Cancer cells rely on the enzyme telomerase (EC 2.7.7.49) to promote cellular immortality. Telomerase inhibitors (i.e., azidothymidine) can represent promising antitumor agents, although showing high toxicity when administered alone. Better outcomes were observed within a multipharmacological approach instead. In this context, we exploited the validated antitumor targets carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII to attain the first proof of concept on CA–telomerase dual-hybrid inhibitors. Compounds 1b, 7b, 8b, and 11b showed good in vitro inhibition potency against the CAs IX and XII, with K_I values in the low nanomolar range, and strong antitelomerase activity in PC-3 and HT-29 cells (IC₅₀ values ranging from 5.2 to 9.1 μM). High-resolution X-ray crystallography on selected derivatives in the adduct with hCA II as a model study allowed to determine their binding modes and thus to set the structural determinants necessary for further development of compounds selectively targeting the tumoral cells.

Introduction: Glaucoma is a group of progressive optic neuropathies in which elevated intraocular pressure (IOP) as a consequence of an increased aqueous humor (AH) outflow resistance, is the main and only clinically modifiable risk factor for its development and progression. Relaxing Trabecular meshwork (TM) tissue, Rho-Kinase (ROCK) inhibitors directly decrease resistance in the conventional AH outflow, thus resulting in a significant IOP-lowering effect. Areas covered: The progress made in the field of ROCK inhibitors for glaucoma treatment will be discussed, referring to the recent patent literature published mainly in the last 3 years. Development and last studies conducted on the recently approved ripasudil and netarsudil will be described, along with newly reported combinations with other antiglaucoma agents. New molecular entities as ROCK inhibitors will be reported as well as new biological approaches to affect the Rho/ROCK pathway. Expert opinion: With three drugs currently available on the market belonging to this class, ROCK inhibitors have been definitely validated as therapeutic agents for glaucoma treatment. The literature of the last 3 years confirmed the success of the soft-drug and bis-functional approaches in the design of ROCK inhibitors. However, few completely new molecular scaffolds have been reported.

Introduction: In all living species, pH regulation is a tightly controlled process, with a plethora of proteins involved in its regulation. These include sodium-proton exchangers, carbonic anhydrases, anion exchangers, bicarbonate transporters/cotransporters, H⁺-ATPases, and monocarboxylate transporters. All of them play crucial roles in acid-base balancing, both in eukaryotic as well as in prokaryotic organisms, making them interesting drug targets for the management of pathological events (in)directly involved in pH regulation. Areas covered: Interfering with pH regulation for the treatment of tumors and microbial infections is the main focus of this review, with particular attention paid to inhibitors targeting the above-mentioned proteins. The latest advances in each field id reviewed. Expert opinion: Interfering with the pH regulation of tumor cells is a validated approach to tackle primary tumors and metastases growth. Carbonic anhydrases are the most investigated proteins of those aforementioned, with several inhibitors in clinical development. Recent advances in the characterization of proteins involved in pH homeostasis of various pathogens evidenced their crucial role in the survival and virulence of bacterial, fungal, and protozoan microorganisms. Some encouraging results shed light on the possibility to target such proteins for obtaining new anti-infectives, overcoming the extensive drug resistance problems of clinically used drugs.