Stereocontrolled Total Synthesis of Muraymycin D1 Having a Dual Mode of Action against Mycobacterium tuberculosis.
A stereocontrolled first total synthesis of muraymycin D1 (1) 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 (epi-capreomycidine). The acid-cleavable protecting groups for secondary alcohol and uridine ureido nitrogen are applied for simultaneous deprotections with the Boc andtBu groups. Muraymycin D1 (1) and its amide derivatives (2 and 3) 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).
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
Katsuhiko
K
Mitachi
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
Bilal A
BA
Aleiwi
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
Christopher M
CM
Schneider
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
Shajila
S
Siricilla
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
Michio
M
Kurosu
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D000900:Anti-Bacterial Agents; D009705:Nucleosides; D010455:Peptides; C000627011:muraymycin D1