Structurally simple inhibitors of lanosterol 14alpha-demethylase are efficacious in a rodent model of acute Chagas disease.
We report structure-activity studies of a large number of dialkyl imidazoles as inhibitors of Trypanosoma cruzi lanosterol-14alpha-demethylase (L14DM). The compounds have a simple structure compared to posaconazole, another L14DM inhibitor that is an anti-Chagas drug candidate. Several compounds display potency for killing T. cruzi amastigotes in vitro with values of EC(50) in the 0.4-10 nM range. Two compounds were selected for efficacy studies in a mouse model of acute Chagas disease. At oral doses of 20-50 mg/kg given after establishment of parasite infection, the compounds reduced parasitemia in the blood to undetectable levels, and analysis of remaining parasites by PCR revealed a lack of parasites in the majority of animals. These dialkyl imidazoles are substantially less expensive to produce than posaconazole and are appropriate for further development toward an anti-Chagas disease clinical candidate.
Suryadevara
Praveen Kumar
PK
Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
Olepu
Srinivas
S
Lockman
Jeffrey W
JW
Ohkanda
Junko
J
Karimi
Mandana
M
Verlinde
Christophe L M J
CL
Kraus
James M
JM
Schoepe
Jan
J
Van Voorhis
Wesley C
WC
Hamilton
Andrew D
AD
Buckner
Frederick S
FS
Gelb
Michael H
MH
D000208:Acute Disease; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D058886:Sterol 14-Demethylase; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase