Synthesis and antibacterial activities of pleuromutilin derivatives

Zhong, Yuan; Zhang, Bo; Ke, Shaoying; Ping,; Xu, Jiang; Dan, Dan; Ren$^{, }$; Shao, Yikai; Rong,; Ge, Ge; A, Yu; Liang, Weifa; Wang, Hong; Zhong, Yi

doi:10.1016/j.cclet.2008.09.009

Cited by 14 publications

(11 citation statements)

References 4 publications

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“…BC-3781 (Nabriva Therapeutics) entered phase II clinical studies, demonstrating a therapeutic potential for the treatment of bacterial skin and lung infections including community-acquired bacterial pneumonia. , As represented by BC-3781 and other effective derivatives, thioether analogues of the C14 side chain promise the increase of antibacterial activity (Figure ). − …”

Section: Introductionmentioning

confidence: 99%

A New Combination of a Pleuromutilin Derivative and Doxycycline for Treatment of Multidrug-Resistant Acinetobacter baumannii

et al. 2017

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Multidrug-resistant (MDR) Acinetobacter baumannii is one of the most difficult Gram-negative bacteria to treat and eradicate. In a cell-based screening of pleuromutilin derivatives against a drug sensitive A. baumannii strain, new molecules (2–4) exhibit bacteriostatic activity with 3.13 μg/mL concentration and 1 shows bactericidal activity with an MBC of 6.25 μg/mL. The pleuromutilin derivative 1 displays strong synergistic effects with doxycycline in a wide range of concentrations. A 35/1 ratio of 1 and doxycycline (1-Dox35/1) kills drug susceptible A. baumannii with the MBC of 2.0 μg/mL and an MDR A. baumannii with the MBC of 3.13 μg/mL. In vitro anti- Acinetobacter activity of 1-Dox35/1 is superior to that of clinical drugs such as tobramycin, tigecycline, and colistin. The efficacy of 1-Dox35/1 is evaluated in a mouse septicemia model; treatment of the infected C57BL/6 mice with 1-Dox35/1 protects from lethal infection of A. baumannii with an ED50 value of <2.0 mg/kg.

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Section: Introductionmentioning

confidence: 99%

A New Combination of a Pleuromutilin Derivative and Doxycycline for Treatment of Multidrug-Resistant Acinetobacter baumannii

et al. 2017

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“…In particular, compound 9 was synthesized using an efficient method characterized by a higher yield and shorter time compared with other published methods. 14,29 In this study, the antibacterial properties of all the above-mentioned synthesized compounds were evaluated using the agar dilution method and Oxford cup assay against three The antibacterial and docking results may provide new insights into the design of novel pleuromutilin derivatives and lay the basis for further studies of promising pleuromutilin antibiotics.…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis and Biological Activities of Novel Pleuromutilin Derivatives with a Substituted Thiadiazole Moiety as Potent Drug-Resistant Bacteria Inhibitors

Shang¹,

et al. 2014

J. Med. Chem.

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A series of novel pleuromutilin derivatives possessing thiadiazole moieties were synthesized via acylation reactions under mild conditions. The in vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by the agar dilution method and Oxford cup assay. The majority of the tested compounds displayed moderate antibacterial activities. Importantly, the three compounds with amino or tertiary amine groups in their side chains, 11, 13b, and 15c, were the most active antibacterial agents. Docking experiments carried out on the peptidyl transferase center (PTC) of 23S rRNA proved that there is a reasonable direct correlation between the binding free energy (ΔGb, kcal/mol) and the antibacterial activity. Moreover, the pharmacokinetic profiles of 11 and 15c in rat were characterized by moderate clearance and oral bioavailability.

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“…BC-3781 (Nabriva Therapeutics)). 10,11,12 The majority of pleuromutilin derivatives reported to date displays a spectrum of activity focused against Gram-positive bacteria, 13,14,15,16,17,18,19,20,21 and very few analogues have been demonstrated to exhibit antimycobacterial activity. Long et.…”

Section: Introductionmentioning

confidence: 99%

An antimycobacterial pleuromutilin analogue effective against dormant bacilli

Lemieux

Siricilla

Mitachi

et al. 2018

Bioorganic & Medicinal Chemistry

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Pleuromutilin is a promising pharmacophore to design new antibacterial agents for Gram-positive bacteria. However, there are limited studies on the development of pleuromutilin analogues that inhibit growth of Mycobacterium tuberculosis (Mtb). In screening of our library of pleuromutilin derivatives, UT-800 (1) was identified to kill replicating- and non-replicating Mtb with the MIC values of 0.83 and 1.20 μg/mL, respectively. UT-800 also kills intracellular Mtb faster than rifampicin at 2xMIC concentrations. Pharmacokinetic studies indicate that 1 has an oral bioavailability with an average F-value of 27.6%. Pleuromutilin may have the potential to be developed into an orally administered anti-TB drug.

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Synthesis and antibacterial activities of pleuromutilin derivatives

Cited by 14 publications

References 4 publications

A New Combination of a Pleuromutilin Derivative and Doxycycline for Treatment of Multidrug-Resistant Acinetobacter baumannii

A New Combination of a Pleuromutilin Derivative and Doxycycline for Treatment of Multidrug-Resistant Acinetobacter baumannii

Synthesis and Biological Activities of Novel Pleuromutilin Derivatives with a Substituted Thiadiazole Moiety as Potent Drug-Resistant Bacteria Inhibitors

An antimycobacterial pleuromutilin analogue effective against dormant bacilli

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