Inhibition Of Ca2 Research Articles

Novel benzenesulfonamide-aroylhydrazone conjugates as carbonic anhydrase inhibitors that induce MAPK/ERK-mediated cell cycle arrest and mitochondrial-associated apoptosis in MCF-7 breast cancer cells

A series of novel 4-alkylthio-2-chloro-5-[(2-arylmethylidene)hydrazinecarbonyl]benzenesulfonamide derivatives 3–22 were synthesized and evaluated for their inhibitory activity against human carbonic anhydrase isozymes hCA I, hCA II, hCA IX, and hCA XII. These compounds showed varying degrees of activity against the studied isoenzymes. However, the importance of substituent choice in designing potent carbonic anhydrase inhibitors is highlighted by the strong inhibition profiles of compounds 3 and 10 against hCA IX and the low average KI values for compounds 9 and 10 (134 nM and 77 nM, respectively). All the synthesized compounds were evaluated for their antiproliferative activity toward HeLa, HCT-116, and MCF-7 cell lines. Compounds 9 and 19 exhibited significant activity, particularly against the MCF-7 cell line (IC50 values of 4 μM and 6 μM, respectively). Notably, compound 9 demonstrated a high selectivity index (SI = 8.2) for MCF-7 cells. The antiproliferative effects of compounds 9 and 19 were linked to the induction of cell cycle arrest and apoptosis via the mitochondrial pathway and involved the activation of the MAPK/ERK signaling pathway. Inhibition of MAPK/ERK activity reduced the compounds’ ability to induce cell cycle arrest and apoptosis, indicating the critical role of this pathway. These findings suggest that compounds 9 and 19 are promising candidates for further development as specific and potent anticancer agents targeting the MAPK/ERK pathway.

Exploration of 1,3,5-trisubstituted pyrazoline derivatives as human carbonic anhydrase inhibitors: Synthesis, biological evaluation and in silico studies

The human carbonic anhydrase (hCA) IX and XII isoforms are overexpressed in hypoxic conditions, contributing to cancer. Lack of isoform selectivity has been one of the main challenges associated with the existing drugs targeting hCAs. Hence, the development of alternative approaches, such as tail approach to develop more selective hCA IX and XII inhibitors is need of the hour. In the present work, we designed and synthesized 24 new 1,3.5-trisubstituted-pyrazoline derivatives with diverse substitutions. The synthesized analogs were evaluated for their hCA inhibitory activities against hCA I, II, IX, and XII isoforms. Among the tested compounds, derivative 8 displayed good inhibitory activity against hCA IX (Ki = 331 nM) and XII (Ki = 96.7 nM). In addition, 9a-g also exhibited some inhibitory activities against hCA IX and XII, with Kis ranging from 574 to 799 nM and 137–369 nM, respectively. Molecular modelling studies of compound 8 displayed metal coordination with zinc ion and hydrophobic, hydrophilic interactions with adjacent amino acid residues, and maintained stable interactions throughout 100 ns. In addition, ADMET studies demonstrated that compound 8 obeyed the Lipinski's rule of five and was found to be druggable and non-toxic. Hence, compound 8 was identified as potential lead for further development.

Superacid-Synthesized Fluorinated Diamines Act as Selective hCA IV Inhibitors.

Carbonic anhydrase (CA) IV is a membrane-bound enzyme involved in important physio-pathological processes, such as excitation-contraction coupling in heart muscle, central nervous system (CNS) extracellular buffering, and mediation of inflammatory response after stroke. Known since the mid-1980s, this isoform is still largely unexplored when compared to other isoforms, mostly for the current lack of inhibitors targeting selectively this isoform. The discovery of selective CA IV inhibitors is thus largely awaited. In this work, we report β-(di) fluoropropyl diamines as effective CA IV inhibitors, opening real perspectives for a new mode of selective inhibition of this isoform. Inhibition data reveal that the essential structure core to ensure a potent and selective inhibition of CA IV is the N-propyldiamine. Molecular modeling studies were employed to understand the binding mode of the synthesized amines. Conformational searches within the active site space carried out in an implicit solvent (water) model were also conducted.

