Structurally Simple Inhibitors of Lanosterol 14α-Demethylase Are Efficacious In a Rodent Model of Acute Chagas Disease

Abstract

We report structure-activity studies of a large number of dialkyl imidazoles as inhibitors of Trypanosoma cruzi lanosterol-14α-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 antiChagas disease clinical candidate.

Pharmacological Characterization, Structural Studies, and In Vivo Activities of Anti-Chagas Disease Lead Compounds Derived from Tipifarnib

“…The finding that 2 of 6 benznidazole-treated mice remained PCR positive demonstrates the high stringency of the mouse model with Y strain parasites used in these experiments. In previous work using a different strain of T. cruzi (Tulahuen), we observed that posaconazole led to negative parasitemia by PCR (25). In addition to using different strains, we also tested for cure by performing PCR after inducing immunosuppression, which further enhances the ability to uncover low-level residual infections.…”

New Treatments for Chagas Disease and the Relationship between Chagasic Patients and Cancers

“…In 2010, the pharmaceutical Merck announced plans to phase II clinical studies evaluating the use of posaconazole for the treatment of chronic CD, to be conducted with 160 adult patients for 360 days. The proposed study is placebo controlled and uses an oral suspension of posaconazole (400 mg twice daily) for 60 days, tested as monotherapy and in combination with benzidazole [94]. The association between posaconazole and amiodarone results in antiproliferative synergism of the drugs (fractional inhibitory concentration < 0.5).…”

Design, structure–activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi

“…[11][12][13][14] More active second generation antifungals posaconazole and a ravuconazole pro-drug are the first compounds to enter clinical trials for the treatment of Chagas disease in more than 40 years. Other compounds targeting T. cruzi CYP51 include the tipifarnib series, [15][16][17][18] dialkyl imidazoles, 19 LP10, 20 and indomethacin amides, 21 with current hit generation efforts potentially fueling further research. 22 The recently reported crystal structure of T. cruzi CYP51 with bound posaconazole and fluconazole is an important step forward in the ongoing story of this target opening up the opportunity for structure based drug design to address potential issues of drug resistance.…”