Synthesis of Ureidomuraymycidine Derivatives for Structure– Activity Relationship Studies of Muraymycins

One of the key constituents of the muraymycins is the 6-membered cyclic guanidine, (2<i>S</i>,3<i>S</i>)-muraymycidine (or <i>epi</i>-capreomycidine). In order to diversify the structure of the oligopeptide moiety of the muraymycins for thorough structure–activity relationship studies, we have developed a highly stereoselective synthesis of ureidomuraymycidine derivatives with the lactone <b>4a</b>

Selective Esterifications of Primary Alcohols in a Water-Containing Solvent

Oxyma and an oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2-(hydroxyimino)acetate (<b>5b</b>), displayed a remarkable effect on selective esterifications of <i>primary</i> alcohols. A wide range of carboxylic acids could be esterified with <i>primary</i> alcohols by using EDCI, NaHCO₃, and Oxyma or Oxyma derivative <b>5b</b> in 5% H₂O–CH₃CN. Oxyma derivative <b>5b</b> is particularly useful, since it could be removed after the reaction via a simple basic or an acidic aqueous workup procedure

Stereocontrolled Total Synthesis of Muraymycin D1 Having a Dual Mode of Action against Mycobacterium tuberculosis

A stereocontrolled first total synthesis of muraymycin D1 (<b>1</b>) has been achieved. The synthetic route is highly stereoselective, featuring (1) selective β-ribosylation of the C2-methylated amino ribose, (2) selective Strecker reaction, and (3) ring-opening reaction of a diastereomeric mixture of a diaminolactone to synthesize muraymycidine (<i>epi</i>-capreomycidine). The acid-cleavable protecting groups for <i>secondary</i> alcohol and uridine ureido nitrogen are applied for simultaneous deprotections with the Boc and ^<i>t</i>Bu groups. Muraymycin D1 (<b>1</b>) and its amide derivatives (<b>2</b> and <b>3</b>) exhibited growth inhibitory activity against Mycobacterium tuberculosis (MIC₅₀ = 1.56–6.25 μg/mL) and strong enzyme inhibitory activities against the bacterial phosphotransferases (MurX and WecA) (IC₅₀ = 0.096–0.69 μM)

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

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