A Fluorine Scan at the Catalytic Center of Thrombin: CF, COH, and COMe Bioisosterism and Fluorine Effects on pK_a and log D Values

Abstract

A series of 16 tricyclic thrombin inhibitors was prepared by using the 1,3-dipolar cycloaddition of azomethine ylides derived from 3- or 4-hydroxyproline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide as the key step. The terminal pyrrolidine ring of the inhibitors was systematically substituted to explore the potential bioisosteric behavior of C-F, C-OH, and C-OMe residues pointing into the environment of the catalytic center of a serine protease. X-ray crystal structure analyses revealed a distinct puckering preference of this ring. Substitution by F, HO, and MeO has a strong effect on the basicity of the adjacent pyrrolidine nitrogen center which originates from two sigma-inductive pathways between this center and the electronegative O and F atoms. gem-Difluorination decreases the pKa value of this tertiary amine center to <2, making the conjugated ammonium ion a moderately strong acid. Unexpectedly, F substitution next to the nitrogen center reduced the lipophilicity of the ligands, as revealed by measurements of the logarithmic partition coefficient log D. The biological assays showed that all compounds are thrombin inhibitors with activities between Ki=0.08 and 2.17 microM. Bioisosteric behavior of F, HO, and MeO substituents was observed. Their electronegative F and O atoms undergo energetically similar polar interactions with positively polarized centers, such as the N atom of His 57 which is hydrogen bonded to the catalytic Ser 195. However, for energetically similar polar interactions of C-F, C-OH, and C-OMe to occur, sufficient space is necessary for the accommodation of the Me group of the C-OMe residue, and a H-bond acceptor must be present to prevent unfavorable desolvation of the C-OH residue.

Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicities

“…[2,[9][10][11][12] In that investigation, we observed that the pK a value of a tertiary non-aromatic amine could be shifted from values of around 10 to below 2 through the cumulative interaction effects of relatively remote functionalities (see Section 2). Simple rules for predictions of amine basicity were subsequently developed based on extensive database mining.…”

“…[12] Inductive effects are transmitted over two s-pathways, as substituents at positions 8 ((+)-26 to (+)-33) and 7 ((+)-34 to (AE )-41) are both located in b-and g-position to the amine center. With one substituent, the pK a is decreased by amounts of À0.3 to À1.2 relative to the parent compound (AE )-6.…”

Bidentate and Tetradentate β‐Aminovinyl Trifluoromethylated Ketones and Their Copper(II) Complexes: Synthesis, Characterization and Redox Chemistry

“…The fluorine atoms are significant as they may induce specific interactions in the solid state such as F···H, F···F, F···O=C, F···N and F···S contacts; these properties have been used with success in materials science and crystal engineering, [30][31] in medicinal chemistry in order to design more active drug candidates and have been exemplified by cocrystallized structures of potent therapeutic agents with target enzymes. [32][33][34] Fluorine is also a useful probe in 19 F NMR spectroscopy with potential implications in biology. [35] In addition, the electron-withdrawing effect of fluorine should alter the redox properties of the ligands and metal complexes and could help cocrystallization due to the enhanced volatility of the latter.…”

The Challenge of Affinity Prediction: Scoring Functions for Structure‐Based Virtual Screening

“…The introduction of halogens to enhance binding affinity and modulate pharmacokinetic properties is well established in lead optimization [37,38]. In particular, organic fluorine is often used as bioisosteric hydrogen or oxygen replacement [39,40] and has been investigated in detail, including its effects on nonbonded interactions in hydrophobic cavities and polar interactions. In general, fluorinated molecules interact with their targets revealing similar binding poses compared to nonfluorinated analogues, while the chemical properties of the CÀF bond influences binding affinities.…”