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Macular holes (MH) are full-thickness retinal defects affecting central vision. While vitrectomy with inner limiting membrane (ILM) peel is the conventional MH treatment, non-surgical alternatives are gaining interest to mitigate surgical risks. This study conducted a comprehensive literature review and analysis of nonsurgical MH management. A systematic literature search was conducted on PubMed, Embase, Scopus, and the Cochrane Library from January 1, 1973, to September 13, 2023. Treatments included laser therapy, carbonic anhydrase inhibitors (CAIs), nonsteroidal antiinflammatory drugs (NSAIDs), steroids (topical, subtenons, peribulbar, intravitreal), intravitreal gas, anti-vascular endothelial growth factors and ocriplasmin injections. Data extraction covered study details, patient characteristics, MH features, treatment outcomes, and recurrence rates. The initial search yielded 3352 articles, refined to 83 articles that met inclusion criteria following screening. Overall reported anatomical closure rates were 36% with laser photocoagulation, 37% with intravitreal ocriplasmin, 55% with intravitreal gas. Closures were more frequently observed with topical NSAIDs (79%), steroids (84%) and CAIs (73%). Closures were more often observed in patients with smaller MH and in the presence of cystic macular oedema. Although non-surgical MH management approaches show potential for conservative therapy, evidence is limited to support routine use. Stage 1 and traumatic MH may benefit from a short period of observation, but the gold standard approach for full-thickness MH remains to be vitrectomy with ILM peel. • Idiopathic macular holes are thought to develop due to vitreomacular traction and retinal hydration. • Macular holes have conventionally required surgical intervention but closures using topical anti-inflammatories, carbonic anhydrase inhibitors, steroids, ocular injections as laser therapy have been reported. • There is lack of evidence to support the use of non-surgical therapy in the management of macular holes. • Development of conservative treatment options may allow patients to avoid the risk profiles associated with surgery. [ABSTRACT FROM AUTHOR]

Guidelines for management of sleep disorders from national or regional societies provide recommendations that may be regionally appropriate but may not always be practical or relevant in other parts of the world. A task force of experts from the World Sleep Society's (WSS) International Sleep Medicine Guidelines Committee and Sleep and Breathing Disorders Task Force reviewed the European Respiratory Society's guideline on non-CPAP therapies for obstructive sleep apnea (OSA) with respect to its relevance and applicability to the practice of sleep medicine by sleep specialists in various regions of the world. The task force and the WSS guidelines committee endorsed the European Respiratory Society's guideline with respect to the utilization of bariatric surgery, mandibular advancement devices, positioning devices, myofunctional therapy, hypoglossal neurostimulation, maxilo-mandibular surgery, and carbonic anhydrase inhibitors for the treatment of OSA. The task force and the WSS guidelines committee noted that there is substantial new evidence for the role of soft tissue, upper airway surgery, not included in the guidelines paper. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is among the most common disabling diseases associated with chronic inflammation. The efficacy of the current therapeutic strategies is limited; therefore, new pharmacological agents and formulation approaches are urgently needed. In this work, we developed a thermosensitive gel incorporating escinosomes, innovative nanovesicles made of escin, stabilized with 10% of tween 20 and loaded with a Carbonic Anhydrase Inhibitor (CAI) bearing a Carbon Monoxide Releasing Moiety (CORM) (i.e. , CAI-CORM 1), previously synthesized by some of the authors as a new potent pain-relieving agent. The light scattering analysis of the developed formulation showed optimal physical parameters, while the chromatographic analysis allowed the quantification of the encapsulation efficiency (90.1 ± 5.91 and 91.6 ± 8.46 for CAI-CORM 1 and escin, respectively). The thermosensitive gel, formulated using 23% w / v of poloxamer 407, had a sol-gel transition time of 40 s and good syringeability. Its stability in simulated synovial fluid (SSF) was morphologically evaluated by electron microscopy. Nanovesicles were physically stable in contact with the medium for two weeks, maintaining their original dimensions and spherical shape. The viscosity increased by about 30- to 100-fold with the temperature change from 25 °C to 37 °C. The gel erosion in SSF occurred within 9 h (88.2 ± 0.743%), and the drug's passive diffusion from escinosomes lasted 72 h, allowing a potential sustained therapeutic effect. The efficacy of a single intra-articular injection of the gel containing escinosomes loaded with CAI-CORM 1 (3 mg/mL; 30 μL, CAI-CORM 1 formulation) and the gel containing unloaded escinosomes (30 μL, blank formulation) was evaluated in a rat model of Complete Freund's Adjuvant (CFA)–induced rheumatoid arthritis. CAI-CORM 1 formulation was assessed to counteract mechanical hyperalgesia, spontaneous pain, and motor impairments on days 7 and 14 after treatment. The histological evaluation of the joints stressed the improvement of several morphological parameters in CFA + CAI-CORM 1 formulation-treated rats. In conclusion, the hybrid molecule CAI-CORM 1 formulated in escinosome-based thermosensitive gel could represent a new valid approach for managing rheumatoid arthritis. [Display omitted] [ABSTRACT FROM AUTHOR]

Amyloid fibrils are protein aggregates formed by protein assembly through cross β structures. Inhibition of amyloid fibril formation may contribute to therapy against amyloid-related disorders like Parkinson's, Alzheimer's, and type 2 diabetes. Here we report that several fluorinated sulfonamide compounds, previously shown to inhibit human carbonic anhydrase, also inhibit the fibrillation of different proteins. Using a range of spectroscopic, microscopic and chromatographic techniques, we found that the two fluorinated sulfonamide compounds completely inhibit insulin fibrillation over a period of 16 h and moderately suppress α-synuclein and Aβ fibrillation. In addition, these compounds decreased cell toxicity of insulin incubated under fibrillation-inducing conditions. We ascribe these effects to their ability to maintain insulin in the native monomeric state. Molecular dynamic simulations suggest that these compounds inhibit insulin self-association by interacting with residues at the dimer interface. This highlights the general anti-aggregative properties of aromatic sulfonamides and suggests that sulfonamide compounds which inhibit carbonic anhydrase activity may have potential as therapeutic agents against amyloid-related disorders. [ABSTRACT FROM AUTHOR]

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 (K i = 331 nM) and XII (K i = 96.7 nM). In addition, 9a-g also exhibited some inhibitory activities against hCA IX and XII, with K i s ranging from 574–799 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. [Display omitted] • Designed and synthesized 24 new 1,3,5-trisubstituted pyrazoline derivatives based on tail approach strategy • Compounds 8 and 9a - g exhibited good hCA inhibition towards the hCA IX and XII isoforms. • Compounds 8 and 9a - g showed selectivity towards hCA IX and XII compared to hCA I and II isoforms. • Compound 8 maintained stable interactions in the catalytic site of hCA IX and XII isoforms throughout 100 ns. • During ADMET predictions, the lead 8 obeyed the Lipinski rule of five and was found to be druggable and non-toxic. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel twenty benzenesulfonamide-aroylhydrazone conjugates have been synthesized. • Potent inhibition of isozymes hCAI, II, IX, and XII has been demonstrated. • Compounds 9 and 19 exhibit high cytotoxicity and selectivity against MCF-7 cell line. • Activation of MAPK/ERK pathway is involved in cell cycle arrest. • Activation of MAPK/ERK pathway is involved in apoptosis induction. 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 K I 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 (IC 50 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. [ABSTRACT FROM AUTHOR]

[Display omitted] • Carbonic anhydrases (CAs) represent one of the promising drug targets and highly explored recently for drug development. • X-ray crystal structures reveal structural properties that could aid in the rationale design of novel CAs inhibitors. • Medicinal perspective of CA inhibitors (CAIs) developed recently have been discussed. • Structure-activity relationships, pharmacological activities, and in silico docking studies have been discussed. • The article helps researchers for the design and development of novel CAIs as promising therapeutic agents for the treatment of human ailments. In the realm of enzymology, Carbonic anhydrase (CA) emerges as a pivotal protagonist orchestrating the rapid conversion of carbon dioxide and water into bicarbonate ions and hydrogen ions, respectively. Carbonic anhydrase inhibitors (CAIs) are the class of drugs that target various isoforms of the enzyme, and these inhibitors play a crucial role in the treatment and management of multiple diseases such as cancer, glaucoma, high altitude sickness, rheumatoid arthritis, obesity, epilepsy, and sleep apnea. Several structural classes of CAIs developed till date possess unique architects of the pharmacophoric requirements around the central core moiety for the selective targeting of various isoforms of the CA. Recent advancements in drug design and development, along with technologies that aid in structure determination, have led to the development of several isoform-selective inhibitors of CA enzymes. However, their clinical development was hampered by the lack of desired therapeutic efficacy, isoform selectivity and safety profile. This review covers the most recent approaches used by different researchers concerned with the development of isoform-selective carbonic anhydrase inhibitors belonging to distinct structural classes like sulphonamides, carbazoles, selenols, coumarin, organotelluride, topiramate, thiophene, triazole, uracil-modified benzylic amines, and thiourea etc. In addition, their structure–activity relationships, biological evaluation, and in silico studies inlcuding the forthcoming avenues of advancements have been discussed. This review serves as a valuable resource for developing potent and efficacious CAIs with remarkable therapeutic implications; offering insights into their potency, specificity, and potential clinical applications. [ABSTRACT FROM AUTHOR]

In today's medical field, there is a growing trend of exploiting a single small molecule to target two different molecular targets concurrently. This approach is proving to be highly effective in fighting against cancer. The 4-anilinoquinazoline scaffold, known for its potential in cancer therapy and its effectiveness as a leading class of tyrosine kinase inhibitors, was employed to develop a novel series of anilinoquinazoline-sulfonamides (AQSs) (8a-d , 9a-f, and 10a-d) as dual inhibitors of the tumor-associated carbonic anhydrases (CA) IX/XII and EGFR. 2-(3-Methoxyphenyl)quinazoline bearing p -sulfanilamide 10b elicited superior hCA IX and XII inhibition in the low nanomolar range (K I s = 38.4 and 8.9 nM, respectively). Also, 10b shined as a potent and selective EGFR inhibitor, boasting an impressive IC 50 value of 51.2 ± 0.97 nM, surpassing the reference EGFR inhibitor Erlotinib (IC 50 = 80 ± 2.0 nM). Compound 10b exhibited broadest-spectrum antiproliferative activity against the NCI-tumor panel with a mean GI% value of 68 %. Of special interest, 10b demonstrated potent growth inhibition (GI% ≥ 80–97 %) toward cell lines reported to express high levels of EGFR belonging to renal, colon, breast, and lung cancers. Compound 10b 's molecular docking in the CA IX/XII and EGFR active sites revealed binding modes that justify its potent enzyme inhibitory effects. Additionally, molecular dynamic simulations demonstrated strong and stable interactions of 10b with the binding sites of these targets. [Display omitted] • A new series of sulfonamide-tethered 2-aryl-4-anilinoquinazolines was developed. • Inhibitory activities of all derivatives were evaluated toward hCA I, II, IX and XII isoforms. • The anticancer activity was explored against a panel of 57 cancer cell lines at the NCI-USA. • The most potent anticancer molecules were evaluated for EGFR inhibitory activity. • 10b was tested against a panel of 40 kinases to assess the selectivity of target quinazolines. [ABSTRACT FROM AUTHOR]

