Synthesis, structure and acetylcholinesterase inhibition activity of new diarylpyrazoles.

A variety of diarylpyrazole derivatives III-VI were synthesized and structurally characterized using FTIR, 1H and 13C NMR spectroscopy, and in case of compound VIb by X-ray single crystal analysis. The in vitro biological studies revealed that seven of the diarylpyrazole derivatives IIIa, IIIb, IIId, IIIe, IVa, IVb and IVd are highly potent inhibitors of acetylcholinesterase enzyme with IC50 values of 0.48 ± 0.092 µg/mL, 0.45 ± 0.093 µg/mL, 0.30 ± 0.014 µg/mL, 0.59 ± 0.072 µg/mL, 0.29 ± 0.084 µg/mL, 0.56 ± 0.010 µg/mL and 0.28 ± 0.096 µg/mL, respectively. All these seven products were more potent than the standard drug, donepezil (IC50 = 0.73 ± 0.015 µg/mL), while compounds IIIc (0.67 ± 0.099 µg/ml) and VIa (0.66 ± 0.069 µg/ml) are almost equipotent to the donepezil. Particularly, compounds IVa and IVd are highly active acetylcholinesterase enzyme inhibitors, demonstrating more than two-fold inhibitory activity than the reference inhibitor. Molecular docking studies were carried out to identify the possible binding modes of the diarylpyrazoles within the active pocket of the enzymes. The docking interactions of the synthesized compounds with acetylcholinesterase also provided high docking scores. These results clearly indicate the potential of these compound as powerful lead molecules for further investigations.

Isatin-hydrazide conjugates as potent α-amylase and α-glucosidase inhibitors: Synthesis, structure and invitro evaluations.

Managing diabetes that is a global life-threatening problem, remains a challenge for the scientific community. The inhibition of α-amylase and α-glucosidase enzymes which are responsible for the digestion of dietary carbohydrates is an effective strategy to control postprandial hyperglycemia. Herein, we report the novel and highly potent inhibitors of α-amylase and α-glucosidase, namely isatin-hydrazide conjugates 1a - 1j that are easily accessed in two steps from simple and inexpensive commercially available isatin. The in vitro bio-evaluations of these compounds revealed that conjugates 1a, 1h and 1f are highly potent inhibitors of α-amylase with IC50 values of 19.6, 12.1 and 18.3 µg/ml, respectively as compared to the standard, acarbose (IC50 = 36.2 µg/ml). Similarly, the conjugates 1a, 1b, 1d, 1f and 1i showed significant activity against α-glucosidase with IC50 values of 14.8, 25.6, 13.2, 14.5 and 16.5 µg/ml, respectively as compared to the acarbose (IC50 = 34.5 µg/ml). Notably, the compounds 1a and 1f were found to be highly potent against both α-amylase and α-glucosidase enzymes, demonstrating about two-fold better inhibitory activity than the reference inhibitor. Molecular docking studies were performed to recognize the possible binding modes of the compounds with the active pocket of the enzymes. The results of this study divulge the potential of these compounds as powerful and inexpensive lead molecules for future investigations.

Novel coumarin-isatin hybrids as potent antileishmanial agents: Synthesis, in silico and in vitro evaluations.

Leishmaniasis being one of the six major tropical diseases that affects nearly 0.7-1.3 million people annually, has so far limited and high toxic therapeutic options. Herein, we report the synthesis, in silico, and in vitro evaluations of novel coumarin-incorporated isatin hydrazones (Spf-1 - Spf-10) as highly potent and safe antileishmanial agents. Molecular docking was initially carried out to decipher the binding confirmation of lead molecules towards the active cavity of the target protein (Leishmanolysin gp63) of Leishmania tropica. Among all the docked compounds, only Spf-6, Spf-8, and Spf-10 showed high binding affinities due to a pattern of strong conventional hydrogen bonds and hydrophobic π-interactions. The molecular dynamics simulations showed the stable pattern of such bonding and structure-based confirmation with a time scale of 50 ns towards the top compound (Spf-10) and protein. These analyses affirmed the high stability of the system. Three out of ten compounds evaluated for their antileishmanial activity against Leishmania tropica promastigotes and amastigotes were found to be active at micromolar concentrations (IC50 range 0.1-4.13 µmol/L), and most importantly, they were also found to be highly biocompatible when screened for their toxicity in human erythrocytes.

