A series of guanidiniocarbonylpyridine receptors has been synthesized, and these compounds bind amino acids (carboxylate forms) in aqueous DMSO with association constants ranging from K = 30 to 460 M(-1) as determined by NMR titration experiments. The differences in the complex stabilities can be correlated with steric and electrostatic effects with the aid of calculated complex structures. For example, the electrostatic repulsion between the pyridine nitrogen lone pair and the bound carboxylate makes anion binding less efficient than with the analogous pyrrole receptors previously introduced by us for carboxylate binding in water. Furthermore, steric interactions between the receptor side chain as in 2 b and the bound substrate also disfavor complexation.

The synthesis of two versatile building blocks for supramolecular anion binding motifs, 5‐(N‐Boc‐guanidinocarbonyl)‐1H‐pyrrole‐2‐carboxylic acid (1) and 5‐(N‐Cbz‐guanidinocarbonyl)‐1H‐pyrrole‐2‐carboxylic acid (2) is reported. Using these building blocks, a guanidiniocarbonyl‐pyrrole anion binding site can easily be introduced into more complex molecules by using standard amide coupling conditions. Both syntheses can be performed on a multi‐gram scale. The products are obtained in pure form and can be stored as solids without decomposition. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

New peptidic Michael acceptor based cysteine protease inhibitors displaying antiparasitic activity were identified by testing a broad series of 45 compounds in total, containing Asn, Gln, or Phe. As target enzymes, falcipain-2 and -3 from P. falciparum and rhodesain from T. b. rhodesiense were used. In the case of the Asn/Gln containing compounds, the trityl-protected, diastereomeric E-configured vinylogous dipeptide esters 16 (Boc-(S)-Phg-(R/S)-vGln(Trt)-OEt) were discovered as most active inhibitors concerning both protease inhibition and antiparasitic acitivity, with inhibition constants in the submicromolar range. The compounds were shown to display time-dependent and competitive inhibition. In the case of the Phe containing compounds, the maleic acid derivatives 42 and 43 (BnO-Phe<--Mal-Phe-OBn, BnO-Phe<--Mal-Phe-Ala-OBn, Mal = maleic acid) displayed good inhibition of rhodesain as well as good antitrypanosomal activity, while the fumaric acid derived E-analogue 14 (BnO-Phe<--Fum-Phe-OBn) only displayed inhibition of the target enzymes but no antiparasitic activity. Inhibition by these Phe derivatives was shown to be time-independent and competitive.

A new class of cysteine protease inhibitors based on fumaric acid derived oligopeptides was successfully identified from a high-throughput screening of a solid-phase bound combinatorial library. As target enzymes falcipain and rhodesain were used, which play important roles in the life cycles of the parasites which cause malaria (Plasmodium falciparum) and African sleeping sickness (Trypanosoma brucei rhodesiense). The best inhibitors with unusual amino acid sequences not reported before for this type of enzyme were also fully analyzed in detail in solution. K(i) values in the lower micromolar and even nanomolar region were found. Some inhibitors are even active against plasmodia and show good selectivity relative to other enzymes. Also the mechanism of action was studied and could be shown to be irreversible inhibition.

The synthesis of a new class of potential anion hosts, the 2‐(guanidiniocarbonyl)furans 5a–d, is presented in this study. The facile decomposition of furans under acidic conditions makes the synthesis of these compounds challenging. First binding studies showed that the (guanidiniocarbonyl)furans are much more acidic (pKa ≈ 5.5) than the analogous pyrroles (pKa ≈ 7) previously introduced by us for oxoanion binding in aqueous solvents. Hence, anion binding with the furan derivatives occurs only in acidic solutions below pH = 5. Therefore, carboxylates are not bound efficiently, whereas, for example, the less basic hydrogen sulfate is bound by 5b with an association constant of K = 600 M–1 in aqueous DMSO even in the presence of a large excess of buffer. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)