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[Display omitted] • A novel series of 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives were designed and synthesized. • Compound 9o exhibited potent inhibitory activity and selective against CA IX over off-target CA II. • Molecular modeling revealed key binding interactions of 9o in the active site of CA IX. • Compound 9o suppressed cell migration, arrested the cell cycle and induced apoptosis and ferroptosis in MDA-MB-231 cells. • Compound 9o inhibited tumor growth and metastasis in a highly metastatic murine breast cancer 4T1xenograft model. A novel series of 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives were designed and synthesized as carbonic anhydrase IX (CA IX) inhibitors and ferroptosis inducers for the treatment of triple-negative breast cancer (TNBC). The representative compound 9o exhibited more potent inhibitory activity and selective against CA IX over off-target CA II, compared with positive control SLC-0111. Molecular docking study was also performed to gain insights into the binding interactions of 9o in the binding pocket of CAIX. Moreover, compound 9o exhibited superior antitumor activities against breast cancer cells under hypoxia than that of normoxia conditions. Mechanism studies revealed that compound 9o could act as DNA intercalator and effectively suppressed cell migration, arrested the cell cycle at G1/S phase and induced apoptosis in MDA-MB-231 cells, while inducing ferroptosis accompanied by the dissipation of MMP and the elevation intracellular levels of ROS. Notably, in vivo studies demonstrated that 9o effectively inhibited tumor growth and metastasis in a highly metastatic murine breast cancer 4 T1 xenograft model. Taken together, this study suggests that compound 9o represents a potent and selective CA IX inhibitor and ferroptosis inducer for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

[Display omitted] Sulfonamides have gained prominence as versatile agents in cancer therapy, effectively targeting a spectrum of cancer-associated enzymes. This review provides an extensive exploration of their multifaceted roles in cancer biology. Sulfonamides exhibit adaptability by acting as tyrosine kinase inhibitors, disrupting pivotal signaling pathways in cancer progression. Moreover, they disrupt pH regulation mechanisms in cancer cells as carbonic anhydrase inhibitors, inhibiting growth, and survival. Sulfonamides also serve as aromatase inhibitors, interfering with estