Synthesis and exploration of 2-morpholino-4-phenylthiazol-5-yl acrylamide derivatives for their effects against carbonic anhydrase I,II, IX and XII isoforms as a non-sulfonamide class of inhibitors

Novel series of 2-morpholino-4-phenylthiazol-5-yl acrylamide derivatives (8a–s) have been synthesized and explored as a non-sulfonamide class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The newly synthesized molecules were evaluated for their CA inhibitory potency against four isoforms: the cytosolic isozyme hCA I, II as well as trans-membrane tumor associated isoform hCA IX and hCA XII taking acetazolamide (AAZ) as standard drug. The results revealed that most of the compounds showed good activity against hCA II, IX, and XII whereas none of them were active against hCA I (K_i >100 μM). It is observed that the physiologically most important cytosolic isoform hCA II was inhibited by these molecules in the range of K_i 9.3–77.7 μM. It is also found the both the transmembrane isoforms hCA IX and XII were also inhibited with K_is ranging between 54.7–96.7 μM and 4.6–8.8 μM, respectively. The binding modes of the active compounds within the catalytic pockets of hCA II, IX and XII were evaluated by docking studies. This new non-sulfonamide class of selective inhibitors of hCA II, IX and XII over the hCA I isoform may be used for further understanding the physiological roles of some of these isoforms in various pathologies.     

Benzenesulfonamide bearing 1,2,4-triazole scaffolds as potent inhibitors of tumor associated carbonic anhydrase isoforms hCA IX and hCA XII

Three series of novel heterocyclic compounds (3a–3g, 4a–4g and 5a–5g) containing benzenesulfonamide moiety and incorporating a 1,2,4-triazole ring, have been synthesized and investigated as inhibitors against four isomers of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozymes hCA I and II, compounds of two series (3a–3g and 4a–4g) showed K_i values in the range of 84–868 nM and 5.6–390 nM, respectively whereas compounds of series 5a–5g were found to be poor inhibitors (K_i values exceeding 10,000 nM in some cases). Against hCA IX and XII, all the tested compounds exhibited excellent to moderate inhibitory potential with K_i values in the range of 2.8–431 nM and 1.3–63 nM, respectively. Compounds 3d, 3f and 4f exhibited excellent inhibitory potential against all of the four isozymes hCA I, II, IX and XII, even better than the standard drug acetazolamide (AZA) whereas compound of the series 5a–5g were comparatively less potent but more selective towards hCA IX and XII.     

4-Functionalized 1,3-diarylpyrazoles bearing 6-aminosulfonylbenzothiazole moiety as potent inhibitors of carbonic anhydrase isoforms hCA I,II, IX and XII

A series of 24 novel heterocyclic compounds—functionalized at position 4 with aldehyde (5a–5f), carboxylic acid (6a–6f), nitrile (7a–7f) and oxime (8a–8f) functional groups—bearing 6-aminosulfonybenzothiazole moiety at position 1 of pyrazole has been synthesized and investigated for the inhibition of four isoforms of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozyme hCA I, compounds 6a–6f showed medium-weak inhibitory potential with K_i values in the range of 157–690 nM with 6a showing better potential than the standard drug acetazolamide (AZA). Against hCA II, all the compounds showed excellent to moderate inhibition with K_i values of compounds 5a, 5d, 5f, 6a–6f, 8d and 8f lower than 12 nM (K_i of AZA). Against hCA IX, all the compounds showed moderate inhibition with the exception of 6e which showed nearly 9 fold a better profile compared to AZA, whereas against hCA XII, four compounds 6e, 7a, 7b and 7d showed K_i in the same order as that of AZA. Carboxylic acid 6e was found to be an excellent inhibitor of both hCA IX and XII, with K_i values of 2.8 nM and 5.5 nM, respectively.     