Fluorescent organic nanoparticles (FONs) as convenient probes for metal ion detection in aqueous medium.

Recently, water contamination caused by metal ions has become one of the most serious problems as it has caused several deaths and socioeconomic problems around the world. Hence, the fast and accurate detection of metal ions in aqueous media has become the most important area of research; from time to time, new probes have been designed for this purpose. Among the previously reported sensors, probes based on fluorescent organic nanoparticles (FONs) have been gaining tremendous attention due to their ease of preparation/fabrication, synthetic diversity according to targeted metal ions, quick response, high selectivity toward different analytes at lower concentrations, tenable optical properties, and less toxicity. This review comprises two main sections, wherein we have tried to summarize the key progresses made in this field. The first section summarizes the literature dealing with FON-based chemosensors, which are used for the detection of transition metal ions of silver, copper, chromium, cadmium, mercury, iron, and zinc. The second section focuses on FON-based chemosensors that have been used for the detection of main group metal ions, namely, cesium, aluminum, strontium, lithium, and tin. Further, this review provides an adequate amount of information about the mechanism of metal ion sensing with FONs. It is expected that this review can provide sufficient information about this area of research and will be useful in fruitful progress in this field in the future.

Xanthenone-based hydrazones as potent α-glucosidase inhibitors: Synthesis, solid state self-assembly and in silico studies.

Xanthenone based hydrazone derivatives (5a-n) have been synthesized as potential α-glucosidase inhibitors. All synthesized compounds (5a-n) are characterized by their FTIR, 1H NMR, 13C NMR and HRMS, and in case of 5g also by X-ray crystallographic technique. The compounds unveiled a varying degree of α-glucosidase inhibitory activity when compared with standard acarbose (IC50 = 375.38 ±â€¯0.12 µM). Amongst the series, compound 5l (IC50 = 62.25 ±â€¯0.11 µM) bearing a trifluoromethyl phenyl group is found to be the most active compound. Molecular modelling is performed to establish the binding pattern of the more active compound 5l, which revealed the significance of substitution pattern. The pharmacological properties of molecules are also calculated by MedChem Designer which determines the ADME (absorption, distribution, metabolism, excretion) properties of molecules. The solid state self-assembly of compound 5g is discussed to show the conformation and role of iminoamide moiety in the molecular packing.

Synthesis of new chiral 1,3,4-thiadiazole-based di- and tri-arylsulfonamide residues and evaluation of in vitro anti-HIV activity and cytotoxicity.

A series of new chiral 1,3,4-thiadiazole-based bis-sulfonamides 4a-4w and tri-sulfonamide analogue 5 was synthesized and evaluated as anti-HIV agents. The reaction of chiral amino acids 1 with sulfonyl chlorides 2, followed by subsequent reaction of resultant N-protected amino acids 2a-2f with thiosemicarbazide in the presence of excess phosphorous oxychloride afforded N-(1-(5-amino-1,3,4-thiadiazol-2-yl)alkyl)-4-arylsulfonamides 3a-3f. Treatment of 2a-2f with substituted sulfonyl chlorides in portions furnished the target bis-sulfonamide analogues 4a-4w in good yields, together with the unexpected 5. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 4s were the most active in inhibiting HIV-1 with IC50 = 9.5 µM (SI = 6.6), suggesting to be a new lead in the development of an antiviral agent. Interestingly, compound 5 exhibited significant cytotoxicity of > 4.09 µM and could be a promising antiproliferative agent.

Synthesis and in vitro Bio-activity Evaluation of N4-benzyl Substituted 5-Chloroisatin-3-thiosemicarbazones as Urease and Glycation Inhibitors.

A series of fifteen N4-benzyl substituted 5-chloroisatin-3-thiosemicarbazones 5a-o were synthesized and screened mainly for their antiurease and antiglycation effects. Lemna aequinocitalis growth and Artemia salina assays were carried out to determine their phytotoxicity and cytotoxicity potential. All the compounds proved to be extremely effective urease inhibitors, demonstrating enzyme inhibition much better than the reference inhibitor, thiourea (IC50 values 1.31 ± 0.06 to 3.24 ± 0.15 vs. 22.3 ± 1.12 µM). On the other hand, eight out of fifteen compounds tested, i.e. 5b, 5c, 5h-k, 5m and 5n were found to be potent glycation inhibitors. Of these, five viz. 5c, 5h-j and 5n proved to be exceedingly efficient, displaying glycation inhibition greater than the reference inhibitor, rutin (IC50 values 114.51 ± 1.08 to 229.94 ± 3.40 vs. 294.5 ± 1.5 µM).

