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

Abstract

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.

Novel 2,4-Dichloro-5-sulfamoylbenzoic Acid Oxime Esters: First Studies as Potential Human Carbonic Anhydrase Inhibitors

“…In such a context, the validation of new druggable targets is highly beneficial for the sustainability of the currently used therapeutical protocols. Among the most promising experimental targets, a place of honor is held by the metalloenzymes carbonic anhydrases (CAs; EC 4.2.1.1), which are proven to be crucial for fundamental cancer-related cellular processes. , CAs are involved in regulating pH levels, transporting ions, and maintaining the CO 2 homeostasis. The α-class of CAs expressed in humans (hCAs) accounts for 16 distinct isoforms and, among them, the transmembrane isoforms IX and XII are directly involved in carcinogenesis, whereas the cytosolic isoforms hCA I and hCA II are widely expressed in organs, such as eyes, erythrocytes, osteoclasts, the gastrointestinal system, and kidney cells, and are cooperative with the tumor-associated isoenzymes. − …”