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Human carbonic anhydrase (hCA) isoforms IX and XII are promising anticancer targets. Yet, their selective inhibition remains elusive due to close similarity with the abundant hCA II, whose off-target inhibition causes harmful side effects. Here, we introduce an interpretable machine learning framework to predict inhibition across hCA II, IX, and XII. To address this issue, our approach combines rigorous data curation, systematic benchmarking of classical and deep learning models, and integration of conformal prediction for uncertainty quantification with counterfactual explanations for molecular interpretability. After extensive benchmarking, we find that Support Vector Machines with extended-connectivity fingerprints consistently outperform more complex models, underscoring the importance of data quality and validation over algorithmic complexity. Here, conformal prediction provides rigorous activity estimation, while counterfactual analysis rationalizes structural features governing isoform selectivity, together enabling interpretable guidance for inhibitor design. To further test our model capability, we examine it on SLC-0111, as a selective inhibitor, which leads to a compatible result with the experiment. Our model reiterates experimental findings that modifications in the tail region strongly affect molecular selectivity, emphasizing the tail group as a key structural determinant for differentiating inhibitor activity among hCA isoforms II, IX, and XII. To facilitate adoption, we also release CAInsight , a user-friendly software with a graphical interface for virtual screening and generative design of a selective hCA inhibition.

Pyrazoles are unique bioactive molecules with a versatile biological profile and they have gained an important place on pharmaceutical chemistry. Pyrazole compounds containing sulfonamide nuclei also attract attention as carbonic anhydrase (CA) inhibitors. In this study, a library of pyrazole-carboxamides were synthesized and the structures of the synthesized molecules were characterized using FT-IR, 1 H-NMR, 13 C-NMR and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. K i values of the compounds were in the range of 0.063–3.368 µM for hCA I and 0.007–4.235 µM for hCA II. Molecular docking studies were performed between the most active compounds 6a , 6b and the reference inhibitor, acetazolamide ( AAZ ) and the hCA I and hCA II receptors to investigate the binding mechanisms between the compounds and the receptors. These compounds showed better interactions than the AAZ . ADMET analyzes were performed for the compounds and it was seen that the compounds did not show AMES toxicity. The stability of the molecular docking results over time was analysed by 50 ns molecular dynamics simulations. Molecular dynamics simulations revealed that 6a and 6b exhibited good stability after docking to the binding sites of hCA I and hCA II receptors, with minor conformational changes and fluctuations. Graphical abstract Synthesis, molecular docking, molecular dynamics simulations, drug-likeness, ADMET prediction and biological evaluation of pyrazole-carboxamides bearing sulfonamide moiety as potent carbonic anhydrase inhibitors

In this study, newly synthesised compounds 6, 8, 10 and other compounds (1-5, 7 and 9) and their inhibitory properties against the human isoforms hCA I and hCA II were reported for the first time. Compounds 1-10 showed effective inhibition profiles with K I values in the range of 5.13-16.9 nM for hCA I and of 11.77-67.39 nM against hCA II, respectively. Molecular docking studies were also performed with Glide XP to get insight into the inhibitory activity and to evaluate the binding modes of the synthesised compounds to hCA I and II. More rigorous binding energy calculations using MM-GBSA protocol which agreed well with observed activities were then performed to improve the docking scores. Results of in silico calculations showed that all compounds obey drug likeness properties. The new compounds reported here might be promising lead compounds for the development of new potent inhibitors as alternatives to classical hCA inhibitors.

A series of benzo[d]thiazole-5- and 6-sulfonamides has been synthesized and investigated for the inhibition of several human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, using ethoxzolamide (EZA) as lead molecule. 2-Amino-substituted, 2-acylamino- and halogenated (bromo-and iodo-derivatives at the heterocyclic ring) compounds led to several interesting inhibitors against the cytosolic hCA I, II and VII, as well as the transmembrane, tumor-associated hCA IX isoforms. Several subnanomolar/low nanomolar, isoform-selective sulfonamide inhibitors targeting hCA II, VII and IX were detected. The sharp structure–activity relationship for CA inhibition with this small series of derivatives, with important changes of activity observed even after minor changes in the scaffold or at the 2-amino moiety, make this class of scarcely investigated sulfonamides of particular interest for further investigations.

