Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase.
Orally bioavailable inhibitors of β-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein.
Scynexis, Inc., PO Box 12878, Research Triangle Park, NC 27709-2878, USA. brian.heasley@scynexis.com
Brian H
BH
Heasley
Gregory J
GJ
Pacofsky
Ahmed
A
Mamai
Hao
H
Liu
Kingsley
K
Nelson
Ghjuvanni
G
Coti
Michael R
MR
Peel
James M
JM
Balkovec
Mark L
ML
Greenlee
Paul
P
Liberator
Dongfang
D
Meng
Dann L
DL
Parker
Robert R
RR
Wilkening
James M
JM
Apgar
F
F
Racine
Ming Jo
MJ
Hsu
Robert A
RA
Giacobbe
Jennifer Nielsen
JN
Kahn
D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002176:Candida albicans / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D051379:Mice; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D006027:Glycosides; D014315:Triterpenes; C421868:enfumafungin; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase