72196-67-9Relevant academic research and scientific papers
Construction and activity evaluation of novel benzodioxane derivatives as dual-target antifungal inhibitors
An, Yunfei,Fan, Haiyan,Han, Jun,Liu, Wenxia,Sun, Bin,Xie, Honglei
, (2021/11/09)
Ergosterol exert the important function in maintaining the fluidity and osmotic pressure of fungal cells, and its key biosynthesis enzymes (Squalene epoxidase, SE; 14 α-demethylase, CYP51) displayed the obvious synergistic effects. Therefore, we expected to discover the novel antifungal compounds with dual-target (SE/CYP51) inhibitory activity. In the progress, we screened the different kinds of potent fragments based on the dual-target (CYP51, SE) features, and the method of fragment-based drug discovery (FBDD) was used to guide the construction of three different series of benzodioxane compounds. Subsequently, their chemical structures were synthesized and evaluated. These compounds displayed the obvious biological activity against the pathogenic fungal strains. Notably, target compounds 10a-2 and 22a-2 possessed the excellent broad-spectrum anti-fungal activity (MIC50, 0.125–2.0 μg/mL) and the activity against drug-resistant strains (MIC50, 0.5–2.0 μg/mL). Preliminary mechanism studies have confirmed that these compounds effectively inhibited the dual-target (SE/CYP51) activity, they could cause fungal rupture and death by blocking the bio-synthetic pathway of ergosterol. Further experiments discovered that compounds 10a-2 and 22a-2 also maintained a certain of anti-fungal effect in vivo. In summary, this study not only provided the new dual-target drug design strategy and method, but also discover the potential antifungal compounds.
Design, synthesis, and structure-activity relationship studies of L-amino alcohol derivatives as broad-spectrum antifungal agents
Zhao, Liyu,Tian, Linfeng,Sun, Nannan,Sun, Yin,Chen, Yixuan,Wang, Xinran,Zhao, Shizhen,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
, p. 374 - 385 (2019/06/05)
To discover broad spectrum antifungal agents, two strategies were applied, and a novel class of L-amino alcohol derivatives were designed and synthesized. 3-F substituted compounds 14i, 14n, 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra against C. albicans and C. tropicalis, with MIC values in the range of 0.03–0.06 μg/mL, and against A. fumigatus and C. neoformans, with MIC values in the range of 1–2 μg/mL. Notably, Compounds 14i, 14n, 14s and 14v also displayed moderate activities against fluconazole-resistance strains 17# and CaR that were isolated from AIDS patients. Moreover, only compounds in the S-configuration showed antifungal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 14v stemmed from inhibition of C. albicans CYP51. Compounds 14n and 14v were almost nontoxic to mammalian A549 cells, and their stability in human plasma was excellent.
NOVEL CYP34A-SPECIFIC INHIBITORS AND METHODS OF USING SAME
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Page/Page column 42; 43, (2017/03/28)
The present invention includes novel compositions inhibiting CYP3 A4. The present invention further includes a novel method of inhibiting CYP3A4 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention. In one embodiment, the subject is further administered at least one additional therapeutic agent.
pH-Controlled recognition of amino acids by urea derivatives of β-cyclodextrin
Stepniak, Pawel,Lainer, Bruno,Chmurski, Kazimierz,Jurczak, Janusz
, p. 15742 - 15746 (2017/03/22)
Water soluble amphiphilic urea-substituted β-cyclodextrins were synthesized and applied as amino acid receptors. A great affinity towards nonpolar amino acids was observed, ranging from 2300 M?1 for alanine to 54?800 M?1 for tryptoph
Structure-Based Inhibitor Design for Evaluation of a CYP3A4 Pharmacophore Model
Kaur, Parminder,Chamberlin, A. Richard,Poulos, Thomas L.,Sevrioukova, Irina F.
, p. 4210 - 4220 (2016/06/01)
Human cytochrome P450 3A4 (CYP3A4) is a key xenobiotic-metabolizing enzyme that oxidizes and clears the majority of drugs. CYP3A4 inhibition may lead to drug-drug interactions, toxicity, and other adverse effects but, in some cases, could be beneficial and enhance therapeutic efficiency of coadministered pharmaceuticals that are metabolized by CYP3A4. On the basis of our investigations of analogs of ritonavir, a potent CYP3A4 inactivator and pharmacoenhancer, we have built a pharmacophore model for a CYP3A4-specific inhibitor. This study is the first attempt to test this model using a set of rationally designed compounds. The functional and structural data presented here agree well with the proposed pharmacophore. In particular, we confirmed the importance of a flexible backbone, the H-bond donor/acceptor moiety, and aromaticity of the side group analogous to Phe-2 of ritonavir and demonstrated the leading role of hydrophobic interactions at the sites adjacent to the heme and phenylalanine cluster in the ligand binding process. The X-ray structures of CYP3A4 bound to the rationally designed inhibitors provide deeper insights into the mechanism of the CYP3A4-ligand interaction. Most importantly, two of our compounds (15a and 15b) that are less complex than ritonavir have comparable submicromolar affinity and inhibitory potency for CYP3A4 and, thus, could serve as templates for synthesis of second generation inhibitors for further evaluation and optimization of the pharmacophore model.
