- Construction and activity evaluation of novel dual-target (SE/CYP51) anti-fungal agents containing amide naphthyl structure
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With the increase of fungal infection and drug resistance, it is becoming an urgent task to discover the highly effective antifungal drugs. In the study, we selected the key ergosterol bio-synthetic enzymes (Squalene epoxidase, SE; 14 α-demethylase, CYP51) as dual-target receptors to guide the construction of novel antifungal compounds, which could achieve the purpose of improving drug efficacy and reducing drug-resistance. Three different series of amide naphthyl compounds were generated through the method of skeleton growth, and their corresponding target products were synthesized. Most of compounds displayed the obvious biological activity against different Candida spp. and Aspergillus fumigatus. Among of them, target compounds 14a-2 and 20b-2 not only possessed the excellent broad-spectrum anti-fungal activity (MIC50, 0.125–2 μg/mL), but also maintained the anti-drug-resistant fungal activity (MIC50, 1–4 μg/mL). Preliminary mechanism study revealed the compounds (14a-2, 20b-2) could block the bio-synthetic pathway of ergosterol by inhibiting the dual-target (SE/CYP51) activity, and this finally caused the cleavage and death of fungal cells. In addition, we also discovered that compounds 14a-2 and 20b-2 with low toxic and side effects could exert the excellent therapeutic effect in mice model of fungal infection, which was worthy for further in-depth study.
- An, Yunfei,Fan, Haiyan,Han, Jun,Liu, Wenxia,Liu, Yating,Sun, Bin,Sun, Zhuang
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- Synthesis and preliminary anti-inflammatory and anti-bacterial evaluation of some diflunisal aza-analogs
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Our aim was to identify new multi-target compounds endowed with both anti-inflammatory and anti-bacterial activities for treatment of human infections. Diflunisal, a nonsteroidal anti-inflammatory agent, has recently been repurposed for its anti-virulence properties against methicillin-resistant Staphylococcus aureus. Effective synthesis of some aza-analogs of the anti-inflammatory drug diflunisal was carried out following the route involving key oxazole intermediates to obtain o- and m-hydroxypyridinecarboxylic acid derivatives. The newly synthesized diflunisal aza-analogs did not exhibit cytotoxic activity up to 80 μM and some of them exhibited anti-inflammatory activities, decreasing the levels of pro-inflammatory cytokines and prostaglandins induced by bacterial lipopolysaccharide in human primary macrophages. Ten of the diflunisal aza-analogs were found to have interesting antibacterial activity, sensitizing S. aureus, Streptococcus pyogenes, Enterococcus faecium, and Pseudomonas aeruginosa to the antibacterial effects of beta-lactam antibiotics and protein synthesis inhibitors.
- Carta, Davide,Brun, Paola,Dal Pra, Matteo,Bernabè, Giulia,Castagliuolo, Ignazio,Ferlin, Maria Grazia
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p. 1017 - 1032
(2018/06/27)
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- Synthesis of methylamino-2-phenyl-2-butyl-3,4,5-trimethoxybenzoate, the main bioactive metabolite of trimebutine maleate
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The first synthesis of the methylamino-2-phenyl-2-butyl-3,4,5- trimethoxybenzoate (desmethyltrimebutine) I is described. This compound is the main bioactive metabolite of trimebutine II (Debridat, CAS 39133-31-8), an antispasmodic widely used for intestinal diseases since 1969. It was used for pharmacokinetic and bioequivalence studies.
- Martin, Arnaud,Figadere, Bruno,Saivin, Sylvie,Houin, Georges,Chomard, Jean Marie,Cahiez, Gerard
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p. 544 - 549
(2007/10/03)
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- A convenient synthesis of protected (R)-α-phenylproline derivatives using the Mitsunobu reaction
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Boc-(R)-α-phenylproline ethyl ester 1 was prepared in good yield starting from racemic phenylglycine. Condensation of phenylglycine ethyl ester with benzaldehyde furnished N-benzylidene phenylglycine ethyl ester which was allylated under phase transfer catalysis conditions. After acidic hydrolysis, tile resulting α-allylphenylglycine ethyl ester was enzymatically resolved using PLE. Hydroboration and oxidation of the double bond, Boc-protection and subsequent ring closure using the Mitsunobu reaction protocol gave rise to Boc-(R)-α-phenylproline ethyl ester.
- Van Betsbrugge,Tourwe,Kaptein,Kierkels,Broxterman
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p. 9233 - 9240
(2007/10/03)
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