Oxindole derivatives as inhibitors of TAK1 kinase.

Several series of oxindole analogues were synthesized and screened for inhibitory activity against transforming growth factor-ß-activating kinase 1 (TAK1). Modifications around several regions of the lead molecules were made, with a distal hydroxyl group in the D region being critical for activity. The most potent compound 10 shows an IC(50) of 8.9 nM against TAK1 in a biochemical enzyme assay, with compounds 3 and 6 showing low micromolar cellular inhibition.

Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methylprop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB-30865) as potent inhibitors of nicotinamide phosphoribosyltransferase (Nampt).

We have shown previously that the target of the potent cytotoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridylmethylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C² of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.

Inhibition of eEF2-K by thieno[2,3-b]pyridine analogues.

Several series of thieno[2-3-b]pyridine analogues were synthesized and screened for inhibitory activity against eukaryotic elongation factor-2 kinase (eEF2-K). Modifications around several regions of the lead molecules were made, with a ring fusion adjacent to the nitrogen on the thienopyridine core being critical for activity. The most active compound 34 shows an IC(50) of 170 nM against eEF2-K in vitro.

Structurally 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 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 anti-Chagas disease clinical candidate.

Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase.

A series of imidazole-containing peptidomimetic PFTase inhibitors and their co-crystal structures bound to PFTase and FPP are reported. The structures reveal that the peptidomimetics adopt a similar conformation to that of the extended CVIM tetrapeptide, with the imidazole group coordinating to the catalytic zinc ion. Both mono- and bis-imidazole-containing derivatives, 13 and 16, showed remarkably high enzyme inhibition activity against PFTase in vitro with IC50 values of 0.86 and 1.7 nM, respectively. The peptidomimetics were also highly selective for PFTase over PGGTase-I both in vitro and in intact cells. In addition, peptidomimetics and were found to suppress tumor growth in nude mouse xenograft models with no gross toxicity at a daily dose of 25 mg kg(-1).

Recent developments in the identification of chemotherapeutics for Chagas disease.

Chagas Disease, caused by the T. cruzi parasite, is one of the largest public health problems in the Western hemisphere. Although its spread has diminished due to vector eradication programs, effective chemotherapeutics for the disease itself remain elusive. Many efforts towards the development of antiparasitic agents active against a number of targets have been described recently in the literature. This review summarizes developments in trypanosidal agents from 2000 through 2003.

Design and synthesis of peptidomimetic protein farnesyltransferase inhibitors as anti-Trypanosoma brucei agents.

On the basis of the structure of the CVIM tetrapeptide substrate of mammalian protein farnesyltransferase, a series of imidazole-containing peptidomimetics was designed and synthesized, and their inhibition activity against Trypanosoma brucei protein farnesyltransferase (TbPFT) was evaluated. Peptidomimetics where the 5-position of the imidazole ring was linked to the hydrophobic scaffold showed over 70% inhibition activity at 50 nM in the enzyme assay, whereas the corresponding C-4 regioisomers were less potent. The ester prodrug 23 was found to be a potent inhibitor against cultured Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense cells with ED(50) values of 0.025 and 0.0026 microM, respectively. Furthermore, introducing a second imidazole group into 23 led to 31, which showed the highest inhibition activity against the parasite with an ED(50) of 0.0015 microM. The potency of the TbPFT inhibitors and the cytotoxicity of the corresponding esters to T. brucei cells were shown to be highly correlated. These studies validate TbPFT as a target for the development of novel therapeutics against African sleeping sickness.

Design and synthesis of potent nonpeptidic farnesyltransferase inhibitors based on a terphenyl scaffold.

By modification of key carboxylate, hydrophobic, and zinc-binding groups projected from a sterically restricted terphenyl scaffold, a series of simple and nonpeptide mimetics of the Cys-Val-Ile-Met tetrapeptide substrate of protein farnesyltransferase (FTase) have been designed and synthesized. A crystal structure of 4-nitro-2-phenyl-3'-methoxycarbonylbiphenyl shows that the triphenyl fragment provides a large hydrophobic surface that potentially mimics the hydrophobic side chains of the three terminal residues in the tetrapeptide. 2-Phenyl-3-(N-(1-(4-cyanobenzyl)-1H-imidazol-5-yl)methyl)amino-3'carboxylbiphenyl, in which the free thiol group was replaced with a 1-(4-cyanobenzyl)imidazole group, shows submicromolar inhibition activity against FTase in vitro and inhibits H-Ras processing in whole cells.