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Design and synthesis of three novel series of aryl enaminones ( 3a - f and 5a - c ) and pyrazole ( 4a-c ) linked compounds with sulphonamides, sulfaguanidine, or carboxylic acid functionalities were reported as carbonic anhydrase inhibitors (CAIs) using the "tail approach" strategy in their design to achieve the most variable amino acids in the middle/outer rims of the hCAs active site. The synthesised compounds were assessed in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IX, and XII using stopped-flow CO 2 hydrase assay. Enaminone sulphonamide derivatives ( 3a - c ) potently inhibited the target tumour-associated isoforms hCA IX and hCA XII (KIs 26.2-63.7 nM) and hence compounds 3a and 3c were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under normoxic and hypoxic conditions. Derivative 3c showed comparable potency against both MCF-7 and MDA-MB-231 cancer cell lines under both normoxic ((IC 50  = 4.918 and 12.27 µM, respectively) and hypoxic (IC 50  = 1.689 and 5.898 µM, respectively) conditions compared to the reference drug doxorubicin under normoxic (IC 50  = 3.386 and 4.269 µM, respectively) and hypoxic conditions (IC 50  = 1.368 and 2.62 µM, respectively). Cell cycle analysis and Annexin V-FITC and propidium iodide double staining methods were performed to reinforce the assumption that 3c may act as a cytotoxic agent through the induction of apoptosis in MCF-7 cancer cells.

Recently, different mechanisms for inhibition of carbonic anhydrases (CAs) have been reported, such as the classical zinc-binding (exerted by sulfonamides and carboxylic acids) as well as occluding the entrance of the CA active site (exerted by coumarins). In this manuscript, we studied the effect of combining the pharmacopheric parts responsible for these two mechanisms on CA inhibitory potency and selectivity through the design and synthesis of novel coumarins tethered with the zinc-binding sulfonamide (5a-f, 11a-b and 13a-b) or carboxylic acid (7a-f) groups. In addition, another set of coumarin derivatives (9a-b) with no zinc-binding group (ZBG) was designed to act as non-classical CA inhibitors. The synthesized coumarins were examined for their inhibitory activities towards four hCA isoforms I, II, IX and XII. Coumarin sulfonamides (5a-f, 11a-b and 13a-b) effectively inhibited both tumor-associated hCA IX (K I s: 8.9-133.5 nM) and hCA XII (K I s: 3.4-42.9 nM) isoforms, whereas coumarin carboxylic acids (7a-f) weakly affected hCA IX (K I s: 0.49-11.2 μM) and hCA XII (K I s: 0.51-10.1 μM) isoforms. The coumarin based inhibitors featuring zinc-binding sulfonamide or carboxylic acid group achieved low to moderate hCA IX/XII selectivity. Interestingly, the ZBG-free coumarin derivatives (9a-b) emerged not only as effective hCA IX (K I s = 93.3 and 63.8 nM, respectively) and hCA XII (K I s = 85.7 and 72.1 nM, respectively) inhibitors, but also as a highly hCA IX/XII selective inhibitors over the off-target hCA I/II isoforms (SIs > 1000). Coumarin 9a was further evaluated for its anti-proliferative effect on MCF-7 and PANC-1 cancer cell lines, as well as its effect on the cell cycle and apoptosis towards MCF-7 cell line., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In this study, diverse series of coumarin derivatives were developed as potential carbonic anhydrase inhibitors (CAIs). A "tail" approach was adopted by selecting the coumarin motif as a tail that is connected to the ZBG benzenesulfonamide moiety via a hydrazine (4a,b) or hydrazide (5a,b) linker. Thereafter, an aryl sulfone tail was incorporated to afford the dual tailed coumarin-sulfonamide arylsulfonehydrazones (13a-d) and hydrazides (14a,b). Then, the ZBG were removed from compounds 13 and 14 to furnish coumarin arylsulfonehydrazones (11a-d) and hydrazides (12a,b). Coumarin-sulfonamides 4 and 5 emerged as non-selective CAIs as they displayed good inhibitory activities toward all the examined CA isozymes (I, II, IX and XII) in the nanomolar ranges. Interestingly, the "dual-tail" approach (compounds 13 and 14) succeeded in achieving a good activity and selectivity toward CA IX/XII over the physiologically dominant CA I/II. In particular, compounds 13d and 14a were the most selective coumarin-sulfonamide counterparts. Concerning non-sulfonamide coumarin derivatives, coumarins 8 exhibited excellent activity and selectivity profiles against the target hCA IX/XII, whereas, coumarins 11 and 12 reported excellent selectivity profile, but they barely inhibited hCA IX/XII with K I s spanning in the micromolar ranges. Furthermore, molecular modelling studies were applied to get a deep focus about the feasible affinities and binding interactions for target coumarin-sulfonamides 4, 5, 13 and 14 with the active site for CA II, IX and XII isoforms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

