Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51.
Chagas disease is a chronic infection in humans caused by Trypanosoma cruzi and manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Limited therapeutic options to prevent and treat Chagas disease put 8 million people infected with T. cruzi worldwide at risk. CYP51, involved in the biosynthesis of the membrane sterol component in eukaryotes, is a promising drug target in T. cruzi. We report the structure-activity relationships (SAR) of an N-arylpiperazine series of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors designed to probe the impact of substituents in the terminal N-phenyl ring on binding mode, selectivity and potency. Depending on the substituents at C-4, two distinct ring binding modes, buried and solvent-exposed, have been observed by X-ray structure analysis (resolution of 1.95-2.48 Å). The 5-chloro-substituted analogs 9 and 10 with no substituent at C-4 demonstrated improved selectivity and potency, suppressing ≥ 99.8% parasitemia in mice when administered orally at 25 mg/kg, b.i.d., for 4 days.
Center for Discovery and Innovation in Parasitic Diseases, ‡Department of Pathology, and §Department of Pharmaceutical Chemistry, University of California-San Francisco , San Francisco, California 94158, United States.
Debora F
DF
Vieira
Jun Yong
JY
Choi
Claudia M
CM
Calvet
Jair Lage
JL
Siqueira-Neto
Jonathan B
JB
Johnston
Danielle
D
Kellar
Jiri
J
Gut
Michael D
MD
Cameron
James H
JH
McKerrow
William R
WR
Roush
Larissa M
LM
Podust
D058888:14-alpha Demethylase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000201:enzymology
D058888:14-alpha Demethylase Inhibitors; D010879:Piperazines; D011725:Pyridines; D014344:Trypanocidal Agents