Design, synthesis, and biological evaluation of molecules of medicinal interest: Inhibitors of mammalian and Trypanosoma cruzi protein farnesyltransferase and Trypanosoma cruzi lanosterol-14-alpha-demethylase

Chagas Disease poses the third largest parasitic disease burden in the world and the largest in the Western Hemisphere. It is caused by the Trypanosoma cruzi parasite, a zooflagellate protozoan. Current chemotherapeutics against T. cruzi are both ineffective and prone to cause harmful side-effects, and consequently new compounds are needed which inhibit the growth of the parasite.; First, a series of compounds based upon a 4-[N-(1-benzyl-1H-imidazol-5-yl)methyl)amino]-2-phenyl-benzoyl-methionine scaffold were synthesized. These molecules and their methyl ester precursors were screened against mammalian farnesyltransferase to explore the effects of modifying the position and nature of the benzyl substituent. Molecules containing a methionine free acid and a hydrogen bond accepting substituent showed low nanomolar activity. The free acids were also moderately potent inhibitors of farnesyltransferase from T. cruzi.; Second, a series based upon a 4-amino-2-phenyl-benzoic acid methyl ester scaffold was made. These molecules were moderate inhibitors of mammalian farnesyltransferase, but were low nanomolar inhibitors of parasitic growth. The compounds were poor inhibitors of T. cruzi farnesyltransferase, and were discovered to be inhibitors of the parasitic sterol biosythesis enzyme lanosterol-14-alpha-demethylase. The most potent in vitro compound 4.3i was found to be a moderate inhibitor of in vivo parasitic growth, causing a 50% reduction of parasitemia in T. cruzi infected mice at a oral dose of 25 mg/kg BID.; Third, a series of molecules replacing the benzoate ester of the second series was synthesized. These molecules were moderate inhibitors of mammalian farnesyltransferase, although 5.4c and 5.23f showed extremely high antitumor activity in vivo. All molecules containing a 4-phenylbenzylimidazole unit were mid-nanomolar inhibitors of T. cruzi growth in vitro. Several compounds ( 5.1i, 5.23a, 5.23d) caused dramatic reductions in murine parasitemia when dosed orally at 50 mg/kg BID.; Fourth, a series of tertiary aniline compounds were synthesized. These compounds were moderate inhibitors of mammalian farnesyltransferase but were inactive against T. cruzi FTase.