Computational Study on the Photo‐Induced Antibiotic Activity of an Azoquinolone with Promising Applications in Photopharmacology

Azocompounds are among the most important group of molecular photoswitches due to their multiple applications in various scientific areas. We studied the thermal and photochemical reactions of an azocompound with photo-induced antibiotic properties using <i>ab-initio</i> calculations based on Kohn-Shan, Spin-Flip and time-dependent Density Functional Theory. Our primary goal is to understand the absorption spectra and isomerization pathways governing the molecule's light-controlled antibiotic activity. The nuclear ensemble approach was used for the most stable <i>trans</i> and <i>cis</i> isomers, and the absorption spectra were calculated and fitted to predict the <i>cis</i>/<i>trans</i> isomer ratios in the carboxylate form, using experimental measurements as a reference. We stablished that rotation is involved in the most favorable <i>cis</i>↔<i>cis</i> and trans↔<i>trans</i> thermal isomerization pathways, while the inversion mechanism is the most likely for <i>cis↔trans</i> isomerizations. We found that the photochemical <i>trans</i>↔<i>cis</i> isomerization follows a consistent mechanism across all <i>trans</i> isomers, involving excitation to <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>S</mml:mtext></mml:mrow> <mml:mrow><mml:mn>2</mml:mn></mml:mrow> </mml:msub> <mml:mo>(</mml:mo> <mml:mi>π</mml:mi> <mml:msup><mml:mrow><mml:mi>π</mml:mi></mml:mrow> <mml:mrow><mml:mi>*</mml:mi></mml:mrow> </mml:msup> <mml:mo>)</mml:mo></mml:math> , an in-plane ultrafast internal conversion to <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>S</mml:mtext></mml:mrow> <mml:mrow><mml:mn>1</mml:mn></mml:mrow> </mml:msub> <mml:mo>(</mml:mo> <mml:mi>n</mml:mi> <mml:msup><mml:mrow><mml:mi>π</mml:mi></mml:mrow> <mml:mrow><mml:mi>*</mml:mi></mml:mrow> </mml:msup> <mml:mo>)</mml:mo></mml:math> , followed by rotation of the <i>azo</i> bond up to a twisted <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>S</mml:mtext></mml:mrow> <mml:mrow><mml:mn>1</mml:mn></mml:mrow> </mml:msub> <mml:mo>(</mml:mo> <mml:mi>n</mml:mi> <mml:msup><mml:mrow><mml:mi>π</mml:mi></mml:mrow> <mml:mrow><mml:mi>*</mml:mi></mml:mrow> </mml:msup> <mml:mo>)</mml:mo> <mml:mo>/</mml:mo> <mml:msub><mml:mrow><mml:mtext>S</mml:mtext></mml:mrow> <mml:mrow><mml:mn>0</mml:mn></mml:mrow> </mml:msub> </mml:math> conical intersection. We used a custom approach to evaluate the most favorable decay pathway from the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:msub><mml:mrow><mml:mtext>S</mml:mtext></mml:mrow> <mml:mrow><mml:mn>1</mml:mn></mml:mrow> </mml:msub> <mml:mo>(</mml:mo> <mml:mi>n</mml:mi> <mml:msup><mml:mrow><mml:mi>π</mml:mi></mml:mrow> <mml:mrow><mml:mi>*</mml:mi></mml:mrow> </mml:msup> <mml:mo>)</mml:mo> <mml:mo>/</mml:mo> <mml:msub><mml:mrow><mml:mtext>S</mml:mtext></mml:mrow> <mml:mrow><mml:mn>0</mml:mn></mml:mrow> </mml:msub> </mml:math> conical intersections to <i>trans</i> and <i>cis</i> photoproducts using static calculations.