Discovery of new ureido benzenesulfonamides incorporating 1,3,5-triazine moieties as carbonic anhydrase I,II, IX and XII inhibitors

A series of twenty novel ureido benzenesulfonamides incorporating 1,3,5-triazine moieties substituted on one side with aromatic amines and on the other side with dimethylamine, morpholine and piperidine is reported. The compounds were synthesized from the 4-(3-(4,6-dichloro-1,3,5-triazin-2-yl)ureido)benzensulfonamide (1) by using stepwise nucleophilic substitution of the chlorine atoms of cyanuric chloride. The intermediates 2(a-e) and final compounds 3(a-o) were tested for their efficiency as carbonic anhydrase (CA) inhibitors against four selected physiologically relevant human carbonic anhydrase (CA, EC 4.2.1.1) isoforms, namely, the cytosolic ones hCA I and II, and the transmembrane, tumor associated ones hCA IX, and XII. The compounds 2a, 2e and 3m showed the highest activity for hCA IX with K_is in the range of 11.8–14.6?nM. Most of the compounds showed high hCA IX selectivity over the abundant off-target isoforms hCA I and II. Since hCA IX is a validated drug target for anticancer/antimetastatic agents, these isoform-selective and potent inhibitors may be considered of interest for further medicinal/pharmacologic studies.     

Syntesis of thio- and seleno-acetamides bearing benzenesulfonamide as potent inhibitors of human carbonic anhydrase II and XII

A novel series of thio- and seleno-acetamides bearing benzenesulfonamide were synthetized and tested as human carbonic anhydrase inhibitors. These compounds were tested for the inhibition of four human (h) isoforms, hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX/XII). Several derivatives showed potent inhibition activity in low nanomolar range such as 3a, 4a, 7a and 8a. Furthermore, based on the tail approach we explain the interesting and selective inhibition profile of compound such as 5a and 9a, which were more selective for hCA I, 9b which was selective for hCA II, 3f selective for hCA IX and finally, 3e and 4b selective for hCA XII, over the other three isoforms. They are interesting leads for the development of more effective and isoform-selective inhibitors.     

New thiopyrimidine-benzenesulfonamide conjugates as selective carbonic anhydrase II inhibitors: synthesis,in vitro biological evaluation,and molecular docking studies

In the present work, a new series of thiopyrimidine-benzenesulfonamide conjugates was designed, synthesized and tested as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Our design strategy was based on the molecular hybridization of the benzenesulfonamide moiety as a zinc binding group (ZBG), an alkylated thiopyrimidine moiety as a spacer and (un)substituted phenyl moieties with various electronic and hydrophobic environments as a tail. The designed and synthesized compounds were evaluated against four human (h) CA isoforms hCA I, hCA II, hCA IX and hCA XII. Series 6 showed promising activity and selectivity toward the cytosolic isoforms hCA I and hCA II versus the membrane bound isoforms hCA IX and hCA XII. Compounds 6e and 6f showed K_i of 0.04 µM against hCA II with a selectivity of 15.8- to 980-fold towards hCA II over hCA I, hCA IX, hCA XII isoforms. Molecular docking in the hCA II active site attributed the promising inhibitory activity of series 6 to the interaction of their sulfonamide moiety with the active site Zn²⁺ ion as well as its hydrogen bonding with the key amino acids Thr199 and Thr200. Through hydrophobic interaction, the benzenesulfonamide and the thiopyrimidine moieties interact with the hydrophobic side chains of the amino acids Val121/Leu198 and Ile91/Phe131, respectively. These results indicated that the designed and synthesized series is an interesting scaffold that can be further optimized for the development of selective antiglaucoma drugs.     

