- Increased antibacterial properties of indoline-derived phenolic Mannich bases
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The search for antibacterial agents for the combat of nosocomial infections is a timely problem, as antibiotic-resistant bacteria continue to thrive. The effect of indoline substituents on the antibacterial properties of aminoalkylphenols was studied, leading to the development of a library of compounds with minimum inhibitory concentrations (MICs) as low as 1.18 μM. Two novel aminoalkylphenols were identified as particularly promising, after MIC and minimum bactericidal concentrations (MBC) determination against a panel of reference strain Gram-positive bacteria, and further confirmed against 40 clinical isolates (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes). The same two aminoalkylphenols displayed low toxicity against two in vivo models (Artemia salina brine shrimp and Saccharomyces cerevisiae). The in vitro cytotoxicity evaluation (on human keratinocytes and human embryonic lung fibroblast cell lines) of the same compounds was also carried out. They demonstrated a particularly toxic effect on the fibroblast cell lines, with IC50 in the 1.7–5.1 μM range, thus narrowing their clinical use. The desired increase in the antibacterial properties of the aminoalkylphenols, particularly indoline-derived phenolic Mannich bases, was reached by introducing an additional nitro group in the indolinyl substituent or by the replacement of a methyl by a bioisosteric trifluoromethyl substituent in the benzyl group introduced through use of boronic acids in the Petasis borono-Mannich reaction. Notably, the introduction of an additional nitro moiety did not confer added toxicity to the aminoalkylphenols.
- Rimpil?inen, Tatu,Nunes, Alexandra,Calado, Rita,Fernandes, Ana S.,Andrade, Joana,Ntungwe, Epole,Spengler, Gabriella,Szemerédi, Nikoletta,Rodrigues, Jo?o,Gomes, Jo?o Paulo,Rijo, Patricia,Candeias, Nuno R.
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- Reductive cyanation of organic chlorides using CO2 and NH3 via Triphos–Ni(I) species
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Cyano-containing compounds constitute important pharmaceuticals, agrochemicals and organic materials. Traditional cyanation methods often rely on the use of toxic metal cyanides which have serious disposal, storage and transportation issues. Therefore, there is an increasing need to develop general and efficient catalytic methods for cyanide-free production of nitriles. Here we report the reductive cyanation of organic chlorides using CO2/NH3 as the electrophilic CN source. The use of tridentate phosphine ligand Triphos allows for the nickel-catalyzed cyanation of a broad array of aryl and aliphatic chlorides to produce the desired nitrile products in good yields, and with excellent functional group tolerance. Cheap and bench-stable urea was also shown as suitable CN source, suggesting promising application potential. Mechanistic studies imply that Triphos-Ni(I) species are responsible for the reductive C-C coupling approach involving isocyanate intermediates. This method expands the application potential of reductive cyanation in the synthesis of functionalized nitrile compounds under cyanide-free conditions, which is valuable for safe synthesis of (isotope-labeled) drugs.
- Dong, Yanan,Li, Yuehui,Yang, Peiju,Zhao, Shizhen
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- Gold-catalyzed C5-alkylation of indolines and sequential oxidative aromatization: Access to C5-functionalized indoles
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A novel protocol for the synthesis of C5-alkylated indole derivatives via a gold-catalyzed reaction of indolines with diazo compounds and subsequent oxidative aromatization has been developed. C-H bond functionalization selectively occurs at the C5-position of indolines without a directing group. The experimental operation is simple and the whole process can be manipulated in one-pot.
- Zhang, Wenzheng,Xu, Guangyang,Qiu, Lin,Sun, Jiangtao
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supporting information
p. 3889 - 3892
(2018/06/08)
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- PYRAZOLOPYRIMIDINE DERIVATIVES USEFUL AS INHIBITORS OF BRUTON'S TYROSINE KINASE
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This invention relates to novel compounds. The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton's tyrosine kinase (BTK). The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton's tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases.
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Paragraph 00550
(2014/12/12)
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- 1-(2-hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitrile derivatives as potent and tissue selective androgen receptor modulators
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We present a novel series of selective androgen receptor modulators (SARMs) which shows excellent biological activity and physical properties. 1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)-indoline-4-carbonitriles showed potent binding to the androgen receptor (AR) and activated AR-mediated transcription in vitro. Representative compounds demonstrated diminished activity in promoting the intramolecular interaction between the AR carboxyl (C) and amino (N) termini. This N/C-termini interaction is a biomarker assay for the undesired androgenic responses in vivo. In orchidectomized rats, daily administration of a lead compound from this series showed anabolic activity by increasing levator ani muscle weight. Importantly, minimal androgenic effects (increased tissue weights) were observed in the prostate and seminal vesicles, along with minimal repression of circulating luteinizing hormone (LH) levels and no change in the lipid and triglyceride levels. This lead compound completed a two week rat toxicology study, and was well tolerated at doses up to 100 mg/kg/day, the highest dose tested, for 14 consecutive days.
- Chekler, Eugene L. Piatnitski,Unwalla, Rayomond,Khan, Taukeer A.,Tangirala, Raghuram S.,Johnson, Mark,St. Andre, Michael,Anderson, James T.,Kenney, Thomas,Chiparri, Sue,McNally, Chris,Kilbourne, Edward,Thompson, Catherine,Nagpal, Sunil,Weber, Gregory,Schelling, Scott,Owens, Jane,Morris, Carl A.,Powell, Dennis,Verhoest, Patrick R.,Gilbert, Adam M.
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supporting information
p. 2462 - 2471
(2014/04/17)
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- RHO KINASE INHIBITORS
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The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein R1 and X are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of Rho Kinase-mediated disorders selected from hypertension, atherosclerosis, restenosis, stroke, myocardial infarction, heart failure, coronary artery disease, peripheral artery disease, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, pulmonary hypertension, angina, erectile dysfunction, renal disease, organ failure, asthma, glaucoma, cancer, Alzheimer's disease, multiple sclerosis, spinal cord injury, neuropathic pain, rheumatoid arthritis, psoriasis inflammatory bowel disease, and combinations of such disorders.
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Page/Page column 85-86
(2012/02/01)
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- N-CYCLYL-3 - (CYCLYLCARBONYLAMINOMETHYL) BENZAMIDE DERIVATIVES AS RHO KINASE INHIBITORS
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The present invention relates to compounds of formula (I) : and pharmaceutically acceptable salts thereof, wherein R1and R2 are various ring systems. The invention also relates to pharmaceutical compositions comprising these compound
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Page/Page column 114-115
(2012/02/01)
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