Nowadays, the scientific community has focused on dealing with different kinds of diseases by exploring the chemistry of various heterocycles as novel drugs. In this connection, medicinal chemists identified carbonic anhydrases (CA) as one of the biologically active targets for curing various diseases. The widespread distribution of these enzymes and the high degree of homology shared by the different isoforms offer substantial challenges to discovering potential drugs. Medicinal and synthetic organic chemists have been continuously involved in developing CA inhibitors. This review explored the chemistry of different heterocycles as CA inhibitors using the last 11 years of published research work. It provides a pathway for young researchers to further explore the chemistry of a variety of synthetic as well as natural heterocycles as CA inhibitors.

Acetazolamide (AZM) is a strong pharmacological sulphonamide-type (R-SO2-NH2, pKa 7.2) inhibitor of the activity of several carbonic anhydrase (CA) isoforms, notably of renal CA II (Ki, 12 nM) and CA IV (Ki, 74 nM). AZM is clinically used for about eighty years in various diseases including epilepsy and glaucoma. Pharmacological AZM increases temporarily the urinary excretion of bicarbonate (HCO3-) and sodium ions (Na+) and sustainably the urinary pH. AZM is excreted almost unchanged over several hours at high rates in the urine. Closely parallel concentrations of circulating and excretory AZM are observed upon administration of therapeutical doses of AZM. In a proof-of-principle study, we investigated the effects of the ingestion of a 250-mg AZM-containing tablet by a healthy volunteer on the urinary excretion of organic and inorganic substances over 5 h (range, 0, 0.5, 1, 1.5, 2, 3, 4, 5 h). Measured analytes included: AZM, amino acids and their metabolites such as guanidinoacetate, i.e. the precursor of creatine, of asymmetrically (ADMA) and symmetrically (SDMA) dimethylated arginine, nitrite (O = N-O-, pKa 3.4) and nitrate (O2N-O-, pKa -1.37), the major metabolites of nitric oxide (NO), the C-H acidic malondialdehyde (MDA; (CHO)2CH2, pKa 4.5), and creatinine for correction of analytes excretion. All analytes were measured by validated isotopologues using gas chromatography-mass spectrometry (GC-MS) methods. AZM excretion in the urine reached its maximum value after 2 h and was fairly stable for the next 3 h. Time series analysis by the ARIMA method was performed. AZM ingestion increased temporarily the urinary excretion of the amino acids Leu + Ile, nitrite and nitrate, decreased temporarily the urinary excretion of other amino acids. AZM decreased sustainably the urinary excretion of MDA, a biomarker of oxidative stress (i.e. lipid peroxidation). Whether this decrease is due to inhibition of the excretion of MDA or attenuation of oxidative stress by AZM is unknown. The acute and chronic effects of AZM on the urinary excretion of electrolytes and physiological substances reported in the literature are discussed in depth in the light of its extraordinary pharmacokinetics and pharmacodynamics. Tolerance development/drug resistance to AZM in chronic use and potential mechanisms are also addressed.

OBJECTIVE: Hypoxia is a characteristic of many solid tumours and an adverse prognostic factor for cancer therapy. Hypoxia results in upregulation of carbonic anhydrase IX (CAIX) expression, a pH-regulating enzyme. Many human tissue studies have examined the prognostic value of CAIX expression in breast cancer but have yielded inconsistent results. Therefore, a systematic review and meta-analysis was undertaken to assess the prognostic value of CAIX expression for breast cancer patients.
METHODS: The electronic databases were systematically searched to identify relevant papers. The clinical outcomes included disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) in breast cancer patients. Review Manager version 5.4 was employed to analysis data from 23 eligible studies (containing 8390 patients).
RESULTS: High CAIX expression was associated with poorer RFS [HR = 1.42, 95% CI (1.32-1.51), p < 0.00001], DFS [HR = 1.64, 95% CI (1.34-2.00), p < 0.00001], and OS [HR = 1.48, 95% CI (1.22-1.80), p < 0.0001]. Heterogeneity was observed across the studies. There was an effect of the CAIX antibody employed, scoring methods, and tumour localisation on CAIX expression.
CONCLUSIONS: CAIX overexpression was significantly associated with poorer RFS, DFS, and OS in breast cancer patients. However, further work in high quantity tissue cohorts is required to define the optimal methodological approach.

A number of studies have claimed that carbonic anhydrase VI (CA VI) is associated with dental caries. The aim of this systematic review and meta-analysis was to systematically review and analyze the literature on the association of CA VI (in terms of concentration and activity) with dental caries.
A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Relevant search terms were employed to search the following databases: PubMed, Web of Science, Scopus, China National Knowledge Infrastructure (CNKI), and Cochrane Library databases. Eligible publications from inception to August 2022 were included. The relevant records were assessed independently by two reviewers, and a meta-analysis was performed using RevMan 5.3.
Out of 237 relevant records from the initial search, 9 met the criteria for this review. The 9 papers, including 477 participants, were qualitatively analyzed. Seven studies with 411 participants (203 caries-free) were included in the meta-analysis on CA VI activity, and 2 studies with 141 participants (71 caries-free) were included in the meta-analysis on CA VI concentration. The results showed that CA VI activity was significantly higher among participants with caries than their caries-free counterparts (standardized mean difference (SMD) = 0.894, 95% confidence interval (CI95% ): 0.386 and 1.392; p < 0.001), whereas the CA VI concentration was significantly lower among participants with caries than their caries-free counterparts (SMD = -0.672, CI95% : -1.011 and -0.332; p < 0.001).
This meta-analysis of a relatively small number of studies suggests that the CA VI concentration is lower and CA VI activity is higher in patients with dental caries than in caries-free individuals; however, further studies are needed to determine the exact role of CA VI in dental caries.

Carbonic anhydrase IX (CAIX) is a transmembrane protein that is specifically overexpressed on the surface of hypoxic tumor cells. With the function of regulating the acidity of tumor cells both inside and outside, CAIX is closely related to tumor proliferation, invasion and metastasis. Therefore, CAIX is a promising target for tumor imaging and therapy. Herein, we summarized recent advances in CAIX-based tumor imaging, therapy and theranostics, and prospected future applications of using CAIX as an anti-tumor target.

Targeted inhibition of misregulated protein-protein interactions (PPIs) has been a promising area of investigation in drug discovery and development for human diseases. However, many constraints remain, including shallow binding surfaces and dynamic conformation changes upon interaction. A particularly challenging aspect is the undesirable off-target effects caused by inherent structural similarity among the protein families. To tackle this problem, phage display has been used to engineer PPIs for high-specificity binders with improved binding affinity and greatly reduced undesirable interactions with closely related proteins. Although general steps of phage display are standardized, library design is highly variable depending on experimental contexts. Here in this review, we examined recent advances in the structure-based combinatorial library design and the advantages and limitations of different approaches. The strategies described here can be explored for other protein-protein interactions and aid in designing new libraries or improving on previous libraries.

Introduction: Glaucoma affects more than 70 million people worldwide. One of the major therapeutic options for its management is based on the inhibition of the metalloenzyme carbonic anhydrases (CAs, EC 4.2.1.1). CA inhibitors (CAIs) diminish ocular hypertension in glaucomatous patients by reducing the rate of bicarbonate formation and thus, the secretion of the aqueous humor. Areas covered: This review is intended to cover the major contributions in terms of patent literature reports for the treatment of ophthalmic diseases by means of CAIs in a time frame spanning from 2013 to date. Expert opinion: The patent literature is dominated by innovative pharmaceutical formulations including a CAI alone or in combination with other therapeutic agents. Very few novelties within drug discovery are currently present and they mainly account for new CAI moieties and classical CAIs merged into scaffolds bearing additional chemical functionalities beneficial for the pharmacological treatment of the disease. It is reasonable to expect that in the near future the so-called \'old drugs\' will achieve pharmacological performances in the management of ocular hypertension beyond any expectations and thus open a new era of drug repurposing merely based on material science advancements.

Eight genetically distinct carbonic anhydrase (EC 4.2.1.1) enzyme families (α-, β-, γ- δ-, ζ-, η-, θ- and ι-CAs) were described to date. On the other hand, 16 mammalian α-CA isoforms are known to be involved in many diseases such as glaucoma, edema, epilepsy, obesity, hypoxic tumors, neuropathic pain, arthritis, neurodegeneration, etc. Although CA inhibitors were investigated for the management of a variety of such disorders, the activators just started to be investigated in detail for their in vivo effects. This review summarizes the activation profiles of α-, β, γ-, δ-, ζ- and η- CAs from various organisms (animals, fungi, protozoan, bacteria and archaea) with the most investigated classes of activators, the amines and the amino acids.

Human carbonic anhydrases (CA, EC 4.2.1.1) IX and XII are tumor-associated proteins, being part of the molecular machinery that tumor cells build as adaptive responses to hypoxia and acidic conditions characteristic of the \'glycolytic shift\' of many tumors. A wealth of research depicts CA IX and CA XII as biomarkers and therapeutic targets for various cancer types.
The review presents an overview of the role of CA IX and CA XII in hypoxic tumors physio-pathology as well as the principal molecular, structural, and catalytic features of both isozymes. The review then covers the patent literature of medically relevant inhibitors of the tumor-associated CAs produced during the period 2008-2018.
A variety of approaches and design strategies were reported which afford CA IX/XII-specific inhibitors and avoid the compromising effects of isoforms-promiscuous compounds. Access to the crystal structures of human CAs isoforms have improved structure-based drug design campaigns related to zinc-binder chemotypes. Nevertheless, great potential still resides in non-classical CAIs that exhibit alternative binding mechanisms able to further distinguish the various active sites architecture. CA IX inhibitors hybrids/conjugates are increasingly emerging in the field as promising therapeutic tools to combine CA inhibition to the anticancer effects of other moieties or antitumor drugs.

Carbon dioxide (CO₂) retention, or hypercapnia, is a known risk of diving that can cause mental and physical impairments leading to life-threatening accidents. Often, such accidents occur due to elevated inspired carbon dioxide. For instance, in cases of CO₂ elimination system failures during rebreather dives, elevated inspired partial pressure of carbon dioxide (PCO₂) can rapidly lead to dangerous levels of hypercapnia. Elevations in PaCO₂ (arterial pressure of PCO₂) can also occur in divers without a change in inspired PCO₂. In such cases, hypercapnia occurs due to alveolar hypoventilation. Several factors of the dive environment contribute to this effect through changes in minute ventilation and dead space. Predominantly, minute ventilation is reduced in diving due to changes in respiratory load and associated changes in respiratory control. Minute ventilation is further reduced by hyperoxic attenuation of chemosensitivity. Physiologic dead space is also increased due to elevated breathing gas density and to hyperoxia. The Haldane effect, a reduction in CO₂ solubility in blood due to hyperoxia, may contribute indirectly to hypercapnia through an increase in mixed venous PCO₂. In some individuals, low ventilatory response to hypercapnia may also contribute to carbon dioxide retention. This review outlines what is currently known about hypercapnia in diving, including its measurement, cause, mental and physical effects, and areas for future study.