Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents.
New dialkylimidazole based sterol 14α-demethylase inhibitors were prepared and tested as potential anti-Trypanosoma cruzi agents. Previous studies had identified compound 2 as the most potent and selective inhibitor against parasite cultures. In addition, animal studies had demonstrated that compound 2 is highly efficacious in the acute model of the disease. However, compound 2 has a high molecular weight and high hydrophobicity, issues addressed here. Systematic modifications were carried out at four positions on the scaffold and several inhibitors were identified which are highly potent (EC50 <1 nM) against T. cruzi in culture. The halogenated derivatives 36j, 36k, and 36p, display excellent activity against T. cruzi amastigotes, with reduced molecular weight and lipophilicity, and exhibit suitable physicochemical properties for an oral drug candidate.
['Suryadevara|Praveen Kumar|PK|', 'Racherla|Kishore Kumar|KK|', 'Olepu|Srinivas|S|', 'Norcross|Neil R|NR|', 'Tatipaka|Hari Babu|HB|', 'Arif|Jennifer A|JA|', 'Planer|Joseph D|JD|', 'Lepesheva|Galina I|GI|', 'Verlinde|Christophe L M J|CL|', 'Buckner|Frederick S|FS|', 'Gelb|Michael H|MH|']
D058888:14-alpha Demethylase Inhibitors D000818:Animals D014355:Chagas Disease D007093:Imidazoles D008958:Models, Molecular D014349:Trypanosoma cruzi
Dialkylimidazole Trypanosoma cruzi CYP51 Chagas disease Sterol 14-alpha demethylase