Synthesis and Crystallographic Characterization of Helical Hairpin Oligourea Foldamers

AbstractOligomers designed to form a helix‐turn‐helix super‐secondary structure have been prepared by covalently bridging aliphatic oligourea foldamer helices with either rigid aromatic or more flexible aliphatic spacers. The relative helix orientation in these dimers was investigated at high resolution using X‐ray diffraction analysis. In several cases, racemic crystallography was used to facilitate crystallization and structure determination. All structures were solved by direct methods. Well‐defined parallel helical hairpin motifs were observed in all cases when 4,4′‐methylene diphenyl diisocyanate was employed as a dimerizing agent, irrespective of primary sequence and chain length

Helix-Forming Propensity of Aliphatic Urea Oligomers Incorporating Noncanonical Residue Substitution Patterns

Aliphatic N,N′-linked oligoureas are peptidomimetic foldamers that adopt a well-defined helical secondary structure stabilized by a collection of remote three-center H-bonds closing 12- and 14-membered pseudorings. Delineating the rules that govern helix formation depending on the nature of constituent units is of practical utility if one aims to utilize this helical fold to place side chains in a given arrangement and elaborate functional helices. In this work, we tested whether the helix geometry is compatible with alternative substitution patterns. The central −NH–CH­(R)–CH₂–NH–CO– residue in a model oligourea pentamer sequence was replaced by guest units bearing various substitution patterns [e.g., −NH–CH₂–CH₂–NH–CO–, −NH–CH₂–CH­(R)–NH–CO–, and −NH–CH­(R¹)–CH­(R²)–NH–CO−], levels of preorganization (cyclic vs acyclic residues), and stereochemistries, and the helix formation was systematically assessed. The extent of helix perturbation or stabilization was primarily monitored in solution by Fourier transform IR, NMR, and electronic circular dichroism spectroscopies. Our results indicate that although three new substitution patterns were accommodated in the 2.5-helix, the helical urea backbone in short oligomers is particularly sensitive to variations in the residue substitution pattern (position and stereochemistry). For example, the <i>trans</i>-1,2-diaminocyclohexane unit was experimentally found to break the helix nucleation, but the corresponding cis unit did not. Theoretical calculations helped to rationalize these results. The conformational preferences in this series of oligoureas were also studied at high resolution by X-ray structure analyses of a representative set of modified oligomers

Substituted 2-phenylimidazopyridines : a new class of drug leads for human African trypanosomiasis

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

5‑Fluoroimidazo[4,5‑<i>b</i>]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors

Fluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy is not easily predicted. On the basis of inhibitor-bound protein crystal structures, we found a beneficial fluorination spot for inhibitors targeting methionyl-tRNA synthetase of Trypanosoma brucei. In particular, incorporating 5-fluoroimidazo­[4,5-<i>b</i>]­pyridine into inhibitors leads to central nervous system bioavailability and maintained or even improved efficacy

Substituted 2‑Phenylimidazopyridines: A New Class of Drug Leads for Human African Trypanosomiasis

A phenotypic screen of a compound library for antiparasitic activity on <i>Trypanosoma brucei</i>, 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 <b>64</b>, 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 <b>64</b> cured mice infected with <i>Trypanosoma brucei</i> when dosed orally down to 2.5 mg/kg. Given its potent antiparasitic properties and its ease of synthesis, compound <b>64</b> represents a new lead for the development of drugs to treat human African trypanosomiasis