Discovery of curcumin inspired sulfonamide derivatives as a new class of carbonic anhydrase isoforms I,II, IX,and XII inhibitors

A series of curcumin inspired sulfonamide derivatives was prepared from various chalcones and 4-sulfamoyl benzaldehyde via Claisen–Schmidt condensation. All new compounds were assayed as inhibitors of four human isoforms of the metalloenzyme carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I, II, IX and XII. Interesting inhibitory activities were observed against all these isoforms. hCA I, an isoform involved in several eye diseases was inhibited moderately with K_Is in the range of 191.8–904.2?nM, hCA II, an antiglaucoma drug target was highly inhibited by the new sulfonamides, with K_Is in the range of 0.75–8.8?nM. hCA IX, a tumor-associated isoform involved in cancer progression and metastatic spread was potently inhibited by the new sulfonamides, with K_Is in the range of 2.3–87.3?nM, whereas hCA XII, and antiglaucoma and anticancer drug target, was inhibited with K_Is in the range of 6.1–71.8?nM. It is noteworthy that one of the new compounds, 5d, was found to be almost 9 times more selective against hCA II (K_I =?0.89?nM) over hCA IX and hCA XII, whereas 5e was 3 and 70 times more selective against hCA II (K_I =?0.75?nM) over hCA IX and hCA XII, respectively.     

Pyrazolylbenzo[d]imidazoles as new potent and selective inhibitors of carbonic anhydrase isoforms hCA IX and XII

Novel pyrazolylbenzo[d]imidazole derivatives (2a–2f) were designed, synthesized and evaluated against four human carbonic anhydrase isoforms belonging to α family comprising of two cytosolic isoforms hCA I and II as well as two transmembrane tumor associated isoforms hCA IX and XII. Starting from these derivatives that showed high potency but low selectivity in favor of tumor associated isoforms hCA IX and XII, we investigated the impact of removing the sulfonamide group. Thus, analogs 3a–3f without sulfonamide moiety were synthesized and biological assay revealed a good activity as well as an excellent selectivity as inhibitors for tumor associated hCA IX and hCA XII and the same was analyzed by molecular docking studies.     

New coumarin/sulfocoumarin linked phenylacrylamides as selective transmembrane carbonic anhydrase inhibitors: Synthesis and in-vitro biological evaluation

Two novel series of phenylacrylamide linked coumarins and sulfocoumarins (6a-p, 8a-i, and 14a-g) were synthesized and evaluated against four physiologically relevant human carbonic anhydrases (hCAs, EC 4.2.1.1), isoforms hCA I, hCA II, hCA IX and hCA XII for their inhibitory action. All new compounds when screened for carbonic anhydrase inhibitory activity have shown selective inhibition towards the tumor associated isoforms hCA IX and XII over CA I and II, with inhibition constants in the submicromolar to low nanomolar range. Compound 6b and 14g exhibited significant inhibition with low nanomolar potency against hCA IX, whereas 6k was effective against hCA XII. Compounds 6b, 14g and 6k may be considered as lead molecules for future development of cancer therapeutics based on a novel mechanism of action.     

Synthesis of novel benzenesulfonamide bearing 1,2,3-triazole linked hydroxy-trifluoromethylpyrazolines and hydrazones as selective carbonic anhydrase isoforms IX and XII inhibitors

A series of twenty four hydroxy-trifluoromethylpyrazoline-carbonyl-1,2,3-triazoles and four hydrazones bearing benzenesulfonamide moieties was obtained by condensation of carboxyhydrazides with substituted 1,3-diketones. All the newly synthesized compounds were investigated as inhibitors of physiologically and pharmacologically relevant human (h) carbonic anhydrsae (CA, EC 4.2.1.1) cytosolic isoforms hCA I and II, as well as transmembrane tumor-assosciated isoforms hCA IX and XII. These compounds exhibited excellent CA inhibitory potency against the four CA isoenzymes as compared to clinically used reference drug acetazolamide (AAZ). Some compounds bearing bulkier group at C-5′ position of 1,2,3-triazoles ring were weaker inhibitors of hCA I. Inhibition assay against hCA II indicates, that several derivatives exhibited upto 27-fold more effective inhibitory activity compared to AAZ. Five of the assayed compounds displayed low nanomolar potency (K_i ≤ 10 nM) against hCA IX, whereas five compounds were found to be endowed with excellent inhibitory potencies (K_i ≤ 5 nM) against hCA XII. The biological activity profile presented herein will be useful for designing new leads and provide candidates for preclinical investigations.     

Synthesis and comparative carbonic anhydrase inhibition of new Schiff’s bases incorporating benzenesulfonamide,methanesulfonamide, and methylsulfonylbenzene scaffolds

Herein, we report the synthesis, characterization, and carbonic anhydrase (CA) inhibition of the newly synthesized Schiff’s bases 4–18 with benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds. The compound inhibition profiles against human CA (hCA) isoforms I, II, IX, and XII were compared to those of the standard inhibitors, acetazolamide (AAZ) and SLC-0111 (a CA inhibitor in Phase II clinical trials for the treatment of hypoxic tumors). The hCA I was inhibited by compounds 4a–8a with inhibition constants (K_I) in the range 93.5–428.1 nM (AAZ and SLC-0111: K_I, 250.0 and 5080.0 nM, respectively). Compounds 4a–8a proved to be effective hCA II inhibitors, with K_I ranging from 18.2 to 133.3 nM (AAZ and SLC-0111: K_I, 12.0 and 960.0 nM, respectively). Compounds 4a–8a effectively inhibited hCA IX, with K_I in the range 8.5–24.9 nM; these values are superior or equivalent to that of AAZ and SLC-0111 (K_I, 25.0 and 45.0 nM, respectively). Compounds 4a–8a displayed effective hCA XII inhibitory activity with K_I values ranging from 8.6 to 43.2 nM (AAZ and SLC-0111: K_I, 5.7 and 4.5 nM, respectively). However, compounds 9b–13b and 14c–18c were found to be micromolar CA inhibitors. For molecular docking studies, compounds 5a, 6a, and 8a were selected.     

Novel benzofuran-based sulphonamides as selective carbonic anhydrases IX and XII inhibitors: synthesis and in vitro biological evaluation

Abstract

Pursuing on our efforts toward searching for efficient hCA IX and hCA XII inhibitors, herein we report the design and synthesis of new sets of benzofuran-based sulphonamides (4a,b, 5a,b, 9a–c, and 10a–d), featuring the zinc anchoring benzenesulfonamide moiety linked to a benzofuran tail via a hydrazine or hydrazide linker. All the target benzofurans were examined for their inhibitory activities toward isoforms hCA I, II, IX, and XII. The target tumour-associated hCA IX and XII isoforms were efficiently inhibited with K _Is spanning in ranges 10.0–97.5 and 10.1–71.8?nM, respectively. Interestingly, arylsulfonehydrazones 9 displayed the best selectivity toward hCA IX and XII over hCA I (SIs: 39.4–250.3 and 26.0–149.9, respectively), and over hCA II (SIs: 19.6–57.1 and 13.0–34.2, respectively). Furthermore, the target benzofurans were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Only benzofurans 5b and 10b possessed selective and moderate growth inhibitory activity toward certain cancer cell lines.     

Synthesis and biological evaluation of coumarin-1,3,4-oxadiazole hybrids as selective carbonic anhydrase IX and XII inhibitors

With an aim to develop novel heterocyclic hybrids as potent anticancer agents, we synthesized a series of coumarin-1,3,4-oxadiazole hybrids (7a-t) and evaluated for their inhibitory activity against the four physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms CA I, CA II, CA IX and CA XII. The CA inhibition results clearly indicated that the coumarin-1,3,4-oxadiazole derivatives (7a-t) exhibited selective inhibition of the tumor associated isoforms, CA IX and CA XII over CA I and II isoforms. Among all, compound 7b, exhibited significant inhibition in lower micromolar potency against hCA XII, with a K_i of 0.16 µM and compound 7n, exhibited significant inhibition in lower micromolar potency against hCA IX, with a K_i of 2.34 µM respectively. Therefore, compound 7b and 7n could be the potential leads for development of selective anticancer agents by exhibiting a novel mechanism of action through hCA IX and XII inhibition.     

Synthesis,biological evaluation and in silico studies with 4-benzylidene-2-phenyl-5(4H)-imidazolone-based benzenesulfonamides as novel selective carbonic anhydrase IX inhibitors endowed with anticancer activity

In the presented work, we report the synthesis of a series of 4-benzylidene-2-phenyl-5(4H)-imidazolone-based benzenesulfonamides 7a-f via the Erlenmeyer–Plöchl reaction. All the prepared imidazolones 7a-f were evaluated as inhibitors of human (h) carbonic anhydrases (CA, EC 4.2.1.1) cytosolic isoforms hCA I and II, as well as transmembrane tumor-associated isoforms hCA IX and XII. All the tested hCA isoforms were inhibited by the prepared imidazolones 7a-f in variable degrees with the following K_Is ranges: 673.2–8169 nM for hCA I, 61.2–592.1 nM for hCA II, 23–155.4 nM for hCA XI, and 21.8–179.6 nM for hCA XII. In particular, imidazolones 7a, 7e, and 7f exhibited good selectivity towards the tumor-associated isoforms (CAs IX and XII) over the off-target cytosolic (CAs I and II) with selectivity index (SI) in the range of 6.2–19.4 and 3.3–8, respectively. Moreover, imidazolones 7a-f were screened for their anticancer activity in one dose (10⁻⁵ M) assay against a panel of 60 cancer cell lines according to US-NCI protocol. Furthermore, 7a, 7e and 7f were evaluated for their anti-proliferative activity against colorectal cancer HCT-116 and breast cancer MCF-7 cell lines. Furthermore, 7e and 7f were screened for cell cycle disturbance and apoptosis induction in HCT-116 cells. Finally, a molecular docking study was carried out to rationalize the obtained results.     

Novel synthesized SLC-0111 thiazole and thiadiazole analogues: Determination of their carbonic anhydrase inhibitory activity and molecular modeling studies

In the presented work, we report the design and synthesis of novel SLC-0111 thiazole and thiadiazole analogues (11a–d, 12a–d, 16a–c and 17a–d). A bioisosteric replacement approach was adopted to replace the 4-fluorophenyl tail of SLC-0111 with thiazole and thiadiazole ones, which were thereafter extended with lipophilic un/substituted phenyl moieties. All the newly synthesized SLC-0111 analogues were evaluated in vitro for their inhibitory activity towards a panel of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, II, IX and XII), using a stopped-flow CO₂ hydrase assay. All the examined isoforms were inhibited by the primary sulfonamide derivatives (11a–d and 12a–d) in variable degrees with the following K_I ranges: 162.6–7136 nM for hCA I, 9.0–833.6 nM for hCA II, 7.9–153.0 nM for hCA IX, and 9.4–94.0 nM for hCA XII. In particular, compounds 12b and 12d displayed 5.5-fold more potent inhibitory activity (K_Is = 8.3 and 7.9 nM, respectively) than SLC-0111 (K_I = 45 nM) towards hCA IX. Molecular docking study was carried out for 12d within the hCA IX (PDB 3IAI) active site, to justify its inhibitory activity.     

Design,synthesis, and carbonic anhydrase inhibition activity of benzenesulfonamide-linked novel pyrazoline derivatives

Carbonic anhydrases (CA, EC 4.2.1.1) are Zinc metalloenzymes and are present throughout most living organisms. Among the catalytically active isoforms are the cytosolic CA I and II, and tumor-associated CA IX and CA XII. The carbonic anhydrase (CA) inhibitory activities of newly synthesized pyrazoline-linked benzenesulfonamides 18–33 against human CA (hCA) isoforms I, II, IX, and XII were measured and compared with that of acetazolamide (AAZ), a standard inhibitor. Potent inhibitory activity against hCA I was exerted by compounds 18–25, with inhibition constant (K_I) values of 87.8–244.1 nM, which were greater than that of AAZ (K_I, 250.0 nM). Compounds 19, 21, 22, 29, 30, and 32 were proven to have inhibitory activities against hCA IX with K_I values (5.5–37.0 nM) that were more effective than or nearly equal to that of AAZ (K_I, 25.0 nM). Compounds 20–22, and 30 exerted potent inhibitory activities (K_Is, 7.1–10.1 nM) against hCA XII, in comparison with AAZ (K_I, 5.7 nM).     

