Synthesis of Trypanosoma cruzi Lanosterol 14α Demethylase (TcCYP51) Inhibitors for the Treatment of Chagas Disease
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منابع مشابه
The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease.
Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED(50) = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were used for the prediction of the binding modes of the substrate lanosterol and of ...
متن کاملSecond generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.
We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and displ...
متن کاملStructurally 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 ran...
متن کاملStructurally Simple Inhibitors of Lanosterol 14r-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-14R-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 EC50 in the 0.4-10 nM range. Tw...
متن کاملStructural Basis for Rational Design of Inhibitors Targeting Trypanosoma cruzi Sterol 14α-Demethylase: Two Regions of the Enzyme Molecule Potentiate Its Inhibition
Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14α-demethylase (CYP51) inhibitors. Here we explore the spectral ...
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تاریخ انتشار 2014