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 , , and with CA II, along with in complex with a hCA XII mimic, were determined. Selected compounds (, , and ) underwent evaluation for their ability to reduce IOP in rabbits with ocular hypertension. Derivative showed significant potency and sustained IOP-lowering effects, surpassing the efficacy of the drugs dorzolamide and bimatoprost. This positions compound as a promising candidate for the development of a novel anti-glaucoma medication.
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