Synthesis, X-ray molecular structure, biological evaluation and molecular docking studies of some N4-benzyl substituted 5-nitroisatin-3-thiosemicarbazones.

A series of fifteen N4-benzyl substituted 5-nitroisatin-3-thiosemicarbazones 5a-o was synthesized and evaluated for urease inhibitory, phytotoxic and cytotoxic influences. All the compounds proved to be highly potent inhibitors of the enzyme, showing inhibitory activity (IC50=0.87±0.25-8.09±0.23µM) much better than the reference inhibitor, thiourea (IC50=22.3±1.12µM) and may thus act as persuasive leads for further studies. In phytotoxicity assay, twelve out of fifteen thiosemicarbazones tested i.e. 5a-e, 5g, 5i and 5k-o appeared to be active, exhibiting weak or non-significant (5-35%) growth inhibition at the highest tested concentrations (1000 or 500µg/mL). In contrast, only one compound i.e. 5i was active in the brine shrimp (Artemia salina) lethality bioassay, demonstrating cytotoxic activity with LD50 value 2.55×10-5M. Molecular docking studies of compounds 5a-o were also performed to identify their probable binding modes in the active site of the enzyme.

Synthesis and biological evaluation of 2-aminobenzamide derivatives as antimicrobial agents: opening/closing pharmacophore site.

A series of new 2-aminobenzamide derivatives (1-10) has been synthesized in good to excellent yields by adopting both conventional and/or a time-efficient microwave assisted methodologies starting from isatoic anhydride (ISA) and characterized on the basis of their physical, spectral and microanalytical data. Selected compounds of this series were then tested against various bacterial (Bacillus subtilis (RCMB 000107) and Staphylococcus aureus (RCMB 000106). Pseudomonas aeruginosa (RCMB 000102) and Escherichia coli (RCMB 000103) and fungal strains (Saccharomyces cerevisiae (RCMB 006002), Aspergillus fumigatus (RCMB 002003) and Candida albicans (RCMB 005002) to explore their potential as antimicrobial agents. Compound 5 was found to be the most active compound among those tested, which showed excellent antifungal activity against Aspergillus fumigatus (RCMB 002003) more potent than standard Clotrimazole, and moderate to good antibacterial and antifungal activity against most of the other strains of bacteria and fungi. Furthermore, potential pharmacophore sites were identified and their activity was related with the structures in the solution.

Synthesis and anti-inflammatory activity of new N-acyl-2-pyrazolines bearing homologous alkyloxy side chains.

A series of new pyrazoline derivatives (1a-2h) equipped with N-acyl arms and homologous alkyloxy side chains were synthesized and characterized on the basis of spectroscopic data and microanalysis. All the synthesized compounds were screened for their in-vitro anti-inflammatory activity to examine the effect of alkyloxy side chain length on activity. Compounds with odd number of carbons in alkyloxy side chain showed better activity as compared to even ones. Compound 2c (96% inhibition, IC(50) = 173.06 ± 2.312 mM) was found to be the most active compound of the series with better activity than the standard (Indomethacine, 92% inhibition, IC(50) = 273.12 ± 2.33 mM). Compound 1a (86%, IC(50) = 296.16 ± 2.091 mM) was the second best with comparable activity to the standard drug. However, the other compounds of series showed moderate to low activity. Interestingly, parallel cytotoxicity studies of compounds 1a-2h against PC-3 cell line revealed either no or very low cytotoxicity. The study may contribute in developing useful alternatives to presently used NSAIDs with harmful gastric effects due to direct cytotoxicity.

Recent drug design strategies and identification of key heterocyclic scaffolds for promising anticancer targets.

Cancer, a noncommunicable disease, is the leading cause of mortality worldwide and is anticipated to rise by 75% in the next two decades, reaching approximately 25 million cases. Traditional cancer treatments, such as radiotherapy and surgery, have shown limited success in reducing cancer incidence. As a result, the focus of cancer chemotherapy has switched to the development of novel small molecule antitumor agents as an alternate strategy for combating and managing cancer rates. Heterocyclic compounds are such agents that bind to specific residues in target proteins, inhibiting their function and potentially providing cancer treatment. This review focuses on privileged heterocyclic pharmacophores with potent activity against carbonic anhydrases and kinases, which are important anticancer targets. Evaluation of ongoing pre-clinical and clinical research of heterocyclic compounds with potential therapeutic value against a variety of malignancies as well as the provision of a concise summary of the role of heterocyclic scaffolds in various chemotherapy protocols have also been discussed. The main objective of the article is to highlight key heterocyclic scaffolds involved in recent anticancer drug design that demands further attention from the drug development community to find more effective and safer targeted small-molecule anticancer agents.

Novel isatin-triazole based thiosemicarbazones as potential anticancer agents: synthesis, DFT and molecular docking studies.

Thiosemicarbazones of isatin have been found to exhibit versatile bioactivities. In this study, two distinct types of isatin-triazole hybrids 3a and 3b were accessed via copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC), together with their mono and bis-thiosemicarbazone derivatives 4a-h and 5a-h. In addition to the characterization by physical, spectral and analytical data, a DFT study was carried out to obtain the optimized geometries of all thiosemicarbazones. The global reactivity values showed that among the synthesized derivatives, 4c, 4g and 5c having nitro substituents are the most soft compounds, with compound 5c having the highest electronegativity and electrophilicity index values among the synthesized series, thus possessing strong binding ability with biomolecules. Molecular docking studies were performed to explore the inhibitory ability of the selected compounds against the active sites of the anticancer protein of phosphoinositide 3-kinase (PI3K). Among the synthesized derivatives, 4-nitro substituted bisthiosemicarbazone 5c showed the highest binding energy of -10.3 kcal mol-1. These findings demonstrated that compound 5c could be used as a favored anticancer scaffold via the mechanism of inhibition against the PI3K signaling pathways.

Synthesis of 2,4-Bis(trifluoromethyl)benzaldehyde Hybrid Thiosemicarbazones as Prolyl Oligopeptidase Inhibitors for Neurodegenerative Disorders and their In-silico Analysis.

INTRODUCTION: Prolyl-specific oligopeptidase (POP), one of the brain's highly expressed enzymes, is an important target for the therapy of central nervous system disorders, notably autism spectrum disorder, schizophrenia, Parkinson's, Alzheimer's disease, and dementia. METHOD: The current study was designed to investigate 2,4-bis(trifluoromethyl) benzaldehyde- based thiosemicarbazones as POP inhibitors to treat the above-mentioned disorders. A variety of techniques, such as nuclear magnetic resonance (NMR), mass spectrometry (MS), and Fourier-transform infrared spectroscopy (FTIR), were used for the structural confirmation of synthesized compounds. After in-vitro evaluation, all of these compounds were found to be prominent inhibitors of the POP enzyme (IC50= 10.14 - 41.73 µM). RESULT: Compound 3a emerged as the most active compound (IC50 10.14 ± 0.72 µM) of the series. The kinetic study of the most active 3a (Ki =13.66 0.0012 µM) indicated competitive inhibition of the aforementioned enzyme. CONCLUSION: Moreover, molecular docking depicted a noticeable role of thiosemicarbazide moiety in the binding of these molecules within the active site of the POP enzyme.

Recent biological applications of heterocyclic hybrids containing s-triazine scaffold.

s-Triazine possesses an auspicious status in the field of drug discovery and development owing to its presence in many naturally occurring compounds as well as commercially available drugs like enasidenib, gedatolisib, bimiralisib, atrazine, indaziflam, and triaziflam. Easy, cost-effective, and efficient access to its derivatives in addition to their splendid biological activities such as anticancer, anti-inflammatory, antiviral, anticonvulsant, anti-tubercular, antidiabetic, antimicrobial, makes it an attractive heterocyclic nucleus in the field of medicinal chemistry. Other than the direct access of its derivatives from simple commercially available starting materials like amidine, the s-triazine derivatives have also been obtained starting from an inexpensive commercially available 2,4,6-trichloro-1,3,5-triazine (TCT) commonly known as cyanuric chloride. Owing to the high reactivity and the possibility of sequential substitution of TCT, a variety of biologically active heterocyclic scaffolds have been installed on this nucleus in order to have more potent compounds. These s-triazine-based heterocyclic hybrids have been reported to show enhanced biological activities in recent years. Therefore, it is important to summarize and highlight recent examples of these hybrids which is imperative to attract the attention of the drug development community.