Hydrogel-Mediated Jamming of Exosome Communications That Counter Tumor Adaption in the Tumor Immune Microenvironment.

Hypoxia, a common occurrence within solid tumors, can stimulate the dissemination of deceptive tumor exosomes, which function as communicative bridges and orchestrate the recruitment of various supportive cell types for enhanced tumor adaptability in a tumor immune microenvironment. Current nanotechnology provides us intelligent strategies to combat the hypoxic tumor microenvironment. However, once exposed to external stimuli, such as chemotherapy, tumor cells simultaneously release malignant signals to develop tumor migration and immunosuppression, posing challenges to clinical practice. Taking advantage of the membrane-targeting therapeutic strategy, the application of a self-assembled short peptide (PepABS-py), affording hydrogels on tumor cell surfaces, can block exosome dissemination with fiber-like nanostructures and effectively limit the systemic adverse effects of traditional therapeutics. Moreover, PepABS-py can attenuate the hypoxic tumor microenvironment in vivo by carrying an inhibitor of the hypoxic tumor-overexpressed CA IX enzyme, where hypoxia is also a crucial regulator to induce tumor exosomes and mediate intercellular communications within the immune system. Herein, its application on jamming exosome communications can target the T cell-related signaling pathway by regulating microRNAs in exosome cargoes and ultimately enhances CD8+ T cell infiltration and alleviates inflammatory monocytes at metastasis sites. Collectively, with the capability of blocking exosome dissemination, PepABS-py can be applied as a promising tumor membrane-targeting therapeutic tool to counter tumor adaption within an immune microenvironment and further advance traditional chemotherapy.

Procoagulant platelet activation promotes venous thrombosis.

Platelets are key players in cardiovascular disease and platelet aggregation represents a central pharmacological target, particularly in secondary prevention. However, inhibition of adenosine diphosphate and thromboxane signaling has low efficacy in preventing venous thromboembolism, necessitating the inhibition of the plasmatic coagulation cascade in this disease entity. Anticoagulation carries a significantly higher risk of bleeding complications, highlighting the need of alternative therapeutic approaches. We hypothesized that procoagulant activation (PA) of platelets promotes venous thrombus formation and that targeting PA could alleviate venous thrombosis. Here, we found elevated levels of procoagulant platelets in the circulation and in thrombi of patients with deep vein thrombosis (DVT) and pulmonary embolism, and in mice developing DVT following inferior vena cava stenosis. Further, we detected procoagulant activation of recruited platelets within murine venous thrombi and human pulmonary emboli. Mice with platelet-specific deficiency in central pathways of procoagulant activation – cyclophilin D and transmembrane protein 16F – were more resistant towards low flow-induced venous thrombosis. Finally, we found that a clinically approved carbonic anhydrase inhibitor, methazolamide, reduced platelet procoagulant activity and alleviated murine thrombus formation without affecting trauma-associated hemostasis. These findings identify an essential role of platelet procoagulant function in venous thrombosis and delineate novel pharmacological strategies targeting platelets in the prevention of venous thromboembolism.

Inhibition Effects of Some Non-Proteinogenic Amino Acid Derivatives on Carbonic Anhydrase Isoenzymes and Acetylcholinesterase: An In Vitro Inhibition and Molecular Modeling Studies.

