ABSTRACT
A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of human African trypanosomiasis, led to the identification of substituted 2-(3-aminophenyl)oxazolopyridines as a starting point for hit-to-lead medicinal chemistry. A total of 110 analogues were prepared, which led to the identification of 64, a substituted 2-(3-aminophenyl)imidazopyridine. This compound showed antiparasitic activity in vitro with an EC50 of 2 nM and displayed reasonable druglike properties when tested in a number of in vitro assays. The compound was orally bioavailable and displayed good plasma and brain exposure in mice. Compound 64 cured mice infected with Trypanosoma brucei when dosed orally down to 2.5 mg/kg. Given its potent antiparasitic properties and its ease of synthesis, compound 64 represents a new lead for the development of drugs to treat human African trypanosomiasis.
Subject(s)
Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Trypanocidal Agents/chemical synthesis , Trypanosomiasis, African/drug therapy , Administration, Oral , Animals , Biological Availability , Cell Line, Tumor , Cell Membrane Permeability , Databases, Chemical , Dogs , Female , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Madin Darby Canine Kidney Cells , Mice , Microsomes, Liver/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/growth & development , Trypanosoma brucei rhodesiense/drug effects , Trypanosoma brucei rhodesiense/growth & development , Trypanosomiasis, African/parasitologyABSTRACT
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.
Subject(s)
14-alpha Demethylase Inhibitors/therapeutic use , Chagas Disease/drug therapy , Imidazoles/pharmacology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/enzymology , 14-alpha Demethylase Inhibitors/administration & dosage , 14-alpha Demethylase Inhibitors/pharmacology , Animals , Chagas Disease/parasitology , Models, MolecularABSTRACT
New compounds with hydrophyllic esters of (-)-carinol were synthesized and evaluated as xanthine oxidase enzyme inhibitors and antioxidants. Aliphatic esterfication of C-9,9'-OH groups of (-)-carinol resulted in lowering antioxidant and xanthine oxidase inhibitory activities. However certain aromatic acyl esters considerably improved the xathine oxidase inhibition. Aromatic esterification with electron withdrawing substitutions would preferred for improvement in XOD inhibition while retaining radical scavenging activity, electron withdrawing substitution led to the loss of free radical scavenging property and neutral substituents decrease the enzyme inhibitory potential.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/pharmacology , Lignans/chemistry , Lignans/pharmacology , Xanthine Oxidase/antagonists & inhibitors , Acylation , Enzyme Activation/drug effects , Esters/chemical synthesis , Esters/chemistry , Esters/pharmacology , Free Radical Scavengers/chemistry , Inhibitory Concentration 50 , Magnetic Resonance SpectroscopyABSTRACT
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 display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14alpha-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.