A new series of isoxazole-fused thiazole-oxazole derivatives ( ) was rationally designed and synthesised with the aim of developing potent carbonic anhydrase (CA) I and II inhibitors. The synthesis was achieved in five steps starting from 4-bromoacetophenone, involving key intermediates such as hydroxylamine hydrochloride, hydrazine hydrate, thioisocyanate, and various phenacyl bromide derivatives, using ethanol, triethylamine, tetrahydrofuran (THF), and dimethylformamide (DMF) as solvents. The synthetic route included the formation of a β-ketoester, isoxazole ester, hydrazine adduct, thiourea derivative, and, ultimately, a thiazole ring. The structures of the final compounds were confirmed by H-NMR, C-NMR, IR spectroscopy, and elemental analysis. All compounds were examined as inhibitors of human carbonic anhydrase (hCA) I and II, and all of them inhibited hCA I and hCA II. Kinetic investigation results revealed that these compounds inhibited hCA I and hCA II in a non-competitive manner. To further explore the molecular basis of their inhibitory activity, in silico studies, including molecular docking and 300 ns molecular dynamics (MD) simulations, were carried out against both CA I and CA II isoforms. These simulations provided detailed insights into the dynamic behaviour, stability, and key binding interactions of the compounds within the enzyme active sites, supporting their potential as promising carbonic anhydrase inhibitors.

In this study, we have aimed to determine the and effects of 23 frequently used dermatologic drugs on human carbonic anhydrase I (hCA I) and II (hCA II). The inhibitory effects of the drugs on hCA I and hCA II were determined by esterase methods. The most potent inhibitors were isotretinoin for hCA I (Ki= 5.75 µM) and valaciclovir for hCA II (Ki= 5.74 µM). Ketotifen (Ki= 6.98 µM), pantoprazole (Ki= 7.16 µM) and acyclovir (Ki= 7.31 µM) were also potent inhibitors for hCA I. Isotretinoin (Ki= 6.54 µM), brivudine (Ki= 7.44 µM) and fluconazole (Ki= 7.91 µM) were also potent inhibitors for hCA II. Terbinafine hydrochloride was a weak CA inhibitor for both of these isoenzymes (Ki= 20.58 µM for hCA I and 20.32 µM for hCA I). Therefore, the drug, having a weak CA inhibitory activity, may be preferred primarily in patients with a skin disease compared to the other drugs due to important physiological functions of CAs. Molecular docking studies have shown that acitretin and isotretinoin, in particular, will inhibit hCA I at lower concentrations and have higher docking scores. For hCA II, it was shown that Isotretinoin and Ketotifen would inhibit at lower concentrations and have higher placement scores.

A library of benzenesulphonamides incorporating 1,2,3-triazole rings functionalised with ester, carboxylic acid, carboxamide, carboxyhydrazide, and hydroxymethyl moieties were synthesised. The carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against four human (h) isoforms, hCA I, hCA II, hCA IV, and hCA IX. Among them, hCA II and IV are anti-glaucoma drug targets, being involved in aqueous humour secretion within the eye. hCA I was inhibited with Ki’s ranging between 8.3 nM and 0.8737 µM. hCA II, the physiologically dominant cytosolic isoform, was excellently inhibited by these compounds, with Ki’s in the range of 1.6–9.4 nM, whereas hCA IV was effectively inhibited by most of them, with Ki’s in the range of 1.4–55.3 nM. Thirteen of the twenty sulphonamides were found to be excellent inhibitors of tumour associated hCA IX with Ki’s ≤ 9.5 nM. Many of the new compounds reported here showed low nM inhibitory action against hCA II, IV, and IX, isoforms involved in glaucoma and some tumours, making them interesting candidates for further medicinal chemistry/pharmacologic studies.