Carbonic anhydrase inhibitors: Synthesis and inhibition of the human carbonic anhydrase isoforms I,II, VII,IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety

A series of 4,5,6,7-tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1–8) was synthesized by reaction of benzene sulfonamide derivatives with 4,5,6,7-tetrabromophthalic anhydride moiety. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I, II and VII and the transmembrane tumor-associated isoform hCA IX and XII. The new compounds were good hCA I inhibitors (Kis in the range of 143 to >10,000 nM), but were moderately effective, as hCA II inhibitors (Kis of 47–190 nM) and poor hCA VII inhibitors (Kis in the range of 54–175 nM) compared to acetazolamide. The tumor-associated hCA IX was effectively inhibited with Kis ranging between 8.5 and 234 nM and hCA XII with inhibition constants in the range of 6.1–197 nM with high selectivity ratio. The structure–activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking study of compounds was performed to rationalize the SAR reported over here.     

Computational investigation of the selectivity of salen and tetrahydrosalen compounds towards the tumor-associated hCA XII isozyme

Abstract

In previous work, 14 salen and tetrahydrosalen compounds have been synthesized and tested in enzyme inhibition assays against cytosolic human carbonic anhydrase isozymes I and II (hCA I and II) and tumor-associated isozymes IX and XII (hCA IX and XII). These compounds show selectivity against hCA XII over hCA I, II and IX. In this study, molecular modeling and docking studies were applied to understand this preference of the compounds for hCA XII. Most likely, the compounds can displace the zinc-bound water molecule of hCA XII to form a direct interaction with the Zn²⁺ ion. In the other isozymes, the compounds might not be able to displace the water molecule nor are they expected to interact with the Zn²⁺ ion.     

Design,synthesis and biological evaluation of coumarin-3-carboxamides as selective carbonic anhydrase IX and XII inhibitors

A series of novel 7-hydroxycoumarin-3-carboxamides was synthesized by the reaction of 7-hydroxy-2-oxo-2H-chromene-3-carboxylic acid with various substituted aromatic amines. The newly synthesized compounds were evaluated for their inhibitory activity against the four physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms CA I, CA II, CA IX and CA XII. The CA inhibition results show that the newly synthesized 7-hydroxycoumarin-3-carboxamides (4a-n) exhibited selective inhibition of the tumor associated isoforms, CA IX and CA XII over CA I and II isoforms. The inhibition constants ranged from sub micromolar to low micromolar. Amongst all the compounds tested, compound 4m was the most effective inhibitor exhibiting sub micromolar potency against both hCA IX and hCA XII, with a K_i of 0.2 µM. Therefore, it can be anticipated that compound 4m can serve as a lead for development of anticancer therapy by exhibiting a novel mechanism of action. The binding modes of the most potent compounds within hCA IX and XII catalytic clefts were investigated by docking studies.     

Carbonic anhydrase inhibitors: Synthesis and inhibition of the human carbonic anhydrase isoforms I,II, IX and XII with benzene sulfonamides incorporating 4- and 3-nitrophthalimide moieties

A series of 4 and 5 nitro-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1–8) was synthesized by reaction of benzenesulfonamide derivatives with 4 and 3-nitrophthalic anhydrides. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated hCA IX and XII. Most of the novel compounds were medium potency-weak hCA I inhibitors (K_is in the range of 295–10,000 nM), but were more effective hCA II inhibitors (K_is of 1.7–887 nM). The tumor-associated hCA IX was also inhibited, with K_is in the micromolar range, whereas against hCA XII the inhibition constants were in the range of 90–3746 nM. The structure–activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking studies was performed in order to rationalize the activities reported and binding mode to different hCA as inhibitors.