Optimized 5-Membered Heterocycle-Linked Pterins for the Inhibition of Ricin Toxin A

Abstract

The optimization of a series of pterin amides for use as Ricin Toxin A (RTA) inhibitors is reported. Based upon crystallographic data of a previous furan-linked pterin, various expanded furans were synthesized, linked to the pterin and tested for inhibition. Concurrently, hetero-analogs of furan were explored, leading to the discovery of more potent triazol-linked pterins. Additionally, we discuss a dramatic improvement in the synthesis of these pterin amides via a dual role by diazabicycloundecene (DBU). This synthetic enhancement facilitates rapid diversification of the previously challenging pterin heterocycle, potentially aiding future medicinal research involving this structure.

Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

“…Similar computational methodologies have been applied before and proven to lead to promising experimental results [18][19][20][21]. We postulated that a ligand that is capable of simultaneously stablishing H-bonds with residues of the active site and of the secondary site of RTA is more likely to show satisfactory inhibitory activity than the current inhibitors that were already shown to occupy solely the active site [14][15][16]. Thus, our ligand selection was primarily based on the analysis of H-bonds formed between the ligand and residues of the active and secondary sites of RTA.…”

“…The competitive RTA inhibitors currently reported in literature are able to inhibit it only at the micromolar range [14][15][16]. This suggests that there is still room for the search of compounds capable of achieving the nanomolar range necessary for an effective inhibition and consequent neutralization of the RTA action inside the cell.…”

Exploring the scope of DBU-promoted amidations of 7-methoxycarbonylpterin

“…We first reported the application of DBU as a crucial additive in the synthesis of pterins used for ricin toxin A (RTA) inhibitors [14]. By deprotonation of the lactam NH, and conversion to the DBU salt, the pterin easily dissolves in methanol at high concentrations, unprecedented for unfunctionalized pterins.…”

“…By deprotonation of the lactam NH, and conversion to the DBU salt, the pterin easily dissolves in methanol at high concentrations, unprecedented for unfunctionalized pterins. This greatly accelerated the development of a library of bioactive pterins, as it bypassed the problematic insolubility and assisted in derivatization [14][15][16]. In addition to this improvement in solubility, we can further take advantage of a mechanistic role of DBU, as it catalyzes the ester-to-amide transformation, allowing for 7-methoxycarbonylpterin (7-CMP, 1) to smoothly generate new pterin amides ( Figure 1) [14,17].…”

“…This greatly accelerated the development of a library of bioactive pterins, as it bypassed the problematic insolubility and assisted in derivatization [14][15][16]. In addition to this improvement in solubility, we can further take advantage of a mechanistic role of DBU, as it catalyzes the ester-to-amide transformation, allowing for 7-methoxycarbonylpterin (7-CMP, 1) to smoothly generate new pterin amides ( Figure 1) [14,17]. The same process used in generating RTA inhibitors was later used as a key step in the development of new aldolase reductase inhibitors [8].…”