Inhibition of carbonic anhydrases (EC 4.2.1.1, h CAs) is known to be a potential target for treatment of several disorders like epilepsy, glaucoma, obesity, and cancer. The current research focuses on the synthesis of a series of 4’-amino-[1,1’-biphenyl]-4-sulfonamide derivatives (9a-e) through cross-coupling reactions in the presence of Cu(OAc) 2 catalyst. The structural elucidation of synthesized derivatives was carried out through 1 H NMR, and 13 C NMR. These sulphonamide derivatives were screened for inhibitory potential towards various isozymes of carbonic anhydrases including h CA-II, h CA-IX, and h CA-XII. Enzyme inhibition assay exhibited that synthesized derivatives with IC 50  ± SEM, 9e (0.38 ± 0.03 µ M), 9d (0.21 ± 0.03 µ M) and 9b (0.69 ± 0.15 µ M) had remarkable inhibition potency against h CA-II, h CA-IX and h CA-XII respectively. It was noted that 9d exhibited 8-fold more inhibitor potential as compared to standard inhibitor acetazolamide. For the most potent inhibitors, enzyme kinetic analysis was also carried out to find inhibition mode. Furthermore, the drug-ability of synthesized compounds was evaluated through SwissADME tools, and found that all the newly prepared derivatives successfully satisfied the drug-ability criteria. Molecular docking studies were conducted to identify the types of interactions between the synthesized ligands and the target proteins.

In the modern age of drug discovery sulfanilamide derivatives are known to have great anti-cancerous potential, the current study aimed to synthesize these derivatives in order to evaluate their biological properties against carbonic anhydrase II (CA-II) and Dickkopf − 1(Dkk1) protein which are highly expressed in many cancers including lung cancer. A series of 10 sulfanilamide derivatives was synthesized under controlled conditions using reflux condensation method. Among all the synthesized derivatives (5a-5j) , the compound 5d was found to possess highest antioxidant activity (90.7397 ± 0.0732 µg/mL) comparable to vitamin C (95.1571 ± 0.057 µg/mL) and also exhibited maximum inhibition against CA-II with an IC 50 value of 0.00690 ± 0.1119 µM, indicating that 5d is significantly more potent as compared to standard i.e., acetazolamide IC 50  = 0.9979 ± 0.0024 µM. Keeping in view the importance of Dkk1 protein in cancer progression, the molecular docking investigations were performed, where compound 5d was proved to be the potential dual inhibitor of CA-II as well as Dkk1 with the binding energy of 8.9 and 9.7 kcal/mol, respectively. In addition to this DNA binding studies also confirmed the significance of compound 5d where it had maximum binding constant value of 6.7 × 10 4 mol − 1 , supporting the other biological investigations and was in agreement with the reported values. All the experimental and computational results reveals the excellent potential of 5d as a candidate medicine in future. Conclusively, the current study may lead to the new therapeutic strategies for the treatment of cancer associated with the aberrant expression of CA-II and less explored DDK1 target.

A series of compounds incorporating 3-(3-(2/3/4-substituted phenyl)triaz-1-en-1-yl) benzenesulfonamide moieties were synthesised and their chemical structure was confirmed by physico-chemical methods. Carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the compounds were evaluated against human isoforms hCA I and II. K I values of these sulphonamides were in the range of 21 ± 4-72 ± 2 nM towards hCA I and in the range of 16 ± 6-40 ± 2 nM against hCA II. The 4-fluoro substituted derivative might be considered as an interesting lead due to its effective inhibitory action against both hCA I and hCA II (K I s of 21 nM), a profile rarely seen among other sulphonamide CA inhibitors, making it of interest in systems where the activity of the two cytosolic isoforms is dysregulated.