- Discovery of Novel Sertraline Derivatives as Potent Anti- Cryptococcus Agents
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Treatment of life-threatening cryptococcal meningitis (CM) is highly challenging due to the limited efficacy of the available antifungal drugs. Antidepressant sertraline (SER) has been proposed to be a potential antifungal agent for CM. However, clinical studies indicated that SER failed to achieve the expected therapeutic effects. Herein, novel SER derivatives were designed by scaffold hopping, and they showed improved anticryptococcal activity both in vitro and in vivo. In particular, compound D16 was identified as a promising anti-CM agent with a new antifungal mode of action. It acted by blocking the biosynthesis of ergosterol through the inhibition of Δ5,6-desaturase. This study provides a new target and a drug-like candidate for CM treatment.
- Ji, Changjin,Li, Jian,Li, Wang,Liu, Na,Sheng, Chunquan,Tu, Jie,Yang, Wanzhen,Yun, Zhaolin
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supporting information
(2022/03/16)
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- Sertraline derivative and preparation method and application thereof
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The invention discloses a sertraline derivative or a medicinal salt thereof. The structural general formula of the sertraline derivative is shown in the specification. The sertraline derivative has a good inhibition effect on cryptococcus neoformans, particularly, the compound D16 disclosed by the invention has a relatively good inhibition effect on candida glabrata 9073, candida tropicalis 10186, cryptococcus neoformans, candida albicans 5314, candida albicans 904, candida tropicalis 10186, drug-resistant candida albicans 103 and cryptococcus gottii.
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Paragraph 0084-0086; 0089-0090
(2021/04/14)
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- Enantiopurity determination of the enantiomers of the triple reuptake inhibitor indatraline
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The present study describes the development of two approaches for the determination of the enantiopurity of both enantiomers of indatraline. Initially, a method was developed using different chiral solvating agents (CSAs) for diastereomeric discrimination regarding signal separation in 1H nuclear magnetic resonance (NMR) spectroscopy, revealing MTPA as a promising choice for the differentiation of the indatraline enantiomers. This CSA was also tested for its ideal molar ratio, temperature, and solvent. Optimized conditions could be achieved that made determination of enantiopurity for (1R,3S)-indatraline up to 98.9% enantiomeric excess (ee) possible. To quantify even higher enantiopurities, a high-performance liquid chromatography (HPLC) method based on a modified β-cyclodextrine phase was established. The influence of buffer type, concentration, pH value, percentage and kind of organic modifier, temperature, injection volume as well as sample solvent on chromatographic parameters was investigated. Afterwards, the reliability of the established HPLC method was demonstrated by validation according to the ICH guideline Q2(R1) regarding specificity, accuracy, precision, linearity, and quantitation limit. The developed method proved to be strictly linear within a concentration range of 1.25-1000 μM for the (1R,3S)-enantiomer and 1.25-750 μM for its mirror image that enables a reliable determination of enantiopurities up to 99.75% ee for the (1R,3S)-enantiomer and up to 99.67% ee for the (1S,3R)-enantiomer.
- Grimm, Stefanie H.,Allmendinger, Lars,Hoefner, Georg,Wanner, Klaus T.
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p. 923 - 933
(2014/01/06)
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- Asymmetric total synthesis of (+)-indatraline via diastereoselective amination of chiral ethers using chlorosulfonyl isocyanate
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A concise asymmetric total synthesis of (+)-indatraline from readily available cinnamic acid is described. The key steps include Corey's oxazaborolidine-catalyzed asymmetric carbonyl reduction and a highly stereoselective amination of chiral benzylic ether with retention of stereochemistry using chlorosulfonyl isocyanate.
- Lee, Sang Hwi,Park, Sook Jin,Kim, In Su,Jung, Young Hoon
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p. 1877 - 1880
(2013/03/13)
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- TREATMENT OF NEURODEGENERATIVE DISEASES USING INDATRALINE ANALOGS
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Methods and compositions useful in the treatment or prevention of synucleinopathies, such as Parkinson''s disease, diffuse Lewy body disease, and multiple system atrophy, or other neurodegenerative diseases (e.g., amyotrophic lateral sclerosis, Huntington''s disease, and Alzheimer''s disease) are provided. The treatment including administering to a subject an indatraline derivative that inhibits the aggregation of a-synuclein.
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Page/Page column 97
(2009/04/25)
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- Iodine(III)-promoted ring contraction of 1,2-dihydronaphthalenes: A diastereoselective total synthesis of (±)-indatraline
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Equation presented A new approach for the synthesis of (±)- indatraline, which is a 3-phenyl-1-indanamine that displays several biological activities, is described. The strategy features as the key step a diastereoselective ring contraction of a 1,2-dihydronaphthalene promoted by Phl(OTs)OH, to construct the indan ring system. The oxidative rearrangement of other 1,2-dihydronaphthalenes was also investigated, generalizing this method to obtain indans.
- Silva Jr., Luiz F.,Siqueira, Fernanda A.,Pedrozo, Eliane C.,Vieira, Fabiana Y. M.,Doriguetto, Antonio C.
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p. 1433 - 1436
(2008/02/02)
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