In Situ Selection of Lead Compounds by Click Chemistry:  Target-Guided Optimization of Acetylcholinesterase Inhibitors

Abstract

The target-guided, in situ click chemistry approach to lead discovery has been successfully employed for discovering acetylcholinesterase (AChE) inhibitors by incubating a selected enzyme/tacrine azide combination with a variety of acetylene reagents that were not previously known to interact with the enzyme's peripheral binding site. The triazole products, formed by the enzyme, were identified by HPLC-mass spectrometry analysis of the crude reaction mixtures. The target-guided lead discovery search was also successful when performed with reagent mixtures containing up to 10 components. From 23 acetylene reagents, the enzyme selected two phenyltetrahydroisoquinoline (PIQ) building blocks that combined with the tacrine azide within the active center gorge to form multivalent inhibitors that simultaneously associate with the active and peripheral binding sites. These new inhibitors are up to 3 times as potent as our previous phenylphenanthridinium-derived compounds, and with dissociation constants as low as 33 femtomolar, they are the most potent noncovalent AChE inhibitors known. In addition, the new compounds lack a permanent positive charge and aniline groups and possess fewer fused aromatic rings. Remarkably, despite the high binding affinity, the enzyme displayed a surprisingly low preference for one PIQ enantiomer over the other.

Refinement of Structural Leads for Centrally Acting Oxime Reactivators of Phosphylated Cholinesterases

“…Two nonquaternary pyridine aldoxime phenyltetrahydroisoquinoline derivatives directed to interact with the AChE peripheral site showed outstanding potency for in vitro reactivation of VX and tabun-conjugated hAChE (2). Thus, uncharged, extended ligands with high affinities for the peripheral site form an alternative means of directing nucleophiles to the organophosphate conjugated active center (28). The overall second order rate constant (k r ) for reactivation of VX-hAChE conjugate by phenyltetrahydroisoquinoline derivatives was an …”

Novel bis-phenanthridine derivatives with easily tunable linkers, study of their interactions with DNA and screening of antiproliferative activity

“…[1][2][3] In addition, it was shown that the chemical modulation of the ethidium substituents is a profitable option to tune the nucleic acid recognition properties of phenanthridine dyes. [4] Very recent reports about numerous applications point toward versatility of the phenanthridine core, [5][6][7][8][9] including even intriguing biological activity. [10] A huge number of bis-phenanthridine derivatives were prepared with the aim of not only enhanced affinity due to the bis-intercalation into DNA/RNA but also with the idea of introducing selectivity.…”

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

“…13). 106 Analysis of binary TZ2/acetylene mixtures with AChE revealed that only phenyltetrahydro-isoquinolines PIQ-A5 and PIQ-A6 formed significant amounts of triazole products identified as syn-isomers. Incubation of a mixture of 10 acetylene building blocks with TZ2 and AChE gave only expected triazole products TZ2PIQ-A5 and TZ2PIQ-A6 demonstrating the feasibility of multicomponent screening.…”