Photopharmacological compounds based on azobenzenes and azoheteroarenes: principles of molecular design, molecular modelling, and synthesis

Abstract

Photopharmacology is a field of medicine and pharmacology that uses light to selectively activate or deactivate pharmaceutical agents. This approach significantly enhances and localizes the drug action and, therefore, reduces its side effects. Apart from the bioactive moiety, any photopharmacological compound should contain a photoactive group that must absorb light at the desired wavelength and reorganize the molecular structure after photoactivation. The design of an effective photopharmacological compound requires careful tuning of physical, chemical, and biological properties. The present review summarizes and analyzes the main approaches to the molecular design of photopharmacological drugs based on azobenzene or azoheteroarenes. The main ideas and methods used for tuning spectral and photochemical properties of compounds of this class are discussed. A comparative analysis of main computational methods for their in silico screening is carried out; the most common approaches to the synthesis of azobenzenes and azoheteroarenes derivatives are systematized. Special attention is given to the methods and approaches that are specific to the molecular design of photopharmacological compounds with required physicochemical and photochemical properties. The bibliography includes 212 references.

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

“…On the other hand, increasing for acceptor substituents leads to a larger overlap of the Z and E ( ) bands and again to difficulties with the population of the less stable Z form. The separation and relative intensity of the Z and E ( ) bands as well as their separations with the E ( ) band is not affected significantly by substituents and deviates slightly from numbers reported for the azobenzene (see [ 5 ] for a review).…”

“…From the perspective of photopharmacological applications of ATPLs two points are the most important: to shift the absorption band to the visible region of spectra and further to the infrared region, and/or to separate Z and E absorption bands as much as possible. Spectra of Z and E azobenzenes exhibit two bands: an intensive S → S ( ) band and a red-shifted weak S → S ( ) band [ 5 ]. As a rule, the ( ) band of E isomer is more intensive and red-shifted compared to the ( ) band of Z isomer.…”

“…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.…”

“…In the context of rational design of ATPLs with required properties, it is important to understand the scope and limits for adjusting ATPLs spectral and kinetic properties via modification of their structures. Generally, absorption band maxima of E and Z isomers of azobenzenes, as well as their thermal isomerization rates, can vary in quite a wide range [ 5 ]. However, for a minimal scaffold required to perform both photoswitching and biological functions, the variety is more limited.…”

Optical Control of N-Methyl-d-aspartate Receptors by Azobenzene Quaternary Ammonium Compounds

“…Soluble photoswitchable ligands have been developed for a number of channel types. The azobenzene moiety is widely used for the design of these drugs because of its structural simplicity, efficient and reversible photoisomerization from thermodynamically stable trans form to less stable cis form, and large-scale differences between the forms. − The attachment of this moiety to known channel ligands does not result in the loss of activity in many cases, but it provides optical control, as the folded cis and extended trans forms differ markedly. In many cases, the transition between cis and trans forms strongly affects specific binding to ion channel ligands.…”