In the search of new cymantrenyl- and ferrocenyl-sulfonamides as potencial inhibitors of human carbonic anhydrases (hCAs), four compounds based on N -ethyl or N -methyl benzenesulfonamide units have been obtained. These cymantrenyl (1a-b) and ferrocenyl (2a - b) derivatives were prepared by the reaction between aminobenzene sulfonamides ([NH 2 -(CH 2) n -(C 6 H 4)-SO 2 -NH 2)], where n = 1, 2) with cymantrenyl sulfonyl chloride (P1) or ferrocenyl sulfonyl chloride (P2), respectively. All compounds were characterized by conventional spectroscopic techniques and cyclic voltammetry. In the solid state, the molecular structures of compounds 1a , 1b , and 2b were determined by single-crystal X–ray diffraction. Biological evaluation as carbonic anhydrases inhibitors were carried out and showed derivatives 1b y 2b present a higher inhibition than the drug control for the Human Carbonic Anhydrase (hCA) II and IX isoforms (K I = 7.3 nM and 5.8 nM, respectively) and behave as selective inhibition for hCA II isoform. Finally, the docking studies confirmed they share the same binding site and interactions as the known inhibitors acetazolamide (AAZ) and agree with biological studies. New cymantrenyl- and ferrocenyl-sulfonamides based on N -ethyl or N -methyl benzenesulfonamide units have been obtained. All compounds were characterized by conventional spectroscopic techniques, cyclic voltammetry, and single-crystal X–ray diffraction. All compounds were evaluated as carbonic anhydrase inhibitors agents, and the docking studies were agreed with biological studies. [Display omitted] • New organometallic-sulfonamides with benzenesulfonamides units have been obtained. • All complexes were full characterized, included single-crystal X–ray diffraction. • Redox behavior of the complexes was studied by cyclic voltammetry. • Biological assays as carbonic anhydrase inhibitors agents were carried out. • The docking studies were carried out and these agreed with biological studies. [ABSTRACT FROM AUTHOR]

• Synthesis and characterization of a novel 1,2,4-triazole-maleamic acid. • Biological evaluation as anticancer agents and carbonic anhydrase inhibitors. • Compounds TM-3, TM-4 , and TM-14 exhibited remarkable antiproliferative activity. • Computational studies, including MM-GBSA, molecular docking, and ADME/T analysis. Hybrid compounds with 1,2,4-triazole ring and a hydrazone moiety were designed and synthesized by amine acylation of uncommon triaminogunidine derivatives using maleic anhydride. Synthesized compounds were characterized by various spectral techniques, including FTIR, 1H NMR, 13C NMR, and HRMS. Furthermore, the proposed structure of TM-2 was resolved by single-crystal X-ray analysis. The compounds were evaluated for their anticancer activity in vitro against the colon cancer cell line HCT116 and the ovarian cancer cell line A2780. Among them, some compounds, TM-3, TM-4, and TM-14, exhibited remarkable antiproliferative activity in the cell line A2780, with IC 50 values of 6.11, 5.15, and 5.93 µM, respectively. Further investigation revealed that these compounds could inhibit cancerous cell growth by inducing an increase in caspase-3 activity. In addition, antioxidant capabilities, interaction with plasmid pBR322 DNA, and inhibitory effects against two physiologically and pharmacologically relevant human carbonic anhydrase (hCA) isoforms, namely hCA I and hCA II, of the synthesized compounds were also assessed. Finally, computational studies, such as DFT calculation, molecular docking, and in silico predictions of ADME/T analysis, were conducted to gain an understanding of the specific reactive sites of the compounds, the binding modes in the active sites, and the pharmacokinetic parameters of the newly synthesized hybrid compounds, which were calculated to establish their drug-likeness properties. [Display omitted] [ABSTRACT FROM AUTHOR]

Attachment of a conjugate assembled from a novel fluorinated carbonic anhydrase inhibitor and rhodamine B onto dehydroabietylamine (DHA) or cyclododecylamine led to first-in-class conjugates of good cytotoxicity; thereby IC 50 values (from SRB assays; employed tumor cell lines A2780, A2780Cis, A549, HT29, MCF7, and non-malignant human fibroblasts CCD18Co) between 0.2 and 0.7 μM were found. Both conjugates showed similar cytotoxic activity but the dehydroabietylamine derived conjugate outperformed its cyclododecyl analog in terms of tumor cell/non-tumor cell selectivity. Both conjugates accumulate intracellular, and the DHA conjugate was able to overcome drug resistance which is effective independent of the expression status of carbonic anhydrase IX. [Display omitted] • Dehydroabietylamine was converted into a sulfonamide/rhodamine B conjugate. • This conjugate was tested for cytotoxic activity with a panel of human cancer cells. • This conjugate as well as a cyclododecyl analog held IC 50 < 1 μM. • Both conjugates were able to overcome drug resistance and accumulated intracellular. [ABSTRACT FROM AUTHOR]

[Display omitted] Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT. [ABSTRACT FROM AUTHOR]

• Synthesis and crystal structure of a novel cerium (III) based MOF with 1,10-phenanthroline and fumaric acid (I): [Ce 2 (phen) 2 (fum) 3 (H 2 O) 2 ] n. • A pseudo 3D network is achieved through π-π interactions along c axis, between parallel and opposed 1.10-phenanthroline ligands. • HS analysis indicated that the O···H, C···H, H···H and π⋯π stacking interactions are responsible for the establishment of the supramolecular assembly of the crystal packing. • A promising interactions between (I) and CA IX are revealed, suggesting its potential as a CA IX inhibitor. • The assessment of drug-likeness properties and ADMET characteristics further supports the viability of (I) as a therapeutic candidate. In this study, a novel Cerium-based MOFs with 1,10-phenanthroline (phen) and fumaric acid (H 2 fum) has been hydrothermally synthesized as single crystal structurally characterized by X-ray diffraction, IR spectroscopy and ATG measurements. This compound corresponds to the formula: [Ce 2 (phen) 2 (fum) 3 (H 2 O) 2 ] n (I) , it crystallizes in the triclinic system with space group P 1 ¯ , with the following parameters: a = 9.062(1) Å, b = 10.0608(5) Å, c = 10.603(1) Å, α = 72.545(6) °, β = 77.57(1) °, γ = 69.959(6) °, V = 859.49(14) Å3, Z = 2. The structure revealed 2D bridged polymeric chains where the adjacent Ce(III) atoms are bridged by fumarate linkers with a mean intermetallic distance of about 9.36 Å. H···O bonds link the 2D sheets leading to a pseudo 3D network, while the stability of the structure is assured by a weak π-π stacking between parallel and opposed phen ligands. The Ce3+ cation is nona-coordinated and it is in a distorted tricapped trigonal prism geometry. Hirshfeld surface analysis was used to investigate the non-covalent intermolecular interactions and the dominant H···O, H···C and H···H contacts were quantified. The thermal properties of the considered coordination polymer (I) are also discussed and disclose that (I) is stable up to 300 °C. Besides, this study explores the potential of (I) as an inhibitor of the carbonic anhydrase IX enzyme (CA IX), a critical player in tumor microenvironment regulation. Through molecular docking simulations, we elucidate the binding interactions between (I) and CA IX, the results suggest the efficiency of (I) as a CA IX inhibitor. Moreover, we assessed the drug-likeness properties and ADMET characteristics of (I) , providing valuable insights for its potential as a therapeutic agent. [ABSTRACT FROM AUTHOR]

Chemodynamic therapy (CDT) has aroused extensive attention as a potent therapeutic modality. However, its practical application is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within metastatic breast cancer. Herein, a copper-based single-site nanocatalyst functionalized with carbonic anhydrase inhibitor (CAI) was constructed for magnetic resonance/photoacoustic imaging (MRI/PA)-guided synergetic photothermal therapy (PTT) and CDT. Once reaching tumor sites, the nanocatalyst can be recognized by tumor cell membranes-overexpressed carbonic anhydrase IX (CA IX). Subsequently, the single-site CuII can be reduced to CuI by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant defense system and triggered CAI release for inducing intracellular H+ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more CuII and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thereby continuously supplying CuI and H+ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst can generate local heat, which not only permits PTT but also enhances the nanocatalyst-mediated CDT. Moreover, the suppression of CA IX can hinder the tumor extracellular matrix degradation to prevent tumor metastasis. Overall, this work highlighted the great application prospect in enhancing CDT via tumor acidic/redox microenvironment remodeling, and provides an insightful paradigm for inhibiting breast cancer metastasis. The practical application of chemodynamic therapy (CDT) is severely restricted by the strong acidity requirement for Fenton reaction and upregulated antioxidant defense within cancer. Herein, we developed a carbonic anhydrase inhibitor (CAI)-functionalized Cu-based nanocatalyst. Once reaching tumor sites, the CuII can be reduced to CuI by the tumor-overexpressed glutathione (GSH), which simultaneously impaired the tumor antioxidant system and triggered CAI release for inducing intracellular H+ accumulation. Further, the decreased intracellular pH can accelerate the nanocatalyst biodegradation to release more CuII and CAI to participate in next-cycle GSH-depletion and cytoplasm acidification, respectively, thus continuously supplying CuI and H+ for self-cyclically amplified CDT. Upon laser irradiation, the nanocatalyst not only permits PTT but also enhances the CDT. [Display omitted] [ABSTRACT FROM AUTHOR]

• Glucoimines incorporating classical and non-classical CA pharmacophores are described. • Conformational behavior of glucoimines has been studied in solution and the crystalline form. • Two potent inhibitors of tumor-associated carbonic anhydrases are found. • Docking simulations were used to understand binding modes in the active site. In this report, a series of glucoimines has been prepared by reaction of d-glucosamine and aromatic aldehydes incorporating classical and non-classical carbonic anhydrase pharmacophores. The conformational behavior of veratrole glucoimine was studied in solution and in crystalline form, by NMR and X-ray diffraction analysis, which revealed that pyranose ring adopted a 4 C 1 conformation. All glucoimines were tested against four isozymes of carbonic anhydrase: hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (tumor-associated isozymes). In this study, per-O-acetylated and deprotected sulfonamide were identified as potent inhibitors of tumor-associated carbonic anhydrase isoforms. Molecular docking simulation was performed inside the active site of hCA II to evaluate the binding modes of veratrole and sulfonamide glucoimines. The last ones demonstrated the most favorable docking scores, indicating strong binding affinity towards hCAII in correlation with experimental inhibition activities. Interestingly, interaction analyses revealed distinct binding modes for ligand-hCAII complexes primarily due to the sulfonamide group. [Display omitted] [ABSTRACT FROM AUTHOR]

• A library of pyrazole-carboxylic acid derivatives were synthesized and fully characterized by spectral and analytical techniques. • Inhibition effects of the synthesized molecules against AChE and hCAs enzymes were investigated. • Novel molecules (5–27) were found as effective inhibitor molecules for the AChE, hCA I and hCA II enzymes. • In silico molecular docking computations were performed using autodock vina tool. • Most active compounds, 21 and 23 potently inhibit hCA I (PDB: 2CAB), hCA II (PDB: 5AML), and AChE (PDB: 1EVE) proteins. In this study, a library of novel alkyl arylamide, anhydride, diester, dinitrile and diketone derivatives of pyrazole-dicarboxylic acid were synthesized. The chemical structures of the compounds were elucidated by FT-IR, 1H NMR, 13C NMR and elemental analysis. These obtained pyrazole derivatives were evaluated to be highly potent inhibitors for acetylcholinesterase (AChE) and carbonic anhydrases (hCAs). Synthesized novel compounds (5–27) were found to be effective inhibitor molecules for the AChE, hCA I and hCA II enzymes. K i values in the range of 7.76–53.78 nM for AChE, 11.27–50.31 nM for hCA I and 9.97–36.22 nM for hCA II. According to the docking results, it was seen that the molecules which we examined were able to inhibit the relevant targets quite successfully. Furthermore, it was found that the in silico estimated K i values were very compatible with the experimental data. In the last section, the compounds' (for ligands 21 and 23) ADME characteristics were examined. [Display omitted] [ABSTRACT FROM AUTHOR]

Glaucoma, a leading cause of irreversible blindness, affects about 70 million people globally. Its treatment focuses on reducing intraocular pressure. Acetazolamide, a potent anti-glaucoma drug, is currently used only systemically due to low solubility and permeation, which cause severe side effects. Developing topical medications with acetazolamide requires robust analytical methods for its detection in biological samples. In this context, this study aimed to develop a method to quantify acetazolamide in rabbit vitreous humor samples. The method involved a simple, fast, inexpensive, and environmentally friendly protein precipitation step for sample preparation, needing just 50 μL of sample and 200 μL of organic solvent, with adequate recovery. This was combined with high-performance liquid chromatography coupled to tandem mass spectrometry, enabling highly sensitive (LOQ of 5 ng/mL) quantification within only 5 min. The method proved to be selective, precise, and accurate, with well-fitted analytical curves, with no carryover, and no matrix effect impacting reliability. The method was successfully applied to analyze vitreous humor samples from rabbits in pharmacokinetic studies, monitoring drug release from intravitreal implants. Results showed a controlled release profile, with a maximum drug concentration (Cmax) of 426.01 ± 64.57 ng/mL, time to reach Cmax (Tmax) of 28 days, and area under the curve (AUC0–42 and AUC0-∞) of 7722.66 ± 1125.96 ng days/mL and 8998.11 ± 1311.92 ng days/mL, respectively. The device demonstrated significantly slower elimination, ensuring therapeutic levels for an extended period when compared to intravitreal injection. [Display omitted] • A LC-MS/MS method for acetazolamide quantification in vitreous humor was developed. • A green, simple and fast sample preparation method was employed. • Experimental design was used in chromatographic and sample preparation development. • Ocular pharmacokinetics of the drug released from intravitreal implants was obtained. • Intravitreal implants ensured therapeutic levels of acetazolamide for extended period. [ABSTRACT FROM AUTHOR]

Herein, we describe the design and synthesis of novel aryl pyrimidine benzenesulfonamides APBSs 5a-n , 6a-c , 7a-b , and 8 as pazopanib analogues to explore new potent and selective inhibitors for the CA IX. All APBSs were examined in vitro for their promising inhibition activity against a small panel of hCAs (isoforms I, II, IX, and XII). The X-ray crystal structure of CA I in adduct with a representative APBS analogue was solved. APBS - 5m , endowed with the best hCA IX inhibitory efficacy and selectivity, was evaluated for antiproliferative activity against a small panel of different cancer cell lines, SK-MEL-173, MDA-MB-231, A549, HCT-116, and HeLa, and it demonstrated one-digit IC 50 values range from 2.93 μM (MDA-MB-231) to 5.86 μM (A549). Furthermore, compound APBS - 5m was evaluated for its influence on hypoxia-inducible factor (HIF-1α) production, apoptosis induction, and colony formation in MDA-MB-231 cancer cells. The in vivo efficacy of APBS - 5m as an antitumor agent was additionally investigated in an animal model of Solid Ehrlich Carcinoma (SEC). In order to offer perceptions into the conveyed hCA IX inhibitory efficacy and selectivity in silico , a molecular docking investigation was also carried out. [Display omitted] • Aryl pyrimidine benzene sulfonamides (APBSs) were synthesized and characterized. • APBS - 5m showed top inhibitory activity towards CA IX (K I = 2.7 nM). • The anticancer activity of APBS - 5m was superior against MDA-MB-231 cancer cells. • APBS - 5m displayed potent proapoptotic activity on hypoxia sensitized MDA-MB-231. • X-ray crystal structure of CA I- APBS - 5b adduct was solved (PDB code: 8QUN). [ABSTRACT FROM AUTHOR]

Tumor imaging and fluorescence-guided surgical resection offers a promising therapeutic approach for the treatment of cancer with simple operation. Hypoxia, as a crucial feature in solid tumor, is closely related to the design of hypoxia-activated fluorescent probes to distinguish tumor and normal tissue. In present, many hypoxia-activated fluorescent probes have received widespread attention in various imaging applications. However, as far as we know, hypoxia-activated near-infrared fluorescent probe for tumor fluorescence-guided surgical resection is not currently reported. Therefore, a hypoxia-activated near-infrared fluorescent probes Fu-Cy was synthesized. It was able to produce near-infrared fluorescence (780 nm) in specific response to overexpressed nitroreductase in hypoxic tumors with rapid response. However, the uptake of the probe in the cell will affect the imaging ability of the probe. Therefore, acetazolamide (AZ), a well-known inhibitor of carbonic anhydrase IX (CAIX) , was coupled to Fu-Cy by clicking reaction to obtain the improved probe Az-Fu-Cy , which is more absorbed by cancer cells than Fu-Cy. Thus, Az-Fu-Cy can effectively distinguish between tumors and normal organs by spraying. Interestingly, it showed accurate guidance during surgical resection. [Display omitted] • The first hypoxic-activated NIR probe for fluorescence guided surgical resection was reported. • The cell uptake of probe in MDA-MB-231 cell was promoted by inhibiting CAIX. • The probe is good at distinguishing between normal tissue and tumors. [ABSTRACT FROM AUTHOR]

Carbonic anhydrase IX (CAIX) is a hypoxia-associated transmembrane protein that is critical in the survival of cells. Because CAIX has a key role in pH regulation, its therapeutic effects have been heavily studied by different research laboratories. This study aims to investigate how a synthetic CAIX inhibitor triggers apoptosis in a cancer cell line, HeLa. In this regard, we investigated the effects of the compound I , synthesized as a CAIX inhibitor, on the survival of cancer cells. The compound I inhibited the proliferation of the CAIX+ HeLa cells, kept the cells in G0/G1 phase (74.7%) and altered the cells morphologies (AO/EtBr staining) and the nuclear structure (γ-H2AX staining). CAIX inhibition triggered apoptosis in HeLa cells with a rate of 47.4%. According to the expression of mediator genes (CASP-3, -8, -9, BAX, BCL-2, BECLIN, LC3), the both death pathways were activated in HeLa cells with the inhibition of CAIX with the compound I. The compound I was also determined to affect the genes and proteins that have a critical role in the regulation of apoptotic pathways (pro casp-3, cleaved casp-3, -8, -9, cleaved PARP and CAIX). Furthermore, CAIX inhibition caused changes in pH balance, disruption in organelle integrity of mitochondria, and increase intracellular reactive oxygen level of HeLa cells. Taken together, our findings suggest that CAIX inhibition has a potential in cancer treatment, and the compound I , a CAIX inhibitor, could be a promising therapeutic strategy in the treatment of aggressive tumours. [ABSTRACT FROM AUTHOR]

Mucoadhesive formulations capable of situ gelation are promising for improving ocular drug delivery. Here we investigated two types of nanogels based on anionic glycosaminoglycans with grafted thermo-responsive poly(N-isopropylacrylamide) chains. One type of nanogels were formed by thermo-induced gelling of heparin- graft -poly(N-isopropylacrylamide) and chondroitin sulfate- graft -poly(N-isopropylacrylamide) copolymers. Another type of nanogels was based on the same copolymers, but terminal groups of thermosensitive macromolecular chains were modified to form covalent disulfide cross-links. All types of nanogels were studied towards their ability to encapsulate and release model drug – dexamethasone. Mucoadhesivity of both thermo-gelled and covalently cross-linked polymeric systems, as well as their ability to interact with dexamethasone, was assessed by microscale thermophoresis (MST). Mucoadhesion properties were also evaluated by isothermal titration calorimetry (ITC), which were in good correlation with MST data. The presence of disulfide linkages and thiol groups were shown to favor improved binding of cross-linked nanogels to mucin. Moreover, in vivo intraocular pressure studies showed that presence of polymers in solution can alter the ocular absorption of carbonic anhydrase inhibitor from eyedrops. The pharmacological effect was in line with mucoadhesive properties of these copolymers. [Display omitted] • Mucoadhesive thermosensitive nanogels based on glycosaminoglycans were prepared. • Microscale thermophoresis was used to evaluate mucoadhesivity of nanogels. • Nanogels allowed prolonged release of dexamethasone. • The biosafety of polymeric systems was proven with application of rats. • Nanogels helped to prolong action of carbonic anhydrase inhibitor on intraocular pressure. [ABSTRACT FROM AUTHOR]

• Adulteration of diuretics in dietary supplements for weight-loss is increasing. • Using UHPLC-Q-Orbitrap (LC-HRMS), simultaneous analysis of diuretics is available. • The fragmentation pathways of diuretics were proposed using UHPLC-Q-Orbitrap (LC-HRMS). Diuretics are used to treat the edematous state in cases of renal insufficiency, nephrotic syndrome, liver cirrhosis, and heart failure. These compounds are used by athletes to lose weight and are included in the list of prohibited substances by the World Anti-Doping Agency. They are also used by obese and overweight people for losing weight, and there are a number of recent reports on the contamination of dietary supplements with diuretics. Due to the alluring online marketing and blogging, there is an extensive misuse of products that are illegally adulterated with diuretics, which has seriously increased health risks. Therefore, it is essential to develop an analytical method for the detection of adulterants in such substances. In this study, 23 diuretics, categorized into four groups, namely, thiazide diuretics (e.g., bendroflumethiazide), loop diuretics (e.g., bumetanide), potassium-sparing diuretics (e.g., amiloride), and carbonic anhydrase inhibitors (e.g., acetazolamide), were analyzed using ultrahigh-performance liquid chromatography-quadrupole orbitrap (UHPLC-Q-Orbitrap). Their fragmentation was elucidated based on the MS/MS data. The 124 products were screened by the UHPLC-Q-Orbitrap (LC-HRMS) method, and the confirmed compounds were quantitated by a previously established LC-MS/MS method. Approximately 5% of the samples were found to be illegally contaminated with diuretics at a concentration of 0.051–162 mg/g. The high selectivity and sensitivity of the UHPLC-Q-Orbitrap (LC-HRMS) method, in combination with the established fragmentation, offer a new approach for the rapid and accurate screening of diuretics in adulterated products, which would be ultimately beneficial for the public health. [ABSTRACT FROM AUTHOR]

The coumarin is one of the most promising classes of non-classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. In continuation of our ongoing work on search of coumarin based selective carbonic anhydrase inhibitors, a new series of 6-aminocoumarin based 16 novel analogues of coumarin incorporating thiazole (4a-p) have been synthesized and studied for their hCA inhibitory activity against a panel of human carbonic anhydrases (hCAs). Most of these newly synthesized compounds exhibited interesting inhibition constants in the nanomolar range. Among the tested compounds, the compounds 4f having 4-methoxy substitution exhibited activity at 90.9 nM against hCA XII isoform. It is noteworthy to see that all compounds were specifically and selectively active against isoforms hCA IX and hCA XII, with K i under 1000 nM range. It is anticipated that these newly synthesized coumarin-thiazole hybrids (4a-p) may emerge as potential leads candidates against hCA IX and hCA XII as selective inhibitors compared to hCA I and hCA II. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Triterpenoic acids benzylamides were synthesized and sulfamoylated. • These compounds were tested as inhibitors of carbonic anhydrases (CA) I, II, VA and IX. • An Asiatic acid derived trisulfamate held strong inhibitory effects for CA VA. • This compound showed a K i = 36.2 nM thus outperforming standard acetalzolamide. This investigation delves into the inhibitory capabilities of a specific set of triterpenoic acids on diverse isoforms of human carbonic anhydrase (h CA). Oleanolic acid (1), maslinic acid (2), betulinic acid (3), platanic acid (4), and asiatic acid (5) were chosen as representative triterpenoids for evaluation. The synthesis involved acetylation of parent triterpenoic acids 1 – 5 , followed by sequential reactions with oxalyl chloride and benzylamine, de-acetylation of the amides, and subsequent treatment with sodium hydride and sulfamoyl chloride, leading to the formation of final compounds 21 – 25. Inhibition assays against h CAs I, II, VA, and IX demonstrated noteworthy outcomes. A derivative of betulinic acid, compound 23 , exhibited a K i value of 88.1 nM for h CA VA, and a derivative of asiatic acid, compound 25 , displayed an even lower K i value of 36.2 nM for the same isoform. Notably, the latter compound displayed enhanced inhibitory activity against h CA VA when compared to the benchmark compound acetazolamide (AAZ), which had a K i value of 63.0 nM. Thus, this compound surpasses the inhibitory potency and isoform selectivity of the standard compound acetazolamide (AAZ). In conclusion, the research offers insights into the inhibitory potential of selected triterpenoic acids across diverse h CA isoforms, emphasizing the pivotal role of structural attributes in determining isoform-specific inhibitory activity. The identification of compound 25 as a robust and selective h CA VA inhibitor prompts further exploration of its therapeutic applications. [ABSTRACT FROM AUTHOR]

In this study, twenty-nine coumarin-3-sulfonamide derivatives, twenty-seven of which are original were designed and synthesized. Cytotoxicity assay indicated that most of these derivatives exhibited moderated to good potency against A549 cells. Among them, compound 8q showed potent inhibition against the four tested cancer cell lines, especially A549 cells with IC 50 value of 6.01 ± 0.81 μM, and much lower cytotoxicity on the normal cells was observed compared to the reference compounds. Bioinformatics analysis revealed human carbonic anhydrase IX (CAIX) was highly expressed in lung adenocarcinoma (LUAD) and associated with poor prognosis. The inhibitory activity of compound 8q against CAIX was assessed by using molecular docking and molecular dynamics simulations, which revealed prominent interactions of both compound 8q and CAIX at the active site and their high affinity. The results of ELISA assays verified that compound 8q possessed strong inhibitory activity against CAIX and high subtype selectivity, and could also down-regulate the expression of CAIX in A549 cells. Furthermore, the significant inhibitory effects of compound 8q on the migration and invasion of A549 cells were also found. After treatment with compound 8q , intracellular reactive oxygen species (ROS) levels increased and mitochondrial membrane potential (MMP) decreased. Mechanistic investigation using western blotting revealed compound 8q exerted the anti-migrative and anti-invasive effects probably through mitochondria-mediated PI3K/AKT pathway by targeting CAIX. In summary, coumarin-3-sulfonamide derivatives were developed as potential and effective CAIX inhibitors, which were worthy of further investigation. • Twenty-nine coumarin-sulfonamide derivatives were designed and synthesized. • Compound 8q had potent anticancer activity against A549 cells with good safety. • Compound 8q exhibited strong inhibition against CAIX and high subtype selectivity. • Compound 8q could also down-regulate the expression of CAIX in A549 cells. • The mechanism of action of compound 8q by targeting CAIX was elucidated. [ABSTRACT FROM AUTHOR]

In this study, crystallographic, molecular geometry, surfaces (MEP, Hirshfeld and Frontiers Orbitals-HOMO and LUMO), molecular docking with carbonic anhydrase II-5AML protein, drug-likeness, ADME and vibrational assignment analyses of the molecule were studied in detail and the results were carefully analyzed. The theoretical studies were carried out in DFT/B3LYP/6–311++G(d,p) quantum chemical method and basis set with the Gaussian 09 W package program. Potential energy distributions (PED) were used in conjunction with the VEDA 4 tool to get the vibrational assignments of the title chemical with %10 precision. In solid phase, the FT-IR experimental spectrum was collected at 4000–400 cm−1. Due to the affinity and binding energy of the title molecule to protein active sites, the results showed that our molecule is a potent potential inhibitor of carbonic anhydrase II. [Display omitted] • Frequency analysis, optimized structures and electronic energy values of the title molecule were investigated. • The theoretical vibrational frequencies were analyzed with PED analysis. • Molecular docking study was conducted with Autodock Vina. • Drug-Likeness Properties and ADME analysis was researched. [ABSTRACT FROM AUTHOR]

• Synthesis, characterization, and x-ray analysis of new naphthoquinone thiazole hybrids were reported. • hCAs, AChE, and BChE enzyme inhibitory properties of the hybrids were reported. • Promising pharmacokinetic profiles were predicted. • Acid dissociation constants were determined. In this study, N -[3-(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-R-thiazol-2(3 H)-ylidene]-2,6-difluorobenzamide derivatives as new 1,4-naphthoquinone thiazole hybrids were synthesized by reacting of N -[(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)carbamothioyl]-2,6-difluorobenzamide with various α-bromoketones in 76–92% yields. Their molecular structures were characterized by 1H NMR, 13C NMR, 19F NMR, FT-IR, and HRMS, and the stereochemistry of one of the hybrids was determined by single crystal x-ray diffraction study. These synthesized new compounds (3a–e) were found to be effective inhibitor molecules for cholinesterases (butyrylcholinesterase (BChE) and acetylcholinesterase (AChE)), and carbonic anhydrase I and II (h CA I and h CA II) enzymes. K I values were found to be in the range of 45.03–84.43 nM for BChE, 26.12–98.42 nM for AChE, 67.86–161.60 nM for h CA I, and 55.27–87.48 nM for h CA II. The acid dissociation constants (p K a) of 1,4-naphthoquinone thiazole hybrids were determined in 25% (v/v) DMSO:water (25.0 ± 0.1 °C, I = 0.1 M by NaCl). Three p K a values for each hybrid were calculated with the HYPERQUAD program from the data obtained as a result of potentiometric titrations. The results obtained from molecular docking studies indicate that the compounds in question favorably fit within the active sites of h CAs and ChEs. Additionally, the acceptability of these compounds, as determined by Lipinski's and Jorgensen's rules, was estimated using the ADME/T results. Based on these estimations, it can be concluded that the synthesized molecules have the potential to be developed as effective and safe inhibitors of h CAs and ChEs, thus making them suitable lead agents for glaucoma and Alzheimer's disease. [Display omitted] [ABSTRACT FROM AUTHOR]

The present study evaluated the effects of heat stress on reproductive parameters of hairy rams. Six animals were subjected to scrotal insulation during four consecutive nights (6 PM – 6 AM). Day (D) 0 was the first day of insulation. Scrotal circumference increased from 30.5 ± 0.3 cm (at pre-insulation) to 31.8 ± 0.4 cm on D4, decreased 3.9 cm on D28, returning to 30.6 ± 0.6 cm on D57. Sperm concentration decreased from 3.7 ± 0.12 ×109 sperm/mL before insulation to 2.6 ± 0.1 ×109 on D23, returning to normal on D57. Sperm motility averaged 75 ± 2.9% before insulation, was undetectable on D23, and became normal on D77. Sperm with normal morphology reached 5.9 ± 2.6% on D35 but recovered (86.8 ± 2.1%) on D91. Sperm DNA integrity decreased from 86.5 ± 4.7% before insulation to 11.1 ± 3.7% on D63, returning to pre-insulation values on D120. Sperm BSP immunostaining was reduced after scrotal insulation. Variations in seminal protein abundances coincided with changes in sperm parameters. Seminal plasma superoxide dismutase, carboxypeptidase Q-precursor and NPC intracellular cholesterol transporter 2 decreased on D18, returning to normal after D28. Albumin, inhibitor of carbonic anhydrase precursor, EGF-like repeat and discoid I-like domain-containing protein 3 and polymeric immunoglobulin receptor increased after insulation. In summary, intermittent scrotal insulation drastically altered ram sperm attributes and seminal proteins, especially those associated with oxidative stress. Knowledge of animal´s response to thermal stress is vital in the scenario of climate changes. [Display omitted] • Heat stress reduced ram testis size, sperm concentration and motility. • Sperm DNA integrity and BSP binding and seminal proteins were critically altered. • Variations in seminal protein expressions coincided with changes in sperm criteria. • Altered seminal proteins were mainly those associated with oxidative stress. • Know animal response to heat stress is vital in the scenario of climate changes. [ABSTRACT FROM AUTHOR]

Diabetes mellitus, a progressive chronic disease, characterized by the abnormal carbohydrate metabolism is associated with severe health complications including long term dysfunction or failure of several organs, cardiovascular and micro-angiopathic problems (neuropathy, nephropathy, retinopathy). Despite the existence of diverse chemical structural libraries of α -glucosidase inhibitors, the limited diabetic treatment due to the adverse side effects such as abdominal distention, flatulence, diarrhoea, and liver damage associated with these inhibitors encourage the medicinal research community to design and develop new and potent inhibitors of α -glucosidase with better pharmacokinetic properties. In this perspective, we demonstrate the successful integration of common functional groups (ketone & ester) in one combined pharmacophore which is favorable for the formation of hydrogen bonds and other weaker interactions with the target proteins. These keto ester derivatives were screened for their α -glucosidase inhibition potential and the in vitro results revealed compound 3c as the highly active inhibitor with an IC 50 value of 12.4 ± 0.16 μM compared to acarbose (IC 50 = 942 ± 0.74 μM). This inhibition potency was ~76-fold higher than acarbose. Other potent compounds were 3f (IC 50 = 28.0 ± 0.28 μM), 3h (IC 50 = 33.9 ± 0.09 μM), 3g (IC 50 = 34.1 ± 0.04 μM), and 3d (IC 50 = 76.5 ± 2.0 μM). In addition, the emerging use of carbonic anhydrase inhibitors for the treatment of diabetic retinopathy (a leading cause of vision loss) prompted us to screen the keto ester derivatives for the inhibition of carbonic anhydrase-II. Compound 3b was found significantly active against carbonic anhydrase-II with an IC 50 of 16.5 ± 0.92 μM (acetazolamide; IC 50 = 18.2 ± 1.23 μM). Compound 3a also exhibited comparable potency with an IC 50 value of 18.9 ± 1.08 μM. Several structure-activity relationship analyses depicted the influence of the substitution pattern on both the aromatic rings. Molecular docking analysis revealed the formation of several H-bonding interactions through the ester carbonyl and the nitro oxygens of 3c with the side chains of His348, Arg212 and His279 in the active pocket of α -glucosidase whereas 3b interacted with His95, -OH of Thr197, Thr198 and WAT462 in the active site of carbonic anhydrase-II. Furthermore, evaluation of ADME properties suggests the safer pharmacological profile of the tested derivatives. The present study investigates the dual inhibitory potential of a series of keto ester derivatives against α -glucosidase and carbonic anhydrase-II enzymes. Unlabelled Image • New structural libraries of compounds were prepared to treat diabetes mellitus and diabetic retinopathy. • Keto esters 3a–m were investigated as potent inhibitors of α -glucosidase and carbonic anhydrase-II enzymes. • Compound 3c was identified as the most potent inhibitor of α -glucosidase enzyme. • Compound 3b inhibited the carbonic anhydrase-II with an IC 50 of 16.5 ± 0.92 μM. • Molecular docking, enzyme kinetics, and detailed ADMET properties were also investigated. [ABSTRACT FROM AUTHOR]

Brinzolamide is a topical carbonic anhydrase inhibitor which reduces the production of aqueous humor in the ciliary body, thereby reducing intra-ocular pressure. It is formulated as an ophthalmic suspension. The pharmacokinetics of ocular suspensions is not well understood. The objective of this study was to characterize the pharmacokinetics of brinzolamide in rabbit aqueous humor, iris-ciliary body, plasma, and whole blood. New Zealand White rabbits were dosed via intracameral, topical and intravenous administration. After intracameral administration (4.5 μg) of solubilized brinzolamide, aqueous humor concentrations were described with a two-compartment model, the estimated clearance was 4.12 μL/min, apparent volume of distribution at steady-state 673 μL, and terminal half-life 3.4 h. After topical administration of 1% brinzolamide suspension (500 μg), absolute bioavailability based on aqueous humor AUC 0-∞ was 0.10%. After intravenous administration of brinzolamide solution (0.75 mg/kg) elimination half-life in plasma and whole blood appeared to be over two weeks. The ratios of the measured concentrations of irisciliary body to whole blood, to plasma, and to aqueous humor concentrations enabled direct comparisons, and helped identify the significant contribution of the conjunctival-scleral pathways of absorption to the ciliary body. This study shows for the first-time the absolute bioavailability in aqueous humor and provides comprehensive pharmacokinetic parameters following administration of a topical suspension. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex, predominant, and progressive form of dementia. The treatment of AD alters depending on the cognitive and behavioral symptoms. The utility of cholinergic replacement by acetylcholinesterase (AChE) inhibitors in AD treatment has been well-documented so far. Recent studies have also demonstrated that human carbonic anhydrases (h CAs) serve as important targets for AD treatment. In an attempt to identify potent AChE and h CA inhibitors, new thiazolyl-pyrazolines (3a - k) were designed based on the molecular hybridization of thiazole and pyrazoline scaffolds. A facile and versatile synthetic route consisting of three steps, namely Claisen-Schmidt reaction, the formation of the 2-pyrazoline ring system, and Hantzsch thiazole synthesis was used to prepare compounds 3a - k. The synthesized derivatives were experimentally validated for efficacy by in vitro and direct enzymatic assays. Furthermore, the compounds were subjected to in silico screening using Schrödinger Suite software to identify the binding affinities of potential compounds based on Glide XP scoring, MM-GBSA calculating, and validation. The results of in vitro and in silico studies revealed that compounds 3a , 3f , and 3d were the most promising derivatives in this series due to their significant effects on AChE, h CA I, and h CA II, respectively. • A new series of thiazolyl-pyrazolines were designed and synthesized. • The synthesized compounds were investigated as inhibitors of AChE and h CA I, II. • All compounds showed KI values in low nanomolar range for AChE, hCA I and II. • Observed SARs were rationalized by in silico docking simulation. [ABSTRACT FROM AUTHOR]

Brinzolamide (BNZ) is a carbonic anhydrase inhibitor commonly used for the treatment of glaucoma. The aim of this study was to prepare BNZ loaded chitosan-pectin mucoadhesive nanocapsules (CPNCs) by polyelectrolyte complex coacervation method for ocular delivery and evaluated for its anti glaucoma efficacy. The prepared CPNCs were characterized for their particle size, polydispersity index, zeta-potential, surface morphology, entrapment efficiency, drug loading efficiency, mucoadhesive strength in-vitro and ex-vivo release. The pharmacodynamic studies were conducted for CPNCs on glaucoma induced rabbit eye model and compared with marketed product. All the formulated CPNCs exhibited the size range from 217.01 ± 0.21 to 240.05 ± 0.08 nm and appropriate physico-chemical parameters, and depicted a couple of erosion- diffusion release of BNZ over a time of 8 h. Ex-vivo corneal permeation study concluded that BNZ loaded CPNCs crosses the cornea potentially higher rate as compared to the marketed product. In pharmacodynamic study, greater intraocular pressure lowering effect was achieved by CPNCs as compared to marketed drug product. The result concluded that CPNCs are a feasible choice to conventional eye drops because of its ability to improve the bioavailability via its longer precorneal retention time and its ability to sustained release of the drug. [ABSTRACT FROM AUTHOR]

Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay. We report eight children with PTU; six of them also exhibiting symptoms of ataxia and/or developmental delay. Treatment with carbonic anhydrase inhibition was offered to children with persisting and/or severe forms. Whole-exome sequencing and genome-wide array analysis (n = 7) did not reveal mutations in the three known genes associated with PTU (CACNA1A, GRID2, SEPSECS), whereas by MLPA a heterozygous deletion of exon 31 of the CACNA1A gene could be detected in one patient, her mother and two further family members. Further exome and array analysis showed no recurrent variants in potentially novel PTU-related genes in more than one patient. A de novo variant at a highly conserved position in the SIM1 gene was detected in one patient, for which a pathogenic effect could be speculated. Carbonic anhydrase inhibition was started in five children and proved at least partially effective in all of them. Irrespective of the clinical background and the molecular basic mechanism of PTU, therapeutic carbonic anhydrase inhibition was effective in all five children (acetazolamide, n = 3; sultiame, n = 2) who received this treatment. • PTU associated with further symptoms such as developmental delay or ataxia seems to be more persistent. • PTU can be associated with genetic mutations in the CACNA1A gene but can also be of multifactorial genesis. • Treatment with carbonic anhydrase inhibitors should be considered in all children with persisting or severe forms of PTU. [ABSTRACT FROM AUTHOR]

Acetazolamide (molecular mass (MM), 222) belongs to the class of sulfonamides (R-SO 2 -NH 2) and is one of the strongest pharmacological inhibitors of carbonic anhydrase activity. Acetazolamide is excreted unchanged in the urine. Here, we report on the development, validation and biomedical application of a stable-isotope dilution GC-MS method for the reliable quantitative determination of acetazolamide in human urine. The method is based on evaporation to dryness of 50 μL urine aliquots, base-catalyzed derivatization of acetazolamide (d 0 -AZM) and its internal standard [ acetylo -2H 3 ]acetazolamide (d 3 -AZM) in 30 vol% pentafluorobenzyl (PFB) bromide in acetonitrile (60 min, 30 °C), reconstitution in toluene (200 μL) and injection of 1-μL aliquots. The negative-ion chemical ionization (NICI) mass spectra (methane) of the PFB derivatives contained several intense ions including [M]‒ at m/z 581 for d 0 -AZM and m/z 584 for d 3 -AZM, suggesting derivatization of their sulfonamide groups to form N,N -dipentafluorobenzyl derivatives (R-SO 2 -N(PFB) 2), i.e., d 0 -AZM-(PFB) 2 and d 3 -AZM-(PFB) 2 , respectively. Quantification was performed by selected-ion monitoring of m/z 581 and 83 for d 0 -AZM-(PFB) 2 and m/z 584 and 86 for d 3 -AZM-(PFB) 2. The limits of detection and quantitation of the method were determined to be 300 fmol (67 pg) and 1 μM of acetazolamide, respectively. Intra- and inter-assay precision and accuracy for acetazolamide in human urine samples in pharmacologically relevant concentration ranges were determined to be 0.3%–4.2% and 95.3%–109%, respectively. The method was applied to measure urinary acetazolamide excretion after ingestion of a 250 mg acetazolamide-containing tablet (Acemit®) by a healthy volunteer. Among other tested sulfonamide drugs, methazolamide (MM, 236) was also found to form a N,N -dipentafluorobenzyl derivative, whereas dorzolamide (MM, 324) was hardly detectable. No GC-MS peaks were obtained from the PFB bromide derivatization of hydrochlorothiazide (MM, 298), xipamide (MM, 355), indapamide and metholazone (MM, 366 each) or brinzolamide (MM, 384). We demonstrate for the first time that sulfonamide drugs can be derivatized with PFB bromide and quantitated by GC-MS. Sulfonamides with MM larger than 236 are likely to be derivatized by PFB bromide but to lack thermal stability. Image 1 • The sulfonamide group of acetazolamide was derivatized for the first time with pentafluorobenzyl bromide. • Other sulfonamides were also derivatized for the first time with pentafluorobenzyl bromide. • Pentafluorobenzyl derivatives of acetazolamide and other sulfonamides are useful for GC-MS. • The validated method was used to quantify pharmacological acetazolamide in human urine. [ABSTRACT FROM AUTHOR]

[Display omitted] • Blockade of carbonic anhydrase reduces axonal excitability during intense firing. • In Schaffer collaterals, the effect is confined to their terminal field in CA1. • The effect depends on extracellular calcium. • The effect is mimicked by imposed intracellular acidosis. Epileptic activity is known to cause a lowering of intraneuronal pH, which has been suggested to serve as a feedback signal to terminate seizures. The mechanism of such signaling is unclear, but likely involves an altered function of several types of ligand- and voltage-gated channels in postsynaptic membranes caused by increasing cytosolic and extracellular [H+]. In addition, axonal conduction properties may be altered by endogenous pH signals, but this has not been investigated. In the present study, we have recorded the axonal compound action potential (fiber volley) in hippocampal slices in the presence of glutamatergic and GABAergic antagonists. During high-frequency stimulation (HFS) of the Schaffer collaterals, the fiber volley was depressed and its latency from stimulus to peak increased. In the CA1 stratum radiatum these changes were enhanced when the carbonic anhydrase inhibitor acetazolamide (1 mM) was co-perfused. The enhancing effect of acetazolamide was absent after lowering of [Ca2+] in the perfusion medium. Acetazolamide had no detectable effect on HFS-evoked fiber volleys recorded from a more proximal site along the Schaffer collaterals (at the CA2-CA3 border) or from axons in the alveus of CA1. Intracellular acidification imposed by washout of NH 4 Cl (5 mM) had qualitatively similar effects on fiber volleys evoked at low frequency as those observed with acetazolamide during HFS in CA1 stratum radiatum. The results suggest that carbonic anhydrase-dependent pH regulation counteracts activity-induced reduction of the excitability of Schaffer collateral axons in CA1. A possible influence from local synaptic terminals on this effect is discussed. [ABSTRACT FROM AUTHOR]

This study aimed to design potent carbonic anhydrase inhibitors (CAIs) based on pyrazole benzenesulfonamide core. Nine series of substituted pyrazole benzenesulfonamide compounds were synthesized with variable groups like sulphamoyl group as in compounds 4a-e , its bioisosteric carboxylic acid as in compounds 5a-e and 8e , ethyl carboxylate ester as in compounds 6a-e and 9a-e, which were designed as potential prodrugs, isothiazole ring as in compound 7 , hydrazide derivative 10e , hydroxamic acid derivatives 11a-e and semicarbazide derivatives 12a-c,e. All the synthesized compounds were investigated for their carbonic anhydrase (CA) inhibitory activity against two human CA isoforms hCA IX and hCA XII and compared to acetazolamide (AAZ). Also, the compounds were assessed for their anticancer activity against 60 cancer cell lines according to the US NCI protocol. Compounds 4b , 5b , 5d , 5e , 6b , 9b , 9e and 11b revealed significant inhibitory activity against both isoforms hCA IX and hCA XII, while 6e , 9d , 11d and 11e showed significant inhibitory activity against hCA XII only compared to acetazolamide as a reference. This would highlight these compounds as promising anticancer drugs. Moreover, compound 6e revealed a remarkable cytostatic activity against CNS cancer cell line (SF-539; TGI = 5.58 μM), renal cancer cell line (786–0; TGI = 4.32 μM) and breast cancer cell line (HS 578 T; TGI = 5.43 μM). Accordingly, compound 6e was subjected to cell cycle analysis and apoptotic assay on the abovementioned cell lines at the specified GI 50 (0.45, 0.89 and 1.18 μM, respectively). Also, it revealed the increment of total apoptotic cells percentage in 786–0 (53.19%), SF-539 (46.11%) and HS 578 T (43.55%) relative to the control cells (2.07, 2.64 and 2.52%, respectively). In silico prediction of BBB permeability showed that most of the calculations for compound 6e resulted as BBB (+), which is required for a compound targeting CNS. Further, the interaction of the most active compounds with the key amino acids in the active sites of hCA IX and hCA XII was highlighted by molecular docking analysis. [Display omitted] • Different novel pyrazole benzenesulfonamide derivatives were synthesized. • All newly synthesized compounds showed promising anticancer activity. • All candidates were investigated for their carbonic anhydrase inhibitory activity. • Compounds 5a and 6a-e were selected by NCI for five dose screening. • Compounds 6e revealed increase in apoptosis and necrosis percentages. [ABSTRACT FROM AUTHOR]

Synthesis, molecular, spectroscopic (1H NMR and FT–IR) properties, biological evaluation, electronic structure calculations and in silico molecular docking of two sulfonamide derivates, namely the 4-Bromo- N -(1 H -tetrazol-5-yl)benzenesulfonamide (4) and 4-Nitro- N -(1 H -tetrazol-5-yl)benzenesulfonamide (5) were reported. Density Functional Theory (DFT) calculations were performed using B3LYP/6-311++G(d,p) to further investigate the molecular, electronic structures and to assist the spectral assignments and provide the useful structural and spectroscopic information. A conformational analysis was completed to obtain stable structures. The simulated 1H NMR and FT–IR spectra were compared with those obtained experimentally and any observed discrepancies were discussed. The synthesized compounds were tested against one Gram-positive, Bacillus subtilis (+), and three Gram-negative, Salmonella typhi (–), Escherichia coli (–), Pseudomonas aeruginosa (–), bacteria. Results show that the compound 5 is highly active antibacterial agent. Carbonic Anhydrase Inhibition and cytotoxicity assay results refer the compounds to be a moderate inhibitor of Carbonic Anhydrase enzyme. The molecular docking results support the experimental observations. The binding affinities of 5 with all the selected enzymes were calculated to be stronger than those of 4 , which is primarily due to the electrostatic interaction between NO 2 − moiety of 5 and NH 2 + group of Lysine of the selected enzymes. The charge transfer, within the molecules and most probable sites for the electrophilic and nucleophilic attack, was explored. Diagram illustrating the combined use of experimental and computational techniques to study the different properties of the systems. (top) Spectroscopic and biological activity study of the synthesized compounds using experimental techniques. (bottom) In silico molecular docking and electronic properties study of systems using computer modeling and simulations. Image 1 • Two sulfonamide synthesized and characterized by 1H NMR and FT–IR spectroscopy. • Sulfonamide tested for biological activities with support molecular docking. • DFT calculations were performed for spectral assignments. • 4-Nitro- N -(1 H -tetrazol-5-yl)benzenesulfonamide highly active antibacterial agent. [ABSTRACT FROM AUTHOR]