Synthetic α-glucosidase inhibitors as promising anti-diabetic agents: Recent developments and future challenges.

Diabetes mellitus is one of the biggest challenges for the scientific community in the 21st century. It is a well-recognized multifactorial health problem contributes significantly to high mortality rates by causing serious health complications mainly related to cardiovascular diseases, kidney damage and neuropathy. The inhibition of α-glucosidase (enzyme that catalyses starch hydrolysis in the intestine) is an effective therapeutic approach for controlling hyperglycemia associated with type-2 diabetes. However, the presently approved drugs/inhibitors such as acarbose, miglitol and voglibose have several undesirable gastrointestinal side effects impeding their applications. Therefore, search for novel and more effective inhibitors with reduced side effects and less cost remains a fascinating area of research. In this context, a large variety of α-glucosidase inhibitors have been identified in recent years that demands attention from drug development community. This review is therefore an effort to summarize and highlight the promising α-glucosidase inhibitors especially those which are primarily based on aromatic heterocyclic scaffolds such as coumarin, imidazole, isatin, pyrimidine, quinazoline, triazine, thiazole etc, having improved safety and pharmacological profiles.

Synthesis of new diphenyl urea-clubbed imine analogs and its Implications in diabetic management through in vitro and in silico approaches.

Type II diabetes mellitus (T2DM) is a global health issue with high rate of prevalence. The inhibition of α-glucosidase enzyme has prime importance in the management of T2DM. This study was established to synthesize Schiff bases of 1,3-dipheny urea (3a-y) and to investigate their in vitro anti-diabetic capability via inhibiting α-glucosidase, a key player in the catabolism of carbohydrates. The structures of all compounds were confirmed through various techniques including, Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) and mass-spectrometry (MS) methods. Interestingly all these compounds displayed potent inhibition IC50 values in range of 2.14-115 µM as compared to acarbose used as control. Additionally, all the compounds were docked at the active site of α-glucosidase to predict their mode of binding. The docking results indicates that Glu277 and Asn350 play important role in the stabilization of these compounds in the active site of enzyme. These molecules showed excellent predicted pharmacokinetics, physicochemical and drug-likeness profile. The anti-diabetic potential of these molecules signifies their medical importance and provide insights into prospective therapeutic options for the treatment of T2DM.

Molecular duplexes featuring NH···N, CH···O and CH···π interactions in solid-state self-assembly of triazine-based compounds.

Synthetic supramolecular structures constructed through the cooperative action of numerous non-covalent forces are highly desirable as models to unravel and understand the complexity of systems created in nature via self-assembly. Taking advantage of the low cost of 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) and the sequential nucleophilic substitution reactions with almost all types of nucleophiles, a series of six structurally related novel s-triazine derivatives 1-6 were synthesized and structurally characterized based on their physical, spectral and crystallographic data. The solid-state structures of all the six compounds showed intriguing and unique molecular duplexes featuring NH···N, CH···O and CH···π interactions. Careful analysis of different geometric parameters of the involved H-bonds indicates that they are linear, significant and are therefore responsible for guiding the three-dimensional structure of these compounds in the solid state. The prevalence of sextuple hydrogen bond array-driven molecular duplexes and the possibility of structural modifications on the s-triazine ring render these novel triazine derivatives 1-6 attractive as a platform to create heteroduplex constructs and their subsequent utility in the field of supramolecular chemistry and crystal engineering.

Synthesis, solid state self-assembly driven by antiparallel π⋯π stacking and {⋯H-C-C-F}2 dimer synthons, and in vitro acetyl cholinesterase inhibition activity of phenoxy pendant isatins.

A series of novel phenoxy pendant isatins PI1-12 have been synthesized in excellent yields by a simple nucleophilic substitution reaction involving isatins and 1-(2-bromoethoxy)-4-substituted benzenes, and characterized by their FT-IR, 1H NMR, 13C NMR and GC-MS data, and in the case of PI4 by its single crystal X-ray analysis. The solid-state structure of PI4 showed an intriguing and unique 1D-supramolecular chain-based self-assembled structure, the driving force of which is mainly the strong antiparallel π⋯π stacking and {⋯H-C-C-F}2 dimer synthons. This compound not only highlights the potential of the isatin moiety in forming strong antiparallel π⋯π stacking interactions but also provides a platform to have considerable insight into the nature, strength and directionality of much debated π-π and C-H⋯F-C interactions. The in vitro biological studies revealed that three phenoxy pendant isatins PI1, PI2 and PI4 are highly potent inhibitors of acetylcholinesterase enzyme with IC50 values of 0.52 ± 0.073 µg ml-1, 0.72 ± 0.012 µg ml-1 and 0.68 ± 0.011 µg ml-1, respectively, showing comparable activity to the standard drug, donepezil (IC50 = 0.73 ± 0.015 µg ml-1). A simple and efficient synthesis of phenoxy pendant isatins PI1-12 from inexpensive and commercially available starting materials, and their high potential of acetyl cholinesterase inhibition provide an attractive opportunity to find more effective medication for Alzheimer's disease (AD).

Phenoxy pendant isatins as potent α-glucosidase inhibitors: reciprocal carbonyl⋯carbonyl interactions, antiparallel π⋯π stacking driven solid state self-assembly and biological evaluation.

Carbonyl-carbonyl (CO⋯CO) interactions are recently explored noncovalent interactions of significant interest owing to their role in the stability of biomacromolecules. Currently, substantial efforts are being made to understand the nature of these interactions. In this study, twelve phenoxy pendant isatins 1-12 have been evaluated for their α-glucosidase inhibitory potential in addition to the analysis of X-ray single crystals of 4 and 9. Both compounds 4 and 9 showed intriguing and unique self-assembled structures. The CO⋯CO and antiparallel displaced π⋯π stacking interactions are mainly involved in the formation of 1D-stair like supramolecular chains of 4 whereas antiparallel π⋯π stacking interactions drive the formation of 1D-columnar stacks of 9. These compounds not only highlight the potential of the isatin moiety in forming strong CO⋯CO and antiparallel π⋯π stacking interactions but also are interesting models to provide considerable insight into the nature of these interactions. The in vitro biological studies revealed that all twelve phenoxy pendant isatins 1-12 are highly potent inhibitors of α-glucosidase enzyme with IC50 values ranging from 5.32 ± 0.17 to 150.13 ± 0.62 µM, showing many fold more potent activity than the standard drug, acarbose (IC50 = 873.34 ± 1.67). Easy access and high α-glucosidase inhibition potential of these phenoxy pendant isatins 1-12 provide an attractive platform for finding more effective medication for controlling postprandial hyperglycemia.

Utilization of transition metal fluoride-based solid support catalysts for the synthesis of sulfonamides: carbonic anhydrase inhibitory activity and in silico study.

The applications of solid support catalysts in catalyzing organic reactions are well-evident. In the present study, we explored a transition metal fluoride (FeF3) adsorbed on molecular sieves (4 Å) as a solid support catalyst for the preparation of sulfonamides 3a-3o. The solid support catalyst was characterized via X-ray diffraction and AFM analysis. The catalyst was further explored for the synthesis of indoles 6a-h, 1H-tetrazoles and 1,4-dihydropyridines. The sulfonamides prepared herein were investigated for their potential to inhibit carbonic anhydrase (hCA II, hCA IX and hCA XII). All compounds were found to be active inhibitors with IC50 values in the low micromolar range. Some compounds were even found to be highly selective inhibitors. Compound 3i only inhibited hCA II (IC50 = 2.76 ± 1.1 µM) and had <27% inhibition against hCA IX and hCA XII. Similarly, 3e (IC50 = 0.63 ± 0.14 µM) only inhibited hCA XII and showed <31% inhibition against hCA II and hCA IX. Molecular docking studies were carried out to rationalize the ligand-binding site interactions. Given the lack of selective CA inhibitors, compounds 3e and 3i can provide significant leads for the further development of highly selective CA inhibitors.