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

Area of Science:

• Medicinal Chemistry
• Antimicrobial Resistance Research
• Photopharmacology

Background:

• Antimicrobial resistance (AMR) is a growing global health threat.
• Photoswitchable antibiotics offer a strategy to control drug action and reduce toxicity.
• Previous azo-based ciprofloxacin derivatives showed reduced potency in their light-induced cis state.

Purpose of the Study:

• To design and synthesize novel azoheteroarene-ciprofloxacin conjugates.
• To investigate the antimicrobial activity and photoisomerization properties of these conjugates.
• To explore the potential of these compounds in combating antibiotic-resistant pathogens.

Main Methods:

• Synthesis of azoheteroarene-ciprofloxacin conjugates.
• Evaluation of antimicrobial potency against Gram-positive and Gram-negative bacteria.
• Assessment of bidirectional photoisomerization, cis half-life, and photofatigue resistance.
• Molecular docking studies with DNA gyrase.

Main Results:

• The cis-isomer of the synthesized conjugates exhibited higher antimicrobial potency than the trans-isomer.
• Conjugate AAP-2-Cip showed a 2.5-fold activity difference between isomers.
• The cis isomer of ABP-Cip demonstrated 1.7-fold increased potency compared to ciprofloxacin.
• All conjugates displayed efficient photoisomerization, long cis half-lives, and good photostability.

Conclusions:

• Azoheteroarene-ciprofloxacin conjugates represent a promising class of photoswitchable antibiotics with tunable potency.
• The cis isomer's enhanced activity and potential for reduced toxicity offer a new approach to combat AMR.
• The molecular design strategy can be applied to develop other photoswitchable antibiotics.