METHODS FOR INHIBITING DRUG DEGRADATION
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Paragraph 0249; 0250, (2015/11/02)
Methods of inhibiting cytochrome P450 enzymes are provided that can be used for improving the treatment of diseases by preventing degradation of drugs or other molecules by cytochrome P450. Pharmaceutical compositions are provided that can act as boosters
A concise enantioselective synthesis of (R)-selegiline, (S)-benzphetamine and formal synthesis of (R)-sitagliptin via electrophilic azidation of chiral imide enolates
Dey, Soumen,Sudalai, Arumugam
, p. 67 - 72 (2015/02/02)
A concise and high yielding enantioselective synthesis of (R)-selegiline, an anti-Parkinson's drug, (S)-benzphetamine, an anti-obesity agent, and (S)-sitagliptin, an anti-diabetic drug has been described starting from commercially available starting materials employing Evans' electrophilic azidation of chiral imide enolates as a key chiral inducing step, which proceeds in a highly diastereoselective manner (>99%).
A rapid entry to amino acid derived diverse 3,4-dihydropyrazines and dihydro[1,2,3]triazolo[1,5-a]pyrazines through 1,3-dipolar cycloaddition
Bera, Saurav,Panda, Gautam
, p. 3976 - 3985 (2014/06/09)
An efficient, general and practical synthesis of diverse 3,4-dihydropyrazines, 6,7-dihydro-[1,2,3]triazolopyrazines and 7,8-dihydro-[1,2,3]triazolodiazepines through intramolecular 1,3-dipolar cycloaddition from amino acid derived common intermediates with high yields is described. Moreover, one-pot access to optically active 3-aryl substituted 6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazines in the palladium-copper co-catalytic system has also been achieved in this work. The easy substrate availability and operational simplicity make the process suitable for further exploration. This journal is the Partner Organisations 2014.
AZAQUINAZOLINE INHIBITORS OF ATYPICAL PROTEIN KINASE C
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Page/Page column 222-223, (2014/04/17)
The present invention provides a compound of formula (I) or a salt thereof, wherein R7, R8, R9, G, and X are as defined herein. A compound of formula (I) and its salts have a PKC inhibitory activity, and may be used to treat proliferative disorders.
Synthesis of iron P-N-P' and P-NH-P asymmetric hydrogenation catalysts
Sonnenberg, Jessica F.,Lough, Alan J.,Morris, Robert H.
supporting information, p. 6452 - 6465 (2015/02/19)
Complexes of the type mer,trans-[Fe(P-N-P)(CO)2Br]BF4 are known to be precatalysts for the asymmetric direct hydrogenation of ketones and imines. Employing related ligand scaffolds, we successfully generated and tested the series of three new precatalysts [Fe(PCy2CH2CH-NCH(R)CH2PPh2)(CO)2Br]BF4 with chirality derived from (S)-amino alcohols with phenyl, benzyl, and isopropyl substituents (R), yielding fairly active and selective systems. For the reduction of acetophenone to (S)-1-phenylethanol turnover frequencies up to 920 h-1 and up to 74% enantiomeric excess at 50 °C and 5-25 atm of H2 were obtained. We found, however, that placing these large groups R next to nitrogen was found to be deleterious to catalytic activity. Extending the scope of the ligand structure, we then developed a series of six P-N-P and five P-NH-P systems starting with o-diphenylphosphinobenzaldehyde and the phosphine-amines PPh2CHR1CHR2NH2 (R1 = H, Ph, CH2Ph, iPr with R2 = H or R1 = Me, Ph with R2 = Ph) as well as their corresponding [Fe(P-N-P)(NCMe)3][BF4]2 and [Fe(P-NH-P)(NCMe)3][BF4]2 complexes, which were not catalytically active. Finally, we made the new achiral iron complex mer,cis-Fe(PPh2(o-C6H4)CHNCH2CH2PPh2)(CO)Br2, which was active for the direct hydrogenation of acetophenone, achieving turnover frequencies of 800 h-1 at 50°C and 25 atm of H2.
