142-78-9Relevant articles and documents
Development and preclinical evaluation of new inhaled lipoglycopeptides for the treatment of persistent pulmonary methicillin-resistant staphylococcus aureus infections
Plaunt, Adam J.,Rose, Sasha J.,Kang, Jeong Yeon,Chen, Kuan-Ju,LaSala, Daniel,Heckler, Ryan P.,Dorfman, Arielle,Smith, Barrett T.,Chun, Donald,Viramontes, Veronica,Macaluso, Antonio,Li, Zhili,Zhou, Yuchen,Mark, Lilly,Basso, Jessica,Leifer, Franziska G.,Corboz, Michel R.,Chapman, Richard W.,Cipolla, David,Perkins, Walter R.,Malinin, Vladimir S.,Konicek, Donna M.
supporting information, (2021/06/22)
Chronic pulmonary methicillin-resistant Staphylococcus aureus (MRSA) disease in cystic fibrosis (CF) has a high probability of recurrence following treatment with standard-of-care antibiotics and represents an area of unmet need associated with reduced life expectancy. We developed a lipoglycopeptide therapy customized for pulmonary delivery that not only demonstrates potent activity against planktonic MRSA, but also against protected colonies of MRSA in biofilms and within cells, the latter of which have been linked to clinical antibiotic failure. A library of next-generation potent lipoglycopeptides was synthesized with an emphasis on attaining superior pharmacokinetics (PK) and pharmacodynamics to similar compounds of their class. Our strategy focused on hydrophobic modification of vancomycin, where ester and amide functionality were included with carbonyl configuration and alkyl length as key variables. Candidates representative of each carbonyl attachment chemistry demonstrated potent activity in vitro, with several compounds being 30 to 60 times more potent than vancomycin. Selected compounds were advanced into in vivo nose-only inhalation PK evaluations in rats, where RV94, a potent lipoglycopeptide that utilizes an inverted amide linker to attach a 10-carbon chain to vancomycin, demonstrated the most favorable lung residence time after inhalation. Further in vitro evaluation of RV94 showed superior activity to vancomycin against an expanded panel of Gram-positive organisms, cellular accumulation and efficacy against intracellular MRSA, and MRSA biofilm killing. Moreover, in vivo efficacy of inhaled nebulized RV94 in a 48 h acute model of pulmonary MRSA (USA300) infection in neutropenic rats demonstrated statistically significant antibacterial activity that was superior to inhaled vancomycin.
Synthesis of: N-acyl amide natural products using a versatile adenylating biocatalyst
Marchetti, Piera M.,Richardson, Shona M.,Kariem, Noor M.,Campopiano, Dominic J.
supporting information, p. 1192 - 1196 (2019/07/31)
Natural products are secondary metabolites produced by many different organisms such as bacteria, fungi and plants. These biologically active molecules have been widely exploited for clinical application. Here we investigate TamA, a key enzyme from the biosynthetic pathway of tambjamine YP1, an acylated bipyrrole that is produced by the marine microorganism Pseudoalteromonas tunicata. TamA is a didomain enzyme composed of a catalytic adenylation (ANL) and an acyl carrier protein (ACP) domain that together control the fatty acid chain length of the YP1. Here we show that the TamA ANL domain alone can be used to generate a range of acyl adenylates that can be captured by a number of amines thus leading to the production of a series of fatty N-acyl amides. We exploit this biocatalytic promiscuity to produce the recently discovered class of N-acyl histidine amide natural products from Legionella pneumophila.
Design, synthesis and CoMFA studies of OEA derivatives as FAAH inhibitors
Han, Daxiong,Wang, Biyan,Jin, Hui,Wang, Haiyan,Chen, Meimei
, p. 2951 - 2966 (2017/10/06)
A total of 26 novel oleoylethanolamide derivatives were designed, synthesized, and characterized. All synthesized targets compounds were screened for their inhibitory activities against fatty acid amide hydrolase. Among of them, 13 compounds inhibit fatty acid amide hydrolase by 50% at the concentration of 100 μM. Of these compounds, the most active one is compound 9, which inhibit fatty acid amide hydrolase activity 98.35% at the concentration of 100 μM. Comparative molecular field analysis analyzes were performed based on obtained biological activities data and resulted in a statistically reliable comparative molecular field analysis model with high predictive abilities (r2 = 0.978, q2 = 0.613).