Sixteen 5-aryl-substituted isothiazol-3(2 H)-one-1,(1)-(di)oxide analogs have been prepared from the corresponding 5-chloroisothiazol-3(2 H)-one-1-oxide or −1,1-dioxide by a Suzuki-Miyaura cross-coupling reaction and screened for their inhibition potency against four human carbonic anhydrase isoenzymes: the transmembrane tumor-associated hCA IX and XII and the cytosolic off-target hCA I and II. Most of the synthesized derivatives inhibited hCA IX and XII isoforms in nanomolar range, whereas remained inactive or modestly active against both hCA I and II isoenzymes. In the N - tert -butylisothiazolone series, the 5-phenyl-substituted analog (1a) excelled in the inhibition of tumor-associated hCA IX and XII (K i = 4.5 and K i = 4.3 nM, respectively) with excellent selectivity against off target hCA I and II isoenzymes (S > 2222 and S > 2325, respectively). Since the highest inhibition activities were observed with N - tert -butyl derivatives, lacking a zinc-binding group, we suppose to have a new binding mode situated out of the active site. Additionally, three free-NH containing analogs (3a , 4a , 3i) have also been prepared in order to study the impact of free-NH containing N -acyl-sulfinamide- (-SO-NH-CO-) or N -acyl-sulfonamide-type (-SO 2 -NH-CO-) derivatives on the inhibitory potency and selectivity. Screening experiments evidenced 5-phenylisothiazol-3(2 H)-one-1,1-dioxide (4a), the closest saccharin analog, to be the most active derivative with inhibition constants of K i = 40.3 nM and K i = 9.6 nM against hCA IX and hCA XII, respectively. The promising biological results support the high potential of 5-arylisothiazolinone-1,(1)-(di)oxides to be exploited for the design of potent and cancer-selective carbonic anhydrase inhibitors. Image 1 • Sixteen 5-arylisothazol-3(2 H)-one-1,(1)-(di)oxide (5-Ar-ITZ) analogs have been synthesized. • Several 5-Ar-ITZ analogs were found to be potent and selective hCA IX/XII inhibitors. • 2- tert -Bu-5-Ph-isothazol-3(2 H)-one-1-oxide is the most active (K i ≈ 4 nM) and selective (S > 2222 vs. hCA I/II) on hCA IX/XII. • 5-Ar-ITZ analogs constitute a new class of potent cancer-selective CAIs. • Non Zn-binding mode, outside the active site may be involved for 2- tert -Bu-5-Ar-ITZ analogs. [ABSTRACT FROM AUTHOR]

• We used conventional 3D-QSAR methods to construct models. • Based on the already established models, we designed seven new compounds. • 3、Molecular Dynamics Simulation proved new compound D7 had good selectivity on hCA IX. • 4、The studies may be helpful in the rational drug design of isoform-selective inhibitors. Nowadays, different approaches have been pursued with the intent to develop sulfonamide-like carbonic anhydrase inhibitors that possess better selectivity profiles toward the different human isoforms of the enzyme. Here, we used conventional 3D-QSAR methods, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA, to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models for benzenesulfonamide derivatives as human carbonic anhydrase (hCA) II/IX inhibitors. The theoretical models had good reliability (R 2>0.75) and predictability (Q 2>0.55), and the contour maps could graphically present the contributions of the force fields for activity and identify the structural divergence between human carbonic anhydrase II inhibitors and human carbonic anhydrase IX inhibitors. Consequently, we explored the selectivity of inhibitor for human carbonic anhydrase II and IX through molecular docking, and the difference of activity coincides with the potential binding mode well. According to the results of the predicted values and the molecule docking, we found that the inhibitors published in the literature had stronger inhibition on the hCA IX; based on the theoretical models, we designed seven new compounds with good potential activity and reasonably good ADMET profile, which could selectively inhibit hCA IX. Molecular Dynamics Simulation showed that newly-designed compound D7 had good selectivity on hCA IX. The findings from 3D-QSAR and docking studies maybe helpful in the rational drug design of isoform-selective inhibitors. [ABSTRACT FROM AUTHOR]

Inhalational anesthetics such as isoflurane, desflurane and halothane are the mainstay medications for surgical procedures; upon inhalation, they produce anesthesia described as reversible unconsciousness with the features of amnesia, sleep, immobility and analgesia. To date, how they produce anesthesia is unknown. This study proposes that carbonic anhydrase enzymes are likely targets mediating the actions of inhalational anesthetics. Carbonic anhydrase enzymes, commonly expressed in living organisms, utilize carbon dioxide (CO2) as a substrate and can generate H+ and HCO3- from CO2 with a great efficiency. There are remarkable lines of evidence for their likely roles in mediating anesthetic actions. Firstly, carbonic anhydrase enzymes are extensively expressed in the brain and spinal cord, and their importance in the brain activity, especially for the GABA and NMDA receptor signaling pathways, has been demonstrated in numerous studies. According to these studies, they provide HCO3- for GABA-A receptor activities and also buffer HCO3- excess resulting from NMDA receptor activation. Activation of GABA-A and inhibition of NMDA receptors are associated with the induction of anesthesia by the intravenous general anesthetics propofol and ketamine, respectively. Secondly, the carbonic anhydrase inhibitors topiramate and zonisamide are effectively used in the treatment of epilepsy for decades; their chronic use results in the requirement of increased levels of amobarbital in order to produce anesthesia in the epileptic patients during WADA test. In addition, given that CO2 is a substrate for these enzymes, their tertiary structure is likely has a hydrophobic pocket suitable for the anesthetic molecules to bind. Inhalational anesthetic molecules, which are lipophilic and inert in nature, have an ability to cross the membranes and inhibit carbonic anhydrases, which might not be accessible by topiramate and zonisamide. Unlike carbonic anhydrase inhibitors, they could bind to the hydrophobic pocket for CO2 molecules and produce a profound effect called anesthesia. Finally, there is a great deal of similarities between the physiological actions of inhalational anesthetics and carbonic anhydrase inhibitors; moreover well-known side effects of inhalational anesthetics could be associated with the inhibition of carbonic anhydrases. Therefore, this article presents a hypothesis that the anesthetic actions of inhalational anesthetics could be due to their inhibitory effects on the carbonic anhydrases. Investigating this hypothesis might lead to the development of new safer anesthetics, and more importantly it might reveal an endogenous anesthetic pathway, in which the carbonic anhydrase system is a component along with the GABA-A and NMDA receptor systems. [ABSTRACT FROM AUTHOR]

Abstract Herein we report the design and synthesis of novel N -substituted isatins-SLC-0111 hybrids (6a-f and 9a-l). A structural extension approach was adopted via N -alkylation and N -benzylation of isatin moiety to enhance the tail hydrophobic interactions within the carbonic anhydrase (CA) IX active site. Thereafter, a hybrid pharmacophore approach was utilized via merging the pharmacophoric elements of isatin and SLC-0111 in a single chemical framework. As planned, a substantial improvement of inhibitory profile of the target hybrids (K I s: 4.7–86.1 nM) towards hCA IX in comparison to N -unsubstituted leads IVa-c (K I s: 192–239 nM), was achieved. Molecular docking of the designed hybrids in CA IX active site unveiled, as planned, the ability of N -alkylated and N -benzylated isatin moieties to accommodate in a wide hydrophobic pocket formed by T73, P75, P76, L91, L123 and A128, establishing strong van der Waals interactions. Hybrid 6c displayed good anti-proliferative activity under hypoxic conditions towards breast cancer MDA-MB-231 and MCF-7 cell lines (IC 50 = 7.43 ± 0.28 and 12.90 ± 0.34 μM, respectively). Also, 6c disrupted the MDA-MB-231 cell cycle via alteration of the Sub-G 1 phase and arrest of G 2 -M stage. Additionally, 6c displayed significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Furthermore, 6c displayed potent VEGFR-2 inhibitory activity (IC 50 = 260.64 nM). Collectively, these data suggest 6c as a promising lead molecule for the development of effective anticancer agents. Graphical abstract A substantial improvement of inhibitory profile of the target hybrids (K I s: 4.7–86.1 nM) towards hCA IX in comparison to N -unsubstituted leads IVa-c (K I s: 192–239 nM), was achieved. Image 1 Highlights • Two novel N -substituted isatins-SLC-0111 hybrids series (6a-f and 9a-l) were developed. • As planned, a substantial improvement of inhibitory profile towards hCA IX was achieved. • Docking unveiled accommodation of N -alkylated isatin moieties in a wide hydrophobic pocket. • Antitumor, cell cycle disturbance and pro-apoptotic activities were evaluated in breast cancer. • Hybrids 6c , 6d , 9c and 9d displayed good VEGFR-2 inhibitory activity (IC 50 : 207–462 nM). [ABSTRACT FROM AUTHOR]

Abstract The effect of some sulfonamide ligands on the structure and function of human carbonic anhydrase II (HCA II) was investigated using different spectroscopic techniques including UV–Vis, fluorescence, circular dichroism and molecular dynamics simulation tools. Kinetic measurements were performed in 50 mM Tris-HCl, pH 7.4 at 27 °C. Kinetic data revealed that sulfonamide ligands inhibit the HCA II esterase activity in a linear competitive manner with K i in the nanomolar range. Fluorescence measurements illustrated that ligands act as the enzyme quenchers. Stern–Volmer analysis of the quenching data at different temperatures demonstrated that the quenching of the HCA II intrinsic fluorescence occurred through static and dynamic quenching mechanisms. Analysis of the binding thermodynamic parameters showed that hydrogen bonding and hydrophobic interactions play an important role in the stabilization of enzyme–drug complex. Job plot confirmed the 1:1 stoichiometry of ligand-protein complex, and therefore, the existence of one binding site for the ligand. Molecular simulations confirmed that acetazolamide induced impressive conformational changes in two domains adjacent to the active site, including amino acids 19–25 and 61–67. RMSF studies showed sharp changes in three distinct regions near the active site including amino acids 15–25, 160–180 and 190–210 upon drug binding. [ABSTRACT FROM AUTHOR]

• Synthesis of alkyl substituted thiourea and its characterization. • Single crystal XRD analysis. • In-Vitro carbonic anhydrase inhibition studies. • Computational studies including DFT, Molecular docking and ADMET Analysis. Carbonic anhydrases (CAs) representing the class of metalloenzymes are expressed widely and play a crucial role in various physiological and pathological processes. The Alkyl substituted Acyl Thiourea was synthesized and characterized by NMR spectroscopic technique. Single crystal X-ray diffraction was applied to determine the molecular and crystal structures. Synthesized compound crystallized in monoclinic system P 2 1 /c space group. Intermolecular N–H···S hydrogen bonds and Intramolecular N–H···O hydrogen bond were found in crystal structure. H ... H interactions have major contributions in crystal packing as depicted by Hirshfeld surface analysis. No large cavity was observed during void volume analysis in the crystal packing. Stabilization was dominated via the dispersion energy contributions in the synthesized compound. In Vitro analysis showed that synthesized compound inhibited the carbonic anhydrase activity to an appreciable extent. Quantum mechanical descriptors were calculated using DFT studies. In molecular docking, reactive parts of the synthesized molecule contributed in forming the hydrogen bond with receptor protein target. Finally, ADMET Analysis were performed to assess the drug-like behavior of synthesized compound. Carbonic Anhydrase enzyme inhibitor of pharmaceutical significance can be developed using the synthesized molecule ES-2 as a lead molecule. [ABSTRACT FROM AUTHOR]

