Design, synthesis and antifungal activity of a novel water soluble prodrug of antifungal triazole.
A highly potent water soluble triazole antifungal prodrug, RO0098557 (1), has been identified from its parent, the novel antifungal agent RO0094815 (2). The prodrug includes a triazolium salt linked to an aminocarboxyl moiety, which undergoes enzymatic activation followed by spontaneous chemical degradation to release 2. Prodrug 1 showed high chemical stability and water solubility and exhibited strong antifungal activity against systemic candidiasis and aspergillosis as well as pulmonary aspergillosis in rats.
Ohwada
Jun
J
Department of Chemistry, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Tsukazaki
Masao
M
Hayase
Tadakatsu
T
Oikawa
Nobuhiro
N
Isshiki
Yoshiaki
Y
Fukuda
Hiroshi
H
Mizuguchi
Eisaku
E
Sakaitani
Masahiro
M
Shiratori
Yasuhiko
Y
Yamazaki
Toshikazu
T
Ichihara
Shigeyasu
S
Umeda
Isao
I
Shimma
Nobuo
N
D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology; D001711:Biotransformation; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008958:Models, Molecular; D008968:Molecular Conformation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D012997:Solvents; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014867:Water
D000935:Antifungal Agents; D011355:Prodrugs; D012997:Solvents; D014230:Triazoles; D014867:Water