Novel Carbonic Anhydrase Inhibitors with Dual-Tail Core Sulfonamide Show Potent and Lasting Effects for Glaucoma Therapy

Glaucoma,
a leading cause of irreversible vision loss
worldwide,
is characterized by elevated intra­ocular pressure (IOP), a well-established
risk factor across all its forms. We present the design and synthesis
of 39 novel carbonic anhydrase inhibitors by a dual-tailed approach,
strategically crafted to interact with distinct hydrophobic and hydrophilic
pockets of CA active sites. The series was investigated against the
CA isoforms implicated in glaucoma (hCA II, hCA IV, and hCA XII),
and the X-ray crystal structures of compounds 25a, 25f, and 26a with CA II, along with 14b in complex with a hCA XII mimic, were determined. Selected compounds
(14a, 25a, and 26a) underwent
evaluation for their ability to reduce IOP in rabbits with ocular
hypertension. Derivative 26a showed significant potency
and sustained IOP-lowering effects, surpassing the efficacy of the
drugs dorzolamide and bimatoprost. This positions compound 26a as a promising candidate for the development of a novel anti-glaucoma
medication.