Access to basic drugs is a major issue in developing countries. Chagas disease caused by Trypanosoma cruzi is a paradigmatic example of a chronic disease without an effective treatment. Current treatments based on benznidazole and nifurtimox are expensive, ineffective, and toxic. N,N'-Squaramides are amide-type compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites. When combined with amine and carboxylic groups, squaramide compounds have increased solubility and therefore make suitable therapeutic agents. In this work, we introduce a group of Lipinski's rule of five compliant squaramides as candidates for treating Chagas disease. The in vivo studies confirmed the positive expectations arising from the preliminary in vitro studies, revealing compound 17 to be the most effective for both acute and chronic phases. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-Chagasic agent.
New tripodal squaramide-based hosts have been synthesised and structurally characterised by spectroscopic methods. In 2.5 % (v/v) [D(6)]DMSO in CDCl(3), compound 4 formed dimeric assemblies [log K(dim)=3.68(8)] as demonstrated by (1)H NMR spectroscopy and UV dilution experiments. AFM and SEM analyses revealed the formation of a network of bundled fibres, which indicates a preferential mechanism for aggregation. These C(3)-symmetric tripodal hosts exhibited two different and mutually exclusive modes of binding, each one easily accessible by simultaneous reorientation of the squaramide groups. In the first, a convergent disposition of the NH squaramide protons allowed the formation of an array of N-H⋅⋅⋅X(-) hydrogen bonds with anions. In the second mode, reorientation of carbonyl squaramide groups allowed multiple C=O⋅⋅⋅H interactions with ammonium cations. The titration of 4 with different tetraalkylammonium iodides persistently showed the formation of 1:1 complexes, as well as 1:2 and 1:3 complexes. The corresponding stoichiometries and binding affinities of the complexes were evaluated by multi-regression analysis. The formation of high-order complexes, supported by ROESY, NOESY and mass spectrometry experiments, has been attributed to the insertion of NR(4)I ion pairs between the carbonyl and NH protons of the squaramide groups located in adjacent arms of 4. The observed effects reflect the induction of significant conformational changes in the hosts, mainly in relation to the relative orientation of the squaramide groups adapting their geometries to incoming ion-pair complementary substrates. The results presented herein identify and fully describe two different modes of ion-pair recognition aimed at directing conformational transitions in the host, therefore establishing a base for controlling more elaborate movements of molecular devices through ion-pair recognition.
A novel tertiary squaramido-based reverse-turn module SQ is reported, and its conformational properties are evaluated. This module is easily incorporated into a α-peptide sequence by conventional solid-phase peptide synthesis. The structure characterization of the hybrid squaramido-peptide 4 is described, showing that the turn segment induces the formation of hairpin structures in water through the formation of both αSQ- and βSQ-turns.
The β-turn unit is one of the most important secondary structure elements in proteins. The access to new conformationally controlled foldable modules can afford compounds with interesting bioactivities. Here, we describe a new family of peptido-squaramide foldable modules based on the considerable potential of the squaramide unit as a hydrogen bond donor and acceptor as well as the low rotational barrier of the C-N bond. The conformational analysis by NMR of these modules in chloroform and acetonitrile solution shows that a disecondary squaramide with the 4-aminobutyric acid in one of its substituents can mimic the β-turn structure driven by the formation of an intramolecular hydrogen bonded ten-membered ring. This structure, although flexible, has been successfully combined with dipeptide chains to induce the formation of a hairpin-like structure driven by the formation of several cross-strand intramolecular hydrogen bonds.
A minimalist squaramide-based chemodosimeter for Cu(2+) is described. Upon selective chelation to 2, Cu(2+) induces the formation of a highly colored zwitterionic radical, which is kinetically stable for hours. The presence of a radical is confirmed by EPR and ESI-MS. It is then possible to use reagent 2 for visual and selective sensing of Cu(2+) at neutral pH.
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