Amino acid derivatives are molecules of interest for medicinal chemistry and drug design studies due to their important chemical properties. In this study, the inhibition effects of some non-proteinogenic amino acid derivatives (hippuric acid (A), N-(9-Fluorenylmethoxycarbonyl)-D-valine (B), N-Z-(1-Benzotriazolylcarbonyl) methylamine (C), (S)-N-Z-1-Benzotriazolylcarbonyl-2-phenylethylamine (D)) on carbonic anhydrase I (hCA-I), II (hCA-II) isoenzymes and acetylcholinesterase (AChE) activity, whose inhibitors are of vital pharmacological importance, were examined. While carbonic anhydrase (CA) inhibitors are effective molecule candidates for the treatment of many diseases from glaucoma to cancer, acetylcholinesterase inhibitors are target molecules for the treatment of Alzheimer's disease. According to the results of this study, compound D had a strong inhibitory effect on hCA-I (IC50: 0.836 μM) and hCA-II (IC50: 0.661 μM), while compound B (IC50: 100 μM) showed a strong inhibitory effect on AChE activity. In addition, inhibition results were supported by molecular modeling studies. We hope that the obtained results will contribute to the synthesis of new and effective amino acid derivative inhibitors for CA and AChE.

New Sulfonate Ester-Linked Fluorinated Hydrazone Derivatives as Multitarget Carbonic Anhydrase and Cholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, Molecular Docking and ADME Analysis.

In this study, some new hydrazone derivatives (2a-g) was designed, synthesized for first time, and evaluated as multitarget inhibitors of AChE, BChE, hCA I and hCA II. The chemical structures of new hybrids were confirmed by elemental analysis and some spectroscopic techniques. All tested compounds showed low nanomolar inhibition with IC50 values of in the range of 30.4-264.0 nM against hCA I, 23.2-251.6 nM against hCA II, 12.1-114.3 nM against AChE, and 76.4-134.0 nM against BChE. These compounds inhibited hCA I and AChE more than acetazolamide (AZA) and neostigmine. Among them, compounds 2c and 2e, which have a linear structure, were determined to be the most active inhibitor candidates against these selected enzymes. Molecular docking studies were carried out on the compounds (2a--g), revealing their binding interactions with the active site of AChE, BChE, hCA I and hCA II thus supporting the experimental findings. Additionally, in silico absorption, distribution, metabolism, and excretion (ADME) prediction studies of the obtained compounds (2a--g) with in silico approaches were carried out to determine their solubility, whether they have the potential to cross the blood-brain barrier (BBB), values such as GI absorption and drug likeness principles.

Preyssler heteropolyacid-mediated direct deprotection/N-benzoylation of N-Boc-protected sulfonamides: synthesis, molecular docking, DFT study and in-silico ADME evaluation of novel benzamides bearing the sulfonamide moiety as possible inhibitors of human carbonic anhydrase II

An adequate method is described for the synthesis of new substituted benzamides containing a sulfonamide moiety using Preyssler heteropolyacid H14[NaP5W30O110] as an efficient catalyst. This method proceeds in one-step, including deprotection and benzoylation of N-(tert-butoxycarbonyl) sulfonamides to give the target compounds good yields (up to 92%). A molecular docking was performed to study the interactions between the synthesized benzamides and human carbonic anhydrases II. It was concluded that all compounds demonstrated good binding score values (up to −9.4 kcal/mol) for the active site of all selected proteins when compared with the reference drug Acetazolamide (−6.3 kcal/mol). In addition, the ADME/T analyses show that all synthesized molecules exhibited good pharmacokinetics and bioavailability. The theoretical calculations for all compounds were performed using the DFT/B3LYP/6–31G (d,p) level of theory. The study yielded optimized structural parameters, global reactivity descriptors, and Frontier Molecular Orbitals (FMO’s).

Association between the use of prostaglandin analogues and ocular surface disease: a systematic review.