In this study, we investigated the development of dual-targeted ligands that bind to both μ-opioid receptor (MOR) and carbonic anhydrase (CA) enzymes, using fentanyl structure as a template. We synthesized and evaluated 21 novel compounds with dual-targeted affinity identifying the lead candidate compound 8 , showing selective affinity for MOR and potent inhibition of several cytosolic CA isoforms. By means of repeated treatment of 3 daily administrations for 17 days, fentanyl (0.1 mg/kg, subcutaneously) led to tolerance development, pain threshold alterations and withdrawal symptoms in CD-1 mice, as well as astrocyte and microglia activation in the dorsal horn of the lumbar spinal cord. In contrast, compound 8 (0.32 mg/kg s.c.) maintained stable during days its analgesic effect at the higher dose tested with fewer withdrawal symptoms, allodynia development and glial cells activation. Our results suggest that targeting both MOR and CA enzymes can lead to the development of new class of potent analgesic agents with fewer side effects and reduced tolerance development. Further studies are needed to explore the potential mechanisms underlying these effects and to further optimize the therapeutic potential of these compounds. [Display omitted] • Development of dual-targeted ligands that bind to both μ-opioid receptor (MOR) and carbonic anhydrase (CA) enzymes. • Compound 8 , showed selective affinity for MOR and potent inhibition of several cytosolic CA isoforms. • Cmp 8 maintained stable analgesic effect with fewer withdrawal symptoms, allodynia development and glial cells activation • Targeting both MOR and CAs lead to potent analgesic agents with fewer side effects and reduced tolerance development. [ABSTRACT FROM AUTHOR]

Phenylthiazol-2(3h)-ylidene-isoquinoline-5-amine derivatives(5a-r) were easily prepared from 5-aminoisoquinoline, thioisocyanate, and phenacyl bromide derivatives in the presence of triethylamine in tetrahydrofuran (THF), and dimethyl formamide (DMF) in two steps. In the first step, thiourea was synthesized in THF reflux, 24 h and then in the second step, the formation of thiazole ring was ensured in EtOH-DMF (5:5 v/v), reflux, 24 h. The newly synthesized compounds were characterized using 1H NMR, 13C NMR, IR, and elemental analysis. The inhibitory effects of 18 newly synthesized compounds (5a-r) on hydratase and esterase activities of carbonic anhydrase isoenzymes (hCA I, II, IX, and X) were studied in vitro. [Display omitted] [ABSTRACT FROM AUTHOR]

In the current medical era, the utilization of a single small molecule to simultaneously target two distinct molecular targets is emerging as a highly effective strategy in the battle against cancer. Carbonic Anhydrase (CA) and Vascular-Endothelial Growth Factor (VEGF) are genes that are activated in response to low oxygen levels (hypoxia) and play a role in the development and progression of tumors in hypoxic conditions. Herein we report the design, synthesis, and biological assessment of a series of novel indolinone-based benzenesulfonamides (8a-k , 11a-d , 15a-d , and 16) as potential dual inhibitors for cancer-associated h CA IX/XII and VEGFR-2. All the synthesized sulfonamides were assessed for their inhibitory effect against four CA isoforms I, II, IX, and XII where they displayed varying degrees of h CA inhibition. The most effective and selective h CA IX and XII inhibitors 8g , 8j and 15b were chosen to be tested for their in vitro inhibitory impact against VEGFR-2 as well as their antiproliferative impact against VEGFR-2 overexpressing MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, molecular docking studies were conducted within the h CA IX, XII, and VEGFR-2 active sites to explain the observed inhibitory results. [Display omitted] • Novel series of isatin-based benzenesulfonamides (8a-k , 11a-d , 15a-d , 16) were synthesized. • Inhibitory activities of all molecules were evaluated towards hCA I, II, IX and XII isoforms. • All isatins efficiently inhibited the cancer-related h CA IX and XII in the low nanomolar ranges. • Isatins 8g , 8j and 15b effectively inhibited VEGFR-2 with good IC 50 values. • 8g , 8j, 15b exerted potent antiproliferative impact against MDA-MB-231 and MCF-7 cell lines. [ABSTRACT FROM AUTHOR]

Overexpression of the hypoxia-induced transmembrane enzyme carbonic anhydrase IX (CA9) has been associated with poor prognosis and chemoresistance in aggressive breast cancer. This study aimed to investigate the involvement of CA9 in the anti-tumor activity of para-toluenesulfonamide (PTS) and elucidate its mechanism of action against breast cancer both in vitro and in vivo. MCF-7 and MDA-MB-231 breast cancer cells were treated with PTS or subjected to hypoxic conditions using cobalt chloride (CoCl 2), with acetazolamide serving as a positive control. Additionally, 4T1 breast cancer cell allograft mice were co-treated with PTS and α-programmed cell death 1 (αPD-1) monoclonal antibody for one month. The results demonstrated that PTS effectively reduced cell viability and reversed migration ability in MCF-7 and MDA-MB-231 cells under CoCl 2 -induced hypoxia. Furthermore, PTS upregulated the expression of apoptosis-related proteins and downregulated CA9, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) proteins, possibly through modulation of p38 MAPK and ERK1/2 phosphorylated proteins. In the animal model, PTS100 inhibited tumor growth and lung metastasis in mammary tumor allograft mice, exhibiting synergistic effects when combined with αPD-1 therapy. Collectively, our findings suggest that PTS inhibits breast cancer growth and metastasis through the p38 MAPK/ERK1/2 pathway. Moreover, PTS may have the potential to prevent the development of resistance to αPD-1 therapy in breast cancer. [Display omitted] • Under CoCl 2 -induced hypoxia, PTS effectively reversed cell viability and migration ability in MCF-7 and MDA-MB-231 cells. • PTS affects the expression of hypoxia and apoptosis proteins, which may involve the p38 MAPK and ERK1/2 signaling pathways. • PTS exhibits protection against breast cancer resistance to αPD-1 therapy in animal models. [ABSTRACT FROM AUTHOR]

[Display omitted] • Controlled release of ACZ by loading to PHBV nanoparticles. • In the pharmacokinetic study, ACZ was found in the highest concentration in the vitreous and retina. • ERG measurements were performed for in vivo toxicity of PHBV-ACZ NP. Diabetic macular edema (DME) is defined as fluid accumulation in the macular region, between the retinal layers, due to many diseases, especially diabetes. DME is one of the major complications of diabetic retinopathy (DRP). Carbonic anhydrase inhibitors (CAI) are a pharmaceutical agent used in different fields, especially glaucoma treatment. Acetazolamide (ACZ), which is a CAI, is an active substance that has been used off-label for many years in the treatment of macular edema due to diabetes and many other diseases. The low solubility and bioavailability of ACZ limit its use in the treatment of DME. In this study, a nanoparticulate formulation was developed that would increase the solubility and bioavailability of ACZ and allow it to be administered intravitreally. ACZ was loaded on poly(3-hydroxybutyrate-co-3-Hydroxyvalerate) (PHBV) nanoparticles and the loading efficiency was 71.58 ± 1.22%. Toxicity of nanoparticles after intravitreal application was evaluated with anterior segment and posterior segment examination findings, intraocular pressure (IOP) measurements and electrophysiological tests. At the end of the 3-month follow-up, electroretinography (ERG) measurements demonstrated that ACZ loaded PHBV (PHBV-ACZ) nanoparticles did not cause loss of function in retinal cells. On histological examination, rare degenerative changes were observed in several cell groups. In addition, pharmacokinetic studies were performed to determine the tissue distribution of ACZ at various periods. ACZ was identified in vitreous humor and retina at the highest concentration. Based on our results, the prepared nanoparticle formulation can release long-term CAI for DRP therapy and accordingly can reduce the need for monthly intravitreal injections. [ABSTRACT FROM AUTHOR]

Hypoxia, a characteristic feature of solid tumors, develops as a result of excessive cell proliferation and rapid tumor growth exceeding the oxygen supply, and can result in angiogenesis activation, increased invasiveness, aggressiveness, and metastasis, leading to improved tumor survival and suppression of anticancer drug therapeutic impact. SLC-0111, a ureido benzenesulfonamide, is a selective human carbonic anhydrase (hCA) IX inhibitor in clinical trials for the treatment of hypoxic malignancies. Herein, we describe the design and synthesis of novel 6-arylpyridines 8a-l and 9a-d as structural analogues of SLC-0111, in the aim of exploring new selective inhibitors for the cancer-associated hCA IX isoform. The para -fluorophenyl tail in SLC-0111 was replaced by the privileged 6-arylpyridine motif. Moreover, both ortho- and meta- sulfonamide regioisomers, as well as an ethylene extended analogous were developed. All 6-arylpyridine-based SLC-0111 analogues were screened in vitro for their inhibitory potential against a panel of hCAs (hCA I, II, IV and IX isoforms) using stopped-flow CO 2 hydrase assay. In addition, the anticancer activity was firstly explored against a panel of 57 cancer cell lines at the USA NCI-Developmental Therapeutic Program. Compound 8g emerged as the best anti-proliferative candidate with mean GI% value equals 44. Accordingly, a cell viability assay (MTS) for 8g was applied on colorectal HCT-116 and HT-29 cancer cell lines as well as on the healthy HUVEC cells. Thereafter, Annexin V-FITC apoptosis detection, cell cycle, TUNEL, and qRT-PCR, colony formation, and wound healing assays were applied to gain mechanistic insights and to understand the behavior of colorectal cancer cells upon the treatment of compound 8g. Also, a molecular docking analysis was conducted to provide in silico insights into the reported hCA IX inhibitory activity and selectivity. [Display omitted] • New series of sulfonamide-tethered 6-arylpyridines 8a-l and 9a-d was designed and synthesized. • Inhibitory activities of all derivatives were evaluated toward hCA I, II, IV and IX isoforms. • The anticancer activity was explored against a panel of 57 cancer cell lines at the NCI-USA. • Compound 8g showed promising CA inhibitory and anti-proliferative activities. • A thorough investigation was done into the anticancer efficacy of 8g against colorectal cell lines. [ABSTRACT FROM AUTHOR]