Photoisomerization and Light-Controlled Antibacterial Activity of Fluoroquinolone-Azoisoxazole Hybrids.

Photopharmacology holds a huge untapped potential to locally treat diseases involving photoswitchable drugs via the elimination of drugs' off-target effects. The growth of this field has created a pressing demand to develop such light-active drugs. We explored the potential for creating photoswitchable antibiotic hybrids by attaching pharmacophores norfloxacin/ciprofloxacin and azoisoxazole (photoswitch). All compounds exhibited a moderate to a high degree of bidirectional photoisomerization, long thermal cis half-lives, and impressive photoresistance. Gram-negative pathogens were found to be insensitive to these hybrids, while against Gram-positive pathogens, all hybrids in their trans states exhibited antibacterial activity that is comparable to that of the parent drugs. Notably, the toxicity of the irradiated hybrid 6 was found to be 2-fold lower than the nonirradiated trans isomer, indicating that the pre-inactivated cis-enriched drug can be employed for the site-specific treatment of bacterial infection using light, which could potentially eliminate the unwanted exposure of toxic antibiotics to both beneficial and untargeted harmful microbes in our body. Molecular docking revealed different binding affinity of the cis and trans isomers with the topoisomerase IV enzyme, due to their different shapes.

Photoswitchable Antibiotic Hybrids: Spacer Length-Dependent Photochemical Control of Antibacterial Activity.

Photopharmacology holds huge potential for the permanent (long-term) eradication of antibiotic resistance by the application of photoswitchable antibiotics. To construct such antibiotics, various methods have been employed to modify known antibiotics with photoswitches, such that the irradiated state shows activity comparable to or higher than that of the parent antibiotic and that a large activity difference between irradiated and nonirradiated states is achieved. However, most of those methods are ineffective when dealing with more than one drug with dissimilar structures. Here, we have demonstrated a new approach, in which two pharmacophores, one being a photoswitch, are covalently linked via a spacer of variable lengths, leading to a set of azopyrazole-norfloxacin antibiotic hybrids. All compounds showed a high degree of bidirectional photoisomerization, long thermal cis half-lives, and excellent photoresistance. Notably, the hybrid with an optimal four-carbon spacer length enabled the irradiated state to become 12-fold more potent than its nonirradiated state without losing much antimicrobial activity of norfloxacin. Only Gram-positive bacteria were found to be sensitive to this hybrid, and the full antibacterial potency of its irradiated state was found to be retained for nearly 24 h.

Direct Growth Control of Antibiotic-Resistant Bacteria Using Visible-Light-Responsive Novel Photoswitchable Antibiotics.

In addition to the discovery of new (modified) potent antibiotics to combat antibiotic resistance, there is a critical need to develop novel strategies that would restrict their off-target effects and unnecessary exposure to bacteria in our body and environment. We report a set of new photoswitchable arylazopyrazole-modified norfloxacin antibiotics that present a high degree of bidirectional photoisomerization, impressive fatigue resistance and reasonably high cis half-lives. The irradiated isomers of most compounds were found to exhibit nearly equal or higher antibacterial activity than norfloxacin against Gram-positive bacteria. Notably, against norfloxacin-resistant S. aureus bacteria, the visible-light-responsive p-SMe-substituted derivative showed remarkably high antimicrobial potency (MIC of 0.25 µg/mL) in the irradiated state, while the potency was reduced by 24-fold in case of its non-irradiated state. The activity was estimated to be retained for more than 7 hours. This is the first report to demonstrate direct photochemical control of the growth of antibiotic-resistant bacteria and to show the highest activity difference between irradiated and non-irradiated states of a photoswitchable antibiotic. Additionally, both isomers were found to be non-harmful to human cells. Molecular modellings were performed to identify the underlying reason behind the high-affinity binding of the irradiated isomer to topoisomerase IV enzyme.

Photoisomerization of 2-Arylazoimidazoles under Visible Light: Identifying a Predictive Tool to Anticipate and Tune Likely Photoswitching Performance and Cis Half-Life.

Azopyrazoles are an emerging class of photoswitches, whereas analogous azoimidazole-based switches are unable to draw much attention because of their short cis half-lives, poor cis-trans photoreversion yields, and toxic ultraviolet (UV) light-assisted isomerization. A series of 24 various aryl-substituted N-methyl-2-arylazoimidazoles were synthesized, and their photoswitching performances and cis-trans isomerization kinetics were thoroughly investigated experimentally and theoretically. Para-π-donor-substituted azoimidazoles with highly twisted T-shaped cis conformations showed nearly complete bidirectional photoswitching, whereas di-o-substituted switches exhibited very long cis half-lives (days-years) with nearly ideal T-shaped conformations. This study demonstrates how the electron density in the aryl ring affects cis half-life and cis-trans photoreversion via twisting of the NNAr dihedral angle that can be used as a predictive metric for envisaging and tuning the likely switching performance and half-life of any given 2-arylazoimidazole. By applying this tool, two better-performing azoimidazole photoswitches were engineered. All switches permitted irradiation by violet (400-405 nm) and orange (>585 nm) light for forward and reverse isomerization, respectively, and displayed comparatively high quantum yields and impressive resistance to photobleaching.

Near-Complete Bidirectional Photoisomerization of para-Dialkylamino-Substituted Arylazopyrazoles under Violet and Green or Red Lights.

para-Dimethylamine- and para-pyrrolidine-substituted arylazopyrazoles display very high to near-quantitative or quantitative bidirectional isomerization under violet and green or red lights in both polar (DMSO and DMSO/aqueous buffer, pH 7.5) and nonpolar solvents. These switches confer a reasonable thermal stability to their cis-states (t1/2 ≈ 4-7 h in DMSO and DMSO/buffer) and also show a high level of resistance to photobleaching and an impressive stability to reduction by glutathione. Using DFT calculations, attempts have been made to decipher the photophysical properties and thermal stabilities of the cis isomers.

Visible-Light-Sensitive Photoliquefiable Arylazoisoxazoles for the Solar Energy Conversion, Storage and Controlled-Release of Heat at Room Temperature or Lower Temperatures.

The photoswitchable MOlecular Solar Thermal (MOST) energy storage systems that are capable of exhibiting high energy storage densities are found to suffer from the poor cyclability, the use of less abundant UV light of the solar spectrum, or reduced charging/discharging rates and poor photoconversions in solid states. Herein, we have designed and readily synthesized a novel set of para-thioalkyl substituted arylazoisoxazoles, that undergo high trans-cis and cis-trans photoconversions under visible light, and show fast charging/discharging and impressive cyclability. Remarkably, the presence of C6-or C10-thioalkyl chainin photochromes permitted reversible solid-liquid phase transition with the formation of cis-enriched charged states by 400 nm light irradiation and trans-enriched discharged states by 530 nm light at various temperatures (10-35 °C). The solid-to-liquid phase transition enabled storage of the latent heat in addition to the isomerization energy, resulting in a high net energy storage density of 189-196 J/g, which are substantially higher than that of many recently reported azobenzene-based MOST compounds (100-161 J/g). Using a high-resolution infrared camera, we further demonstrated that a brief irradiation of green light can be employed to readily release the trapped photon energy as heat. Our results suggest that the arylazoisoxazole with C6-thioalkyl chain at para-position can serve as an effective and eco-friendly photoliquefiable MOST material.

Robust bi-directional photoswitching of thiomethyl substituted arylazopyrazoles under visible light.

Mono-ortho- and para-thiomethyl-substituted arylazopyrazoles show substantial absorbance in visible wavelengths, enabling very high to near-quantitative forward and reverse isomerization in DMSO and aqueous solution by visible light. cis isomers display excellent thermal stability (∼3 days, 27 °C). Additionally, these switches possess good photostability and are resistant to reduction by glutathione.