A fluorine scan of the phenylamidinium needle of tricyclic thrombin inhibitors: effects of fluorine substitution on pK_aand binding affinity and evidence for intermolecular C–F⋯CN interactions

Abstract

The H-atoms of the phenylamidinium needle of tricyclic thrombin inhibitors, which interacts with Asp189 at the bottom of the selectivity pocket S1 of the enzyme, were systematically exchanged with F-atoms in an attempt to improve the pharmacokinetic properties by lowering the pK(a) value. Both the pK(a) values and the inhibitory constants K(i) against thrombin and trypsin were decreased upon F-substitution. Interestingly, linear free energy relationships (LFERs) revealed that binding affinity against thrombin is much more affected by a decrease in pK(a) than the affinity against trypsin. Surprising effects of F-substitutions in the phenylamidinium needle on the pK(a) value of the tertiary amine centre in the tricyclic scaffold of the inhibitors were observed and subsequently rationalised by X-ray crystallographic analysis and ab initio calculations. Evidence for highly directional intermolecular C-F...CN interactions was obtained by analysis of small-molecule X-ray crystal structures and investigations in the Cambridge Structural Database (CSD).

Orthogonal Multipolar Interactions in Structural Chemistry and Biology

“…[9] This preferred geometry for organofluorine···carbonyl interactions was further corroborated by crystal structure analyses of fluorine-containing small molecules [9][10][11] and database searches in the Protein Data Bank (PDB) and the Cambridge Structural Database (CSD). [12] The latter furnished numerous cases of CÀF···C = O contacts with F···C distances below the sum of the van der Waals radii and an F···C = O angle tending toward 908.…”

“…[9,13] A similar directional interaction motif was also uncovered in small-molecule X-ray crystal structure analyses and subsequent CSD searches for CÀF···C N contacts. [11,14] Anticipating a more general importance of such orthogonal multipolar interactions, the database mining has now been extended to explore such contacts between other dipoles, revealing a list of various cases such as CÀX···C = O (X = halogen), C = O···C = O, C N···C = O, S = O···C = O, CÀ OH···CO, and H 2 O···C = O. (Table 1).…”

Fluorous-Enhanced Multicomponent Reactions for Making Drug-Like Library Scaffolds

“…Each of these three scaffolds has four stereocenters on the central pyrrolidine ring and up to four points of diversity (R 1 to R 4 ). The structure of compound 21 is similar to tricyclic thrombin inhibitors [49], the structure of compound 23 is similar to diketopiperazine-based inhibitors of human hormone-sensitive lipase [50], while compound 25 contains a privileged benzodiazepine moiety which has a wide range of pharmaceutical utilities. N-acylation of 19 with 2-nitrobenzoyl chloride followed by zinc-acetic acid reduction under sonication gave compound 24.…”

A Novel Synthesis of Highly Substituted Perhydropyrrolizines, Perhydroindolizines, and Pyrrolidines: Inhibition of the Peptidyl‐Prolyl cis/trans Isomerase (PPIase) Pin1

“…Regioselective hydrolysis of (AE)-endo-28a -28d under very mild conditions (0.05M NaOH in THF/H 2 O 2 :1, 208) [35], followed by esterification of the crude sodium carboxylates with MeOH in the presence of SOCl 2 , afforded esters (AE)-30a -30d, which were subsequently reduced to alcohols (AE)-31a -31d with DIBAL-H (Scheme 5). The formation of the tricylic derivatives (AE)-28a -28d as by-products, resulting from back-cyclization of (AE)-30a -30d, accounted for the low yield of this step.…”