Patients with glaucoma often experience chronic ocular surface diseases, potentially underestimated in frequency and severity. To provide updated estimates of ocular surface diseases linked to prostaglandin analogue antiglaucoma eye medication, a systematic review was conducted. Twenty-seven publications were selected from databases like PubMed, Scopus, and Web of Science, following a search strategy targeting glaucoma and prostaglandins while excluding certain medications '(Glaucoma AND prostaglandins OR 'prostaglandin analogues')('eye drops' OR 'artificial tears' OR 'ocular surface' OR 'dry eye' OR 'dry eye syndrome' OR 'ocular surface disease' OR 'tear film') NOT ('beta blockers' OR 'alpha adrenergic agonists' OR 'carbonic anhydrase inhibitors' OR 'rho-quinase')'. The review revealed a correlation between prostaglandin analogue use and ocular surface damage, assessing parameters such as tear break-up time, Schirmer test value, ocular surface staining, hyperaemia score, and meibomian gland characteristics. Some studies explored switching patients to alternative glaucoma medications, noting varied effects on ocular surface parameters. Comparisons suggested better tolerance and outcomes with preservative-free options over prostaglandins. Additionally, the impact of treatment duration and diquafosol on ocular health, including meibomian gland loss, was examined across different formulations. Although a link between prostaglandin analogues (with or without preservatives) and ocular surface damage was established, inconsistencies in methodologies and assessment across studies were noted. This comprehensive review, spanning a decade of glaucoma research, underscores the need for re-evaluation of treatment strategies in ophthalmology. It stresses the significance of informed decision-making for enhanced glaucoma care, taking into account the observed effects of various medications on eye health.

Benzoxaborinine, New Chemotype for Carbonic Anhydrase Inhibition: Ex Novo Synthesis, Crystallography, In Silico Studies, and Anti-Melanoma Cell Line Activity.

The benzoxaborinine scaffold, a homologue of benzoxaborole with an additional carbon atom in the boracycle, shows significant potential in developing new therapeutic agents. This study reports the synthesis, inhibition assays against four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, and anti-melanoma evaluation of 7-aryl(thio)ureido-substituted benzoxaborinines. Some derivatives, particularly compound 11, exhibited potent inhibitory activity (below 65 nM) against hCA IX and XII and stronger antiproliferative effects than SLC-0111 on human melanoma cells under hypoxia. Crystallographic studies of benzoxaborinine 3 adducts with hCA I and II demonstrated the binding mode of this chemotype, revealing that although both benzoxaborinine 3 and benzoxaborole 10 share a similar zinc-binding mode, the expanded ring in benzoxaborinine led to a different orientation within the active site. These findings suggest that benzoxaborinines hold promise for designing novel carbonic anhydrase inhibitors.

Exploring the binding mode of phenyl and vinyl boronic acids to human carbonic anhydrases

Boronic acids are an interesting but still poorly studied class of carbonic anhydrase inhibitors. Previous investigations proved that derivatives incorporating aromatic, arylalkyl, and arylalkenyl moieties are low micromolar to millimolar inhibitors for several α- and β-CAs involved in pathologic states.Here we report a high-resolution X-ray study on two classes of boronic acids (phenyl and vinyl) in complex with hCA II. Our results unambiguously clarify the binding mode of these molecules to the human carbonic anhydrase active site, which occurs through their tetrahedral anionic form, regardless of the nature of the organic scaffold. Data here presented contribute to the understanding of the inhibition mechanism of boronic acids that can be fruitfully used for the rational design of novel and effective isozyme-specific carbonic anhydrase inhibitors.

Synthesis and investigation of selective human carbonic anhydrase IX, XII inhibitors using coumarins bearing a sulfonamide or biotin moiety

The role of carbonic anhydrases isoforms (CAs) IX and XII in the pathogenesis and progression of many types of solid tumors is well known. In this context, selective CA inhibitors (CAIs) towards the mentioned isoforms is a validated strategy for the development of agents to target cancer. For this purpose, novel coumarin derivatives based on the hybridization with arylsulfonamide or biotin scaffolds were synthesized and tested as inhibitors of four different human carbonic anhydrases isoforms: hCA I, II, IX and XII. Coumarin-sulfonamide derived 27, with a thiourea moiety and triazole as linker, showed the highest inhibition activity against hCA XII with an inhibition constant (KI) of 7.5 nM and afforded a very good selectivity over hCA I. Compound 32 was the most potent inhibitor against hCA IX (KI = 6.3 nM), 4-fold stronger than the drug acetazolamide AAZ (KI = 25 nM), used herein as a reference compound, and showed remarkable selectivity over hCA I and II. The coumarin-biotin derivatives 37-39 showed outstanding selectivity towards on-target enzymes (hCA IX and XII) and appear as plausible leads for designing of CAIs.