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 s spanning in ranges 10.0-97.5 and 10.1-71.8 nM, respectively. Interestingly, arylsulfonehydrazones I s 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.

Herein we describe the design and synthesis of two series of sulfonamides featuring N-unsubstituted (4a-c) or N-substituted (7a-o) isatin moieties (as tails) connected to benzenesulfonamide moiety via a hydrazine linker. All the prepared sulfonamides (4a-c and 7a-o) showed potent inhibitory activities toward transmembrane tumor-associated human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, IX and XII with K I range (8.3-65.4 nM) and (11.9-72.9 nM), respectively. Furthermore, six sulfonamides (7e, 7i, 7j, 7m, 7n and 7o) were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Compounds 7j and 7n were the most promising counterparts in this assay displaying broad spectrum anti-proliferative activity toward diverse cell lines. Also, sulfonamide 7n significantly inhibited clonogenicity of HCT-116 cells in a concentration dependent manner in the colony forming assay. Moreover, molecular modeling studies were performed to gain insights for the plausible binding interactions and affinities for the target isatin-based sulfonamides (4a-c and 7a-o) within hCA isoforms II and IX active sites., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

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 CO 2 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 I s = 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

As a part of our ongoing efforts towards developing novel carbonic anhydrase inhibitors based on the isatin moiety, herein we report the synthesis and biological evaluation of novel sulfonamides (5a-h, 10a-g and 11a-c) incorporating substituted 2-indolinone moiety (as tail) linked to benzenesulfonamide (as zinc anchoring moiety) through a hydrazide linker. The synthesized sulfonamides were evaluated in vitro for their inhibitory activity against the following human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. All these isoforms were inhibited by the sulfonamides reported here in variable degrees. hCA I was inhibited with K I s in the range of 671.8: 3549.5 nM, hCA II in the range of 36.8: 892.4 nM; hCA IX in the range of 8.9: 264.5 nM, whereas hCA XII in the range of 9.0: 78.1 nM. In particular, compound 10b emerged as a single-digit nanomolar hCA IX and XII inhibitor (8.9 and 9.2 nM, respectively). Molecular docking studies carried out for compound 10b within the hCA II, IX and XII active sites allowed us to rationalize the obtained inhibition results., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

New series of benzenesulfonamide derivatives incorporating pyrazole and isatin moieties were prepared using celecoxib as lead molecule. Biological evaluation of the target compounds was performed against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more precisely against the human isoforms hCA I, II (cytosolic), IX and XII (transmembrane, tumor-associated enzymes). Most of the tested compounds efficiently inhibited hCA I, II and IX, with KIs of 2.5-102 nM, being more effective than the reference drug acetazolamide. Compounds 11e, 11f, 16e and 16f were found to inhibit hCA XII with Ki of 3.7, 6.5, 5.4 and 7.2 nM, respectively. Compounds 11e and 16e, with 5-NO2 substitution on the isatin ring, were found to be selective inhibitors of hCA IX and hCA XII. Docking studies revealed that the NO2 group of both compounds participate in interactions with Asp132 within the hCA IX active site, and with residues Lys67 and Asp130 in hCA XII, respectively., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)