type III inhibitors consist of triazolylphenyl of the benzoxazepinones/benzazepinones, and isoxazolidanephenyl of the dihydropyridine and isoxazolidines. In addition, there are modifications of type II inhibitors with referring to type III inhibitors occupying hydrophobic allosteric pockets. Recently, research on type III inhibitors of indole-hyaline scaffold has been sharply decreased and only one patent was published by Zhejiang University. This may result from the narrow structure–activity relationship and poor metabolic stability of this scaffold. Research on benzoxazepinones/benzazepinone type III inhibitor is still a hot topic. Several recent patents are aimed at the development of dual-mode benzoxazine RIPK1 inhibitors by alkynyl bridges, combining ATP competition (type I and type II) and allosteric regulation (type III) modes. Thus, the chemical space is extended from the allosteric of RIPK1 to ATP-binding pocket. However, limited clinical activity has been reported, and the optimal therapeutic uses of this heterozygous RIPK1 inhibitor await the results in future clinical studies.
Multicomponent reactions (MCR) in medicinal chemistry: a patent review (2010-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Hafiza Amna Younus, Mariya Al-Rashida, Abdul Hameed, Maliha Uroos, Uzma Salar, Sobia Rana, Khalid Mohammed Khan
Transition metal-free, single step, multicomponent, one-pot reaction of N-heterocycles (186 and 189), arynes, and carbonyl derivatives (186, 189) was carried out to yield diastereoselective novel benzoxazine quinoline derivatives 188 as well as benzoxazine isoquinoline derivatives 191, Scheme 26). Synthesized compounds were obtained in high yields (up to 96%) and were tested for their antimalarial activities by taking atovaquone and chloroquine as standard antimalarial compounds. IC50 value of atovaquone was 7.11 whereas for selected derivatives its value ranges from 1692 to 3874. A method of treating malaria is formulated by synthesized compound, mannitol, iron oxide red, and strawberry flavor and magnesium stearate [63].
From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Serena Massari, Angela Corona, Simona Distinto, Jenny Desantis, Alessia Caredda, Stefano Sabatini, Giuseppe Manfroni, Tommaso Felicetti, Violetta Cecchetti, Christophe Pannecouque, Elias Maccioni, Enzo Tramontano, Oriana Tabarrini
The suitability of this peculiar moiety was further confirmed and even improved by the successive series of derivatives, all bearing the catechol moiety at C-2 position of different oxazinone-based scaffolds (Table 2). In particular, when compared to compound 10, the reduction of cycloheptane ring to cyclohexane (compound 20) slightly decreased the anti-RNase H activity (IC50=3.35 µM), while its further reduction to cyclopentane (compound 21) permitted to maintain the same biological activity (IC50=1.00 µM). The replacement of the cycloheptane with a benzene ring improved the activity, as shown by compound 22 that emerged as the most potent derivative of the series, with IC50 of 0.53 µM. When the geometry of the core was changed by reversing the thiophene portion in compound 23, a slight decreased anti-RNase H activity emerged, while the aromatic derivative 24 showed a potent inhibitory activity (IC50=0.96 µM) similarly to its analogue 22. These results suggested how the geometry of the scaffold does not influence the interaction with the target and above all that the aromatic derivatives are more suitable inhibitors than the corresponding cycloheptathiophene analogues. For the bicyclic derivatives 25 and 26, a reduced ability to inhibit the RNase H function was observed. Finally, quinazolinone derivative 27 showed an IC50 comparable to that of the benzoxazine analogue 26, indicating that the nature of the heteroatom does not play essential role in the interaction to the target domain.