Azobenzene/Tetraethyl Ammonium Photochromic Potassium Channel Blockers: Scope and Limitations for Design of Para-Substituted Derivatives with Specific Absorption Band Maxima and Thermal Isomerization Rate

Daniil M Strashkov,Mikhail N Ryazantsev,Vladimir N Mironov,Stanislav A Linnik,Andrey V Vasin,Andrey S Mereshchenko,Maxim S Panov,Vladimir A Kochemirovsky,Dmitrii M Nikolaev

doi:10.3390/ijms222313171

Abstract

Azobenzene/tetraethyl ammonium photochromic ligands (ATPLs) are photoactive compounds with a large variety of photopharmacological applications such as nociception control or vision restoration. Absorption band maximum and lifetime of the less stable isomer are important characteristics that determine the applicability of ATPLs. Substituents allow to adjust these characteristics in a range limited by the azobenzene/tetraethyl ammonium scaffold. The aim of the current study is to find the scope and limitations for the design of ATPLs with specific spectral and kinetic properties by introducing para substituents with different electronic effects. To perform this task we synthesized ATPLs with various electron acceptor and electron donor functional groups and studied their spectral and kinetic properties using flash photolysis and conventional spectroscopy techniques as well as quantum chemical modeling. As a result, we obtained diagrams that describe correlations between spectral and kinetic properties of ATPLs (absorption maxima of E and Z isomers of ATPLs, the thermal lifetime of their Z form) and both the electronic effect of substituents described by Hammett constants and structural parameters obtained from quantum chemical calculations. The provided results can be used for the design of ATPLs with properties that are optimal for photopharmacological applications.

Highlights

The present study focuses on azobenzene/tetraethyl ammonium photochromic ligands (ATPLs, Figure 1) and aims to provide information that can be used for the rational design of ATPLs with specific absorption band maxima and thermal lifetime (τ) of less stable isomers
ATPLs belong to a well-known family of light-sensitive Kv channel blockers that can be applied in a variety of contexts, such as nociception control or vision restoration [7,8,9,10,11,12,13]
Techniques that are already widely used in drug design, such as scaffold-based design and structure/properties correlations, can be implemented in photopharmacology research [40]

Summary

Introduction

Photopharmacology is a fast-growing research area that is based on the conception of switching on/off the biological activity by the light stimulus [1,2,3,4,5,6]. Such processes become possible due to a structural reorganization that, after light absorption, occurs in the photoactive moiety and subsequently in the entire molecular system, changing its biological activity. The minimal required scaffold of a photopharmacological compound has to include both a photoactive part and a part that determines biological activity, e.g., ion channel blocking, signal transduction, etc.

Objectives

Methods

Conclusion