Development Of Carbonic Anhydrase Inhibitors Research Articles

Advances in the Development of Carbonic Anhydrase Inhibitors as New Antiprotozoal Agents.

Parasitic diseases are a public health problem despite the existence of drugs for their treatment. These treatments have variable efficacy and, in some cases, serious adverse effects. There has been interest in the enzyme carbonic anhydrase (CA) in the last two decades since it is essential in the life cycle of various parasites due to its important participation in processes such as pyrimidine synthesis, HCO3- transport across cell membranes, and the maintenance of intracellular pH and ion transport (Na+, K+, and H+), among others. In this review, CA was analyzed as a pharmacological target in etiological agents of malaria, American trypanosomiasis, leishmaniasis, amoebiasis, and trichomoniasis. The CA inhibitors´ design, binding mode, and structure-activity relationship are also discussed. According to this review, advances in discovering compounds with potent inhibitory activity suggest that CA is a candidate for developing new antiprotozoal agents.

The effect of benzenesulfonamide's side chains on their human carbonic anhydrase Ⅰ/Ⅱ inhibitory activities

Benzenesulfonamides are well-known potent carbonic anhydrase inhibitors (CAIs). They are usually composed of benzenesulfonamide heads and hydrophobic side chain tails. However, hydrophobic side chain tails contribute to poor water solubility, which is a major challenge in the development of CAIs. Herein, to elaborate whether benzenesulfonamides with hydrophilic/hydrophobic tails are effective against carbonic anhydrases (CAs), 12 benzenesulfonamides containing hydrophilic tails and 16 benzenesulfonamides containing hydrophobic tails were designed and synthesized. Benzenesulfonamides with hydrophilic tails including 4b, 4c, and 5b and benzenesulfonamides with hydrophobic tails including 2e, 4b, and 4c are potent carbonic anhydrase Ⅰ/Ⅱ dual inhibitors whose Ki to CA I and CA II were below 10 nM, and below 50 nM, respectively. However, the water solubility of 4b, 4c, and 5b was 52, 148, and 71 mg/100 g of water, respectively, which is much better than that of benzenesulfonamides with hydrophobic tails. In a hypoxic mouse model, compounds 4c and 5b extended the survival of mice by 34.46% and 28.23%, respectively, compared to the blank control. Treatment with 4c and 5b extended survival better than acetazolamide treatment did (16.86%). Moreover, 5b also has better anti-convulsant effect than AAZ. Molecular docking analysis demonstrated that hydrogen bonds between the oxygen atoms in the hydrophilic tails of 4b, 4c, and 5b and H2O in hCA I and hCA II protein facilitated ligand-receptor binding. Therefore, considering the good water solubility and potent CA I/II inhibition, 4c and 5b are worth exploring as therapeutic options for acute mountain sickness. In conclusion, benzenesulfonamides containing hydrophilic tails could offer innovative opportunities for potent, water-soluble anti-AMS (Acute Mountain Sickness) compounds.

Recent advances in the medicinal chemistry of carbonic anhydrase inhibitors.

Carbonic anhydrase (CA, EC 4.2.1.1) is an enzyme and a very omnipresent zinc metalloenzyme which catalyzed the reversible hydration and dehydration of carbon dioxide and bicarbonate; a reaction which plays a crucial role in many physiological and pathological processes. Carbonic anhydrase is present in human (h) with sixteen different isoforms ranging from hCA I-hCA XV. All these isoforms are widely distributed in different tissues/organs and are associated with a range of pivotal physiological activities. Due to their involvement in various physiological roles, inhibitors of different human isoforms of carbonic anhydrase have found clinical applications for the treatment of various diseases including glaucoma, retinopathy, hemolytic anemia, epilepsy, obesity, and cancer. However, clinically used inhibitors of CA (acetazolamide, brinzolamide, dorzolamide, etc.) are not selective causing the undesirable side effects. One of the major hurdles in the design and development of carbonic anhydrase inhibitors is the lack of balanced isoform selectivity which thrived to new chemotypes. In this review, we have compiled the recent strategies of various researchers related to the development of carbonic anhydrase inhibitors belonging to different structural classes like pyrimidine, pyrazoline, selenourea, isatin, indole, etc. This review also summarizes the structure-activity relationships, analysis of isoform selectivity including mechanistic and in silico studies to afford ideas and to provide focused direction for the design and development of novel isoform-selective carbonic anhydrase inhibitors with therapeutic implications.

Pyrrolidinone-bearing methylated and halogenated benzenesulfonamides as inhibitors of carbonic anhydrases.

Two series of benzenesulfonamides bearing methyl groups at ortho/ortho or meta/ortho positions and a pyrrolidinone moiety at para position were synthesized and tested as inhibitors of the twelve catalytically active human carbonic anhydrase (CA) isoforms. Observed binding affinities were determined by fluorescent thermal shift assay and intrinsic binding affinities representing the binding of benzenesulfonamide anion to the Zn(II)-bound water form of CA were calculated. Introduction of dimethyl groups into benzenesulfonamide ring decreased the binding affinity to almost all CA isoforms, but gained in selectivity towards one CA isoform. A chloro group at the meta position of 2,6-dimethylbenzenesulfonamide derivatives did not influence the binding to CA I, but it increased the affinity to all other CAs, especially, CA VII and CA XIII (up to 500 fold). The compounds may be used for further development of CA inhibitors with higher selectivity to particular CA isoforms.

Cancer Drug Development of Carbonic Anhydrase Inhibitors beyond the Active Site.

Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to produce bicarbonate and a proton. Multiple CA isoforms are implicated in a range of diseases, including cancer. In solid tumors, continuously dividing cells create hypoxic conditions that eventually lead to an acidic microenvironment. Hypoxic tumor cells have different mechanisms in place to regulate and adjust the surrounding microenvironment for survival. These mechanisms include expression of CA isoform IX (CA IX) and XII (CA XII). These enzymes help maintain a physiological intracellular pH while simultaneously contributing to an acidic extracellular pH, leading to tumor cell survival. Expression of CA IX and CA XII has also been shown to promote tumor cell invasion and metastasis. This review discusses the characteristics of CA IX and CA XII, their mechanism of action, and validates their prospective use as anticancer targets. We discuss the current status of small inhibitors that target these isoforms, both classical and non-classical, and their future design in order to obtain isoform-specificity for CA IX and CA XII. Biologics, such as monoclonal antibodies, monoclonal-radionuclide conjugated chimeric antibodies, and antibody-small molecule conjugates are also discussed.

Inhibition of carbonic anhydrases by a substrate analog: benzyl carbamate directly coordinates the catalytic zinc ion mimicking bicarbonate binding

N-Unsubstituted carbamates have scarcely been investigated so far as carbonic anhydrase inhibitors (CAIs). By means of kinetic and structural studies, in this paper we demonstrate that such molecules can effectively inhibit hCAs and can be used as lead compounds for the development of CAIs possessing a binding mode similar to one of the CA substrates, bicarbonate.

Carbohydrazones as new class of carbonic anhydrase inhibitors: Synthesis, kinetics, and ligand docking studies

Discovery and development of carbonic anhydrase inhibitors is crucial for their clinical use as antiepileptic, diurectic and antiglaucoma agents. Keeping this in mind, we have synthesized carbohydrazones 1–27 and evaluated them for their in vitro carbonic anhydrase inhibitory potential. Out of twenty-seven compounds, compounds 1 (IC50=1.33±0.01µM), 2 (IC50=1.85±0.24µM), 3 (IC50=1.37±0.06µM), and 9 (IC50=1.46±0.12µM) have showed carbonic anhydrase inhibition better than the standard drug zonisamide (IC50=1.86±0.03µM). Moreover, compounds 4 (IC50=2.32±0.04µM), 5 (IC50=3.96±0.35µM), 7 (IC50=2.33±0.02µM), and 8 (IC50=2.67±0.01µM) showed good inhibitory activity. Cheminformatic analysis has shown that compounds 1 and 2 possess lead-like properties. In addition, kinetic and molecular docking studies were also performed to investigate the binding interaction between carbohydrazones and carbonic anhydrase enzyme. This study has identified a novel and potent class of carbonic anhydrase inhibitors with the potential to be investigated further.

Hydroxylamine-O-sulfonamide is a versatile lead compound for the development of carbonic anhydrase inhibitors.

Hydroxylamine-O-sulfonamide, a molecule incorporating two zinc-binding groups (ZBGs), has been investigated as a carbonic anhydrase inhibitor (CAI) by means of kinetic, crystallographic and Raman spectroscopy studies, highlighting interesting results on its mechanism of action. These data can be exploited to design new, effective and selective CAIs.

Salicylaldoxime derivatives as new leads for the development of carbonic anhydrase inhibitors

New compounds containing a novel zinc binding group (salicylaldoxime system) were identified as effective inhibitors of carbonic anhydrases (CAs). This structural motif seems to bind the catalytic zinc ion of CAs, revealing itself as a new valid alternative to the sulfonamide group. Computational procedures were used to investigate the binding mode of this class of compounds, within the active site of CAII. This study suggests that the salicylaldoxime moiety binds the zinc ion through the oxime oxygen atom that also forms an H-bond with T199. The results herein obtained will allow the development of new CA-inhibitors bearing the salicylaldoxime moiety.

Carbonic Anhydrase Inhibitors Developed Through ‘Click Tailing’

In recent years there has been renewed activity in the literature concerning the 1,3-dipolar cycloaddition reaction (1,3-DCR) of organic azides (R-N₃) with alkynes (R'-C≡CH) to form 1,2,3-triazoles, i.e. the Huisgen synthesis. The use of catalytic Cu(I) leads to a dramatic rate enhancement (up to 10(7)-fold) and exclusive synthesis of the 1,4-disubstituted 1,2,3-triazole product. The reaction, now referred to as the copper-catalyzed azide-alkyne cycloaddition (CuAAC), meets the stringent criteria of a click-reaction in that it is modular, wide in scope, high yielding, has no byproducts, operates in water at ambient temperature, product purification is simple and the starting materials are readily available. The 1,3-DCR reaction has rapidly become the premier click chemistry reaction with applications spanning modern chemistry disciplines, including medicinal chemistry. Recently the 'tail' approach initiative for the development of carbonic anhydrase inhibitors (CAIs) has been combined with the synthetic versatility of click chemistry. This has proven a powerful combination leading to the synthesis of CAIs with useful biopharmaceutical properties and activities. This review will discuss complementary and contrasting applications that have utilized 'click tailing' for the development of CAIs. Applications encompass i) medicinal chemistry and drug discovery; ii) radiopharmaceutical development of positron emission topography (PET) chemical probes; and iii) in situ click chemistry.

Carbonic anhydrase: chemistry, physiology, and inhibition.

Carbonic anhydrase: chemistry, physiology, and inhibition.