Investigation and conformational analysis of fluorinated nucleoside antibiotics targeting siderophore biosynthesis.
Antibiotic resistance represents one of the greatest threats to public health. The adenylation inhibitor 5'-O-[N-(salicyl)sulfamoyl]adenosine (SAL-AMS) is the archetype for a new class of nucleoside antibiotics that target iron acquisition in pathogenic microorganisms and is especially effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. Strategic incorporation of fluorine at the 2' and 3' positions of the nucleoside was performed by direct fluorination to enhance activity and improve drug disposition properties. The resulting SAL-AMS analogues were comprehensively assessed for biochemical potency, whole-cell antitubercular activity, and in vivo pharmacokinetic parameters. Conformational analysis suggested a strong preference of fluorinated sugar rings for either a 2'-endo, 3'-exo (South), or a 3'-endo,2'-exo (North) conformation. The structure-activity relationships revealed a strong conformational bias for the C3'-endo conformation to maintain potent biochemical and whole-cell activity, whereas improved pharmacokinetic properties were associated with the C2'-endo conformation.
†Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Surendra
S
Dawadi
†Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Kishore
K
Viswanathan
‡Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, United States.
Helena I
HI
Boshoff
‡Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, United States.
Clifton E
CE
Barry
†Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Courtney C
CC
Aldrich
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D054879:Halogenation; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D009690:Nucleic Acid Conformation; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry*; D017262:Siderophores / Q000096:biosynthesis* / Q000737:chemistry
C526816:5'-O-(N-(salicyl)sulfamoyl)adenosine; D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D009705:Nucleosides; D017262:Siderophores; D000241:Adenosine