Discovery of anti-glaucoma agents with dual hCA II inhibitory and nitric oxide-releasing activity and their neuroprotective effects.

Glaucoma-related vision loss is driven by intraocular pressure (IOP)-induced neuronal apoptosis, and current IOP-lowering therapies often incompletely prevent optic nerve damage. Therefore, the development of drugs that combine IOP regulation with neuroprotection holds significant clinical importance. In this study, we designed a series of novel bifunctional anti-glaucoma agents possessing both carbonic anhydrase II (CA II) inhibitory and nitric oxide (NO)-releasing activities. These compounds achieve synergistic IOP lowering by suppressing aqueous humor (AH) production through CA II inhibition and enhancing AH outflow via NO release. In acute and chronic ocular hypertension models, the most potent compound B6 demonstrated superior efficacy in lowering IOP compared to the clinical reference drug brinzolamide (BRZ), with no significant in vitro or in vivo toxicity observed. Interestingly, the representative compound B6 also demonstrated neuroprotective activity in vitro. Mechanistic studies further revealed that B6 effectively reduces neuronal apoptosis by alleviating oxidative stress and inhibiting NLRP3 inflammasome activation. In summary, compound B6 demonstrates promising potential as a dual-mechanism lead compound for glaucoma treatment, based on its unique synergistic action that combines IOP regulation with protective effects observed in relevant cellular models.