64122-23-2Relevant academic research and scientific papers
Novel fluorinated pyrrolomycins as potent anti-staphylococcal biofilm agents: Design, synthesis, pharmacokinetics and antibacterial activities
Yang, Zunhua,Liu, Yan,Ahn, Jongsam,Qiao, Zhen,Endres, Jennifer L.,Gautam, Nagsen,Huang, Yunlong,Li, Jerry,Zheng, Jialin,Alnouti, Yazen,Bayles, Kenneth W.,Li, Rongshi
, p. 129 - 137 (2016)
Staphylococcus aureus (SA) is a major cause of hospital- and community-associated bacterial infections in the U.S. and around the world. These infections have become increasingly difficult to treat due to the propensity to develop antibiotic resistance and form biofilm. To date, no antibiofilm agents are available for clinical use. To add to the repertoire of antibiotics for clinical use and to provide novel agents for combating both SA and biofilm infections, we previously reported marinopyrroles as potent anti-SA agents. In this study, we used fragment-based and bioisostere approaches to design and synthesize a series of novel fluorinated pyrrolomycins for the first time, performed analyses of their physicochemical and drug-like properties, and investigated structure activity relationships and pharmacokinetics. These promising fluorinated pyrrolomycins demonstrate potent antibacterial activity against SA with favorable drug-like properties and pharmacokinetic profiles. Importantly, these compounds kill staphylococcal biofilm-associated cells with a lack of mammalian cell cytotoxicity and no occurrence of bacterial resistance. Our novel fluorinated pyrrolomycin 4 has a clogP value of 4.1, an MIC of 73 ng/mL, MBC of 4 μg/mL, kill staphylococcal-associated biofilm at 8 μg/mL, bioavailability of 35%, and the elimination half-life of 6.04 h and 6.75 h by intravenous and oral administration, respectively. This is the first report of comprehensive drug discovery studies on pyrrolomycin-based antibiotics.
Pyrrolomycins are potent natural protonophores
Valderrama, Katherine,Pradel, Elizabeth,Firsov, Alexander M.,Drobecq, Hervé,Roy, Hélène Bauderlique-le,Villemagne, Baptiste,Antonenko, Yuri N.,Hartkoorn, Ruben Christiaan
supporting information, (2019/09/30)
The escalating burden of antibiotic drug resistance necessitates research into novel classes of antibiotics and their mechanism of action. Pyrrolomycins are a family of potent natural product antibiotics with nanomolar activity against Gram-positive bacteria, yet with an elusive mechanism of action. In this work, we dissect the apparent Gram-positive specific activity of pyrrolomycins and show that Gram-negative bacteria are equally sensitive to pyrrolomycins when drug efflux transporters are removed and that albumin in medium plays a large role in pyrrolomycin activity. The selection of resistant mutants allowed for the characterization and validation of a number of mechanisms of resistance to pyrrolomycins in both Staphylococcus aureus and an Escherichia coli ΔtolC mutant, all of which appear to affect compound penetration rather than being target associated. Imaging of the impact of pyrrolomycin on the E. coli ΔtolC mutant using scanning electron microscopy showed blebbing of the bacterial cell wall often at the site of bacterial division. Using potentiometric probes and an electrophysiological technique with an artificial bilayer lipid membrane, it was demonstrated that pyrrolomycins C and D are very potent membrane-depolarizing agents, an order of magnitude more active than conventional carbonyl cyanide m-chlorophenylhydrazone (CCCP), specifically disturbing the proton gradient and uncoupling oxidative phosphorylation via protonophoric action. This work clearly unveils the until-now-elusive mechanism of action of pyrrolomycins and explains their antibiotic activity as well as mechanisms of innate and acquired drug resistance in bacteria.
PYRROLOMYCINS AND METHODS OF USING THE SAME
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Paragraph 0076, (2017/02/09)
Provided herein are pyrrolomycin derivatives, which can be used to modulate Mcl-1, inhibit proliferation of bacteria and pathogens, as well as to treat infectious diseases and cancers.
Synthesis of ω-Fluoroalkoxy and Alkoxy Derivatives of Raclopride: Evaluation as Radioligands for PET study of Cerebral Dopamine D2 Receptors
Banks, William R.,Moerlein, Stephen M.,Parkinson, David,Welch, Michael J.
, p. 150 - 173 (2007/10/03)
A series of analogues of the dopamine D2 receptor antagonist raclopride were evaluated as radiopharmaceuticals for positron emission tomography (PET). In vitro assays indicate that the D2 affinity of the ligands are descreased by replacement of the 2-methoxy group of raclopride with ω-fluoroalkoxy substituents, and increased by removal of the 6-hydroxy substituent. The 2-fluoroethoxy derivative of deshydroxy raclopride, [(S)-2-[(3,5)-dichloro-2-(2'-fluoroethoxy)benzamido)-methyl]-1-ethylpyrrolidine], exhibited a D2 affinity (Ki = 12nM) close to that of raclopride itself (Ki = 9.5 nM). A one-step radiosynthesis of the fluorine-18 labeled analogue of this ligand with specific radioactivity > 2 Ci/μmol and 35 percent radiochemical yield (decay-corrected) was developed; there was poor receptor-specific localization of this radioligand in vivo in rats, however. These results underscore the inadequacy of in vitro receptor assays as the sole screening test for PET radiopharmaceuticals. Future development of this series of ligands should emphasize placement of the fluorine-18 label at an aromatic site remote from the intramolecular hydrogen-bonding sites necessary for receptor-active conformations
Marine Bacteria, I. - Synthesis of Pentabromopseudiline, a Cytotoxic Phenylpyrrole from Alteromonas luteo-violaceus
Laatsch, Hartmut,Pudleiner, Heinz
, p. 863 - 882 (2007/10/02)
A new synthesis of 2,3,4-tribromo-5-(3,5-dibromo-2-hydroxyphenyl)pyrrole (1a, pentabromopseudiline), an antibiotic, enzymeinhibitory and cytotoxic active constituent of the marine bacterium Alteromonas luteo-violaceus, is described.For investigation of structure-activity relationships further 2-phenylpyrroles are investigated.Key step in their synthesis is the Grignard reaction of 2-(1,3-dioxan-2-yl)ethylmagnesium bromide (9d) with benzoyl chlorides yielding γ-phenyl-γ-ketoaldehydes 24, and the Paal-Knorr cyclisation of the latter. - Key Words: Alteromonas luteo-violaceus / Bromopyrrole / Marine bacteria / Pentabromopseudiline
1-ACYL-3-CYCLOOCTYLGUANIDINES
Sluka, Jaroslav,Smejkal, Frantisek,Budesinsky, Zdenek
, p. 1595 - 1600 (2007/10/02)
On reaction of cyclooctylamine with the sulfate of S-methylisothiourea cyclooctylguanidine was formed which was acylated with the methyl esters of 5-halogeno- and 3,5-dihalogeno-2-alkoxybenzoic acids.The 1-acyl-3-cyclooctylguanidine I-XVII formed were tes
