Marcfortine and paraherquamide class of anthelmintics: discovery of PNU-141962.
Three distinct chemical classes for the control of gastrointestinal nematodes are available: benzimidazoles, imidazothiazoles, and macrocyclic lactones. The relentless development of drug resistance has severely limited the usefulness of such drugs and the search for a new class of compounds   preferably with a different mode of action   is an important endeavor. Marcfortine A (1), a metabolite of Penicillium roqueforti, is structurally related to paraherquamide A (2), originally isolated from Penicillium paraherquei. Chemically the two compounds differ only in one ring; in marcfortine A, ring G is six-membered and carries no substituents, while in paraherquamide A, ring G is five-membered with methyl and hydroxyl substituents at C14. Paraherquamide A (2) is superior to marcfortine A as a nematocide. 2-Desoxoparaherquamide A (PNU-141962, 53) has excellent nematocidal activity, a superior safely profile, and is the first semi-synthetic member of this totally new class of nematocides that is a legitimate candidate for development. This review describes the chemistry, efficacy and mode of action of PNU-141962.
Lee
Byung H
BH
Animal Health Discovery Research, Kalamazoo, MI 49001, USA. byung.h.lee@pharmacia.com
Clothier
Michael F
MF
Dutton
Fred E
FE
Nelson
Stephen J
SJ
Johnson
Sandra S
SS
Thompson
David P
DP
Geary
Timothy G
TG
Whaley
Howard D
HD
Haber
Christopher L
CL
Marshall
Vincent P
VP
Kornis
Gabe I
GI
McNally
Patty L
PL
Ciadella
Joyce I
JI
Martin
David G
DG
Bowman
Jerry W
JW
Baker
Carol A
CA
Coscarelli
Eileen M
EM
Alexander-Bowman
Susan J
SJ
Davis
John P
JP
Zinser
Erich W
EW
Wiley
Veronica
V
Lipton
Michael F
MF
Mauragis
Michael A
MA
D000818:Animals; D000871:Anthelmintics / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007212:Indolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D015394:Molecular Structure; D009349:Nematode Infections / Q000188:drug therapy / Q000517:prevention & control / Q000662:veterinary; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship
C476163:2-desoxoparaherquamide A; D000871:Anthelmintics; D007212:Indolizines; D013141:Spiro Compounds; C103037:marcfortine A; C063985:paraherquamide