Phosphorylation strongly affects the inhibition of human carbonic anhydrase I CO2 hydration activity

Human carbonic anhydrases (hCAs) have essential roles in respiration, acid-base balance, and fluid secretion, with implications in diseases such as glaucoma, epilepsy, obesity, and cancer. Of the fifteen known hCAs, human CA I (hCA I) is particularly abundant in erythrocytes, playing a critical role in CO2 transport. Despite extensive research on hCA I, the impact of post-translational modifications (PTMs), particularly phosphorylation, on its catalytic activity and inhibitor binding remains poorly understood. Although multiple phosphorylation sites have been identified in hCA I in vivo through high-throughput proteomics studies including at the highly conserved Ser51 residue, the functional consequences of these modifications are not well characterized. We investigated the effects of a phosphomimetic mutation at Ser51 on hCA I, examining its catalytic efficiency and susceptibility to inhibition by sulfonamides and anions. Using a recombinant expression system and a stopped-flow kinetic assay, we characterized the CO2 hydration activity and inhibition profiles of S51E hCA I compared to the wild type enzyme. Our results demonstrate that the S51E mutation increases the catalytic turnover rate (kcat) from 2.0 × 105 s−1 to 2.6 × 105 s−1 but significantly decreases substrate affinity, raising the Michaelis constant (KM) from 4.0 mM to 13.9 mM, reducing overall catalytic efficiency by over 50 %. Inhibition studies with a panel of 41 sulfonamides revealed that the S51E mutation dramatically alters inhibitor sensitivity, particularly for the most effective inhibitors. For example, 15 of the 16 most effective sulfonamide inhibitors for hCA I (with KIs <350 nM) were an average of over 35-fold less effective in inhibiting S51E hCA I than the wild type. The KI of the anticonvulsant zonisamide increased from 31 nM for the wild type hCA I to 4.0 μM. The inhibition profile with a panel of 37 small anions further indicated that the S51E mutant exhibited significantly reduced susceptibility to inhibition by 24 out of 37 tested anions, with some KI values increasing by up to 11,000-fold for inhibitors like hydrogen sulfide. This study underscores the significant impact that phosphorylation may have on hCA I function and inhibition. By characterizing the effects of phosphorylation on the CO2 hydration activity and inhibitor sensitivity of hCA I, these findings represent early steps in developing more selective proteoform-specific inhibitors, which could lead to more effective treatments for diseases involving carbonic anhydrases.

Interactions of novel 1,3-diaryltriazene-sulfamethazines with carbonic anhydrases: Kinetic studies and in silico simulations

Sulfonamides, recognized as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, are crucial in treating diverse diseases, including epilepsy, glaucoma, bacterial infections, and various pathological processes, e.g., high blood pressure, rheumatoid arthritis, ulcerative colitis, pain, and inflammation. Additionally, therapeutically, 1,3-diaryl-substituted triazenes and sulphamethazines (SM) are integral components in various drug structures, and the synthesis of novel compounds within these two categories holds substantial significance. Herein, ten 1,3-diaryltriazene-substituted sulphamethazine derivatives SM(1-10), which were created by reacting the diazonium salt of sulphamethazine with substituted aromatic amines, were synthesized and the physiologically and pharmacologically relevant human (h) isoforms hCA I and II, cytosolic isozymes, were included in the study. The synthesized compounds showed excellent inhibition versus hCAs; the 4-butoxy (SM7, KI of 5.69 ± 0.59 nM) compound exhibited a potent inhibitory effect against the hCA I compared with the reference drug acetazolamide (AAZ, KI of 116.00 ± 8.48 nM). The 4-cyano (SM4, KI of 5.87 ± 0.57 nM) compound displayed higher potency than AAZ (KI of 57.25 ± 4.15 nM) towards hCA II. Meanwhile, among the synthesized molecules, the 3,4-dimethoxy (SM9, KI of 74.98 ± 10.49 nM, SI of 9.94) compound (over hCA I) displayed a noticeable selectivity for hCA isoform II. The target compounds in the molecular docking investigation were determined to take part in various hydrophilic and hydrophobic interactions with nearby amino acids and fit nicely into the active sites of the hCAs. This research has yielded compounds displaying varying affinity toward hCA isoenzymes, ultimately serving as potent and selective hCA inhibitors. Given its substantial biological inhibitory potency, this particular derivative series is determined to hold the potential to serve as a promising lead compound against these hCAs.

The effectiveness of transferring patients with open-angle glaucoma to therapy with a preservative-free fixed combination of a carbonic anhydrase inhibitor and a prostaglandin analogue

The effectiveness of transferring patients with open-angle glaucoma to therapy with a preservative-free fixed combination of a carbonic anhydrase inhibitor and a prostaglandin analogue

Novel thiazolotriazole and triazolothiadiazine scaffolds as selective tumor associated carbonic anhydrase inhibitors endowed with cathepsin B inhibition.

The present research focused on the tail-approach synthesis of novel extended thiazolotriazoles (8a-8j) and triazolothiadiazines (11a-11j) including aminotriazole intermediate 10. After successful synthesis, all the compounds were evaluated for their inhibition potential against cytosolic isoforms of human carbonic anhydrase (hCA I, II), tumor-linked transmembrane isoforms (hCA IX, XII), and cathepsin B. As per the inhibition data, the newly synthesized compounds showed poor inhibition against hCA I. Many of the compounds showed effective inhibition toward hCA IX and/or XII in low nanomolar concentration. Despite the strong to moderate inhibition of hCA II by these compounds, more than half of them demonstrated better inhibition against hCA IX and/or XII, comparatively. Further, insights of CA inhibition data of these extended analogs and their comparison with earlier reported thiazolotriazole and triazolothiadiazine derivatives might help in the rational design of novel potent and selective hCA IX and XII inhibitors. The novel compounds were also found to possess anti-cathepsin B potential at a low concentration of 10-7 M. Broadly, compounds of series 11a-11j presented more effective inhibition against cathepsin B than their counterparts in series 8a-8j. Moreover, these in vitro results with respect to cathepsin B inhibition were also supported by the in silico insights obtained via molecular modeling studies.

Computational Analysis and Inhibition Study of Carbonic Anhydrase from Azadirachta indica Leaves

Introduction: Carbonic anhydrase (CA) has been an enzyme of great interest for its application in carbon dioxide sequestration. A total of 66 protein sequences of plant CAs were computationally analyzed and submitted to bioinformatics for motif and domain identification, multiple sequence alignment, and phylogenetic analysis. Method: The current work aims to extend knowledge among researchers in better understanding the structure of AZDI CA by analyzing its physicochemical properties, secondary structure prediction, 3D modeling of protein sequence, and its validation using a variety of conventional computational methods. Results: The accuracy of the predicted 3D structure checked by the Ramachandran plot generated by PROCHECK showed that for the CA protein sequence 93.1%, was observed in the most favored regions, VERIFY 3D 69.44% and ERRAT 98.09%. AZDI CA was docked with various anions and sulphonamide derivatives to study their inhibitory effect and calculate binding energy by using Autodock 4.2. Ethoxzolamide is found to be a better inhibitor of AZDI CA with binding energy -8.71 kCal/mol and KI value 0.0004 mM. Further MD simulation of the docked complex of ethoxzolamide with AZDI CA was done using SCHRODINGER DESMOND software. Conclusion: The outcomes of this research will have a significant influence on biochemistry, biotechnology, and potential applications of AZDI CA and similar plant CAs in determining potent inhibitors for drug targets in treating various diseases.

Lasamide, a Potent Human Carbonic Anhydrase Inhibitor from the Market: Inhibition Profiling and Crystallographic Studies.

Lasamide is a synthetic precursor and a contaminant of the diuretic Furosemide manufacturing process and represents a highly valuable building block for fragment-based drug discovery approaches. We assessed the ability of Lasamide to inhibit in vitro the human-expressed Carbonic Anhydrases by means of the stopped-flow technique, and we assessed its binding modes within hCAs II and XII-mimic catalytic clefts by X-ray crystallography. Interestingly, an unprecedented crystal form for the hCA IX mimic H-tag is reported and discussed herein.

Multi- and poly-pharmacology of carbonic anhydrase inhibitors.

Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) were described in organisms allover the phylogenetic tree. They catalyze the hydration of CO2 to bicarbonate and protons, and are involved in pH regulation, chemosensing and metabolism. The 15 α-CA isoforms present in humans are pharmacological drug targets known for decades, their inhibitors being used as diuretics, antiglaucoma, antiepileptic or antiobesity drugs, as well as for the management of acute mountain sickness, idiopathic intracranial hypertension and recently, as antitumor theragnostic agents. Other potential applications include the use of CA inhibitors (CAIs) in inflammatory conditions, cerebral ischemia, neuropathic pain, or for Alzheimer's/Parkinson's disease management. CAs from pathogenic bacteria, fungi, protozoans and nematodes started to be considered as drug targets in recent years, with notable advances registered ultimately. CAIs have a complex multipharmacology probably unique to this enzyme, which has been exploited intensely but may lead to other relevant applications in the future, due to the emergence of drug design approaches which afforded highly isoform-selective compounds for most α-CAs known to date. They belong to a multitude of chemical classes (sulfonamides and isosteres, (iso)coumarins and related compounds, mono- and dithiocarbamates, selenols, ninhydrines, boronic acids, benzoxaboroles, etc). The polypharmacology of CAIs will also be discussed since drugs originally discovered for the treatment of non-CA related conditions (topiramate, zonisamide, celecoxib, pazopanib, thiazide and high-ceiling diuretics) show efective inhibition against many CAs, which led to their repurposing for diverse pharmacological applications. Significance Statement Carbonic anhydrase inhibitors have multiple pharmacologic applications as diuretics, antiglaucoma, antiepileptic, antiobesity, anti-acute mountain sickness, anti-idiopathic intracranial hypertension and as antitumor drugs. Their use in inflammatory conditions, cerebral ischemia, neuropathic pain, or neurodegenerations started to be investigated recently. Parasite carbonic anhydrases are also drug targets for antiinfectives with novel mechanisms of action which can by pass drug resistance to commonly used such agents. Drugs discovered for the management of other conditions that effectively inhibit these enzymes exert interesting polypharmacologic effects.

Near Add Power of Glaucoma Patients with Early Presbyopia.

Purpose: Glaucoma medication may accelerate the progression of presbyopia. The aim of this study was to compare presbyopia between controls and patients with glaucoma in their 40s. Methods: This was a cross-sectional study of bilateral phakic participants aged between 40 and 49, which included controls (n = 114, mean age 46.1 ± 2.7 y) and patients with primary open-angle glaucoma (n = 105, 46.4 ± 2.7 y) who had been using FP receptor agonists, beta blockers, and carbonic anhydrase inhibitors for at least six months. We compared the near add power between the two groups. Results: The mean near add power and the prevalence of symptomatic presbyopia (near add power ≥ 1.50 D) were 1.16 ± 0.74 D and 42.1% for controls and 1.77 ± 0.71 D (p < 0.01) and 79.0% (p < 0.01) for glaucoma patients, respectively. The odds ratio (OR) and confidence interval for symptomatic presbyopia were associated with age (1.36, 1.21-1.52), ganglion cell complex thickness (0.96, 0.94-0.99), presence of glaucoma (6.19, 3.13-12.23), and number of glaucoma medications (4.26, 2.42-7.43). Among medications, only FP receptor agonists (5.79, 2.68-12.32) produced significant results. Survival analysis showed that glaucoma patients reached the threshold of a near add power of +1.50 D significantly sooner than controls (p < 0.05; log-rank test). Conclusions: Glaucoma patients, especially those using FP receptor agonists, had higher near add power than controls.