Azo(bis)pyrazole-Ciprofloxacin Conjugates: Tuning Photopharmacological Performance Through Structural Engineering

Limiting the action of antimicrobials by employing photoswitchable antibiotics holds immense potential to combat the emergence of antimicrobial resistance. These photoswitchable antibiotics are expected to be less/nontoxic in their thermally stable states than the light-induced metastable forms, such that after treatment with the active isomer, the drug toxicity will be automatically reduced or drastically lost after excretion from human and animal bodies into the environment. However, the design of such light-sensitive antibiotics has proven to be very challenging. Most of the previously reported azo-based ciprofloxacin derivatives exhibited diminished potency with the light-induced cis state. Herein, we present the design and synthesis of azoheteroarene-ciprofloxacin conjugates, which exhibited higher antimicrobial potency by the cis-isomer than the trans-isomer against Gram-positive and Gram-negative pathogens. The potency was tuned by varying molecular design. All conjugates displayed a high degree of bidirectional photoisomerization, long cis half-lives, and impressive photofatigue resistance. Notably, the conjugate AAP-2-Cip carrying a flexible linker and pyrazole at the exterior of arylazopyrazole furnished the highest activity difference of 2.5-fold between two isomers, and the cis isomer of ABP-Cip showed 1.7-fold increased potency than ciprofloxacin. Docking studies revealed different binding affinities for two isomers with the DNA gyrase. The molecular design concept unfolded herein may be applied to other antibiotics to transform them into potent photoswitchable antibiotics for suppressing the growth of antibiotic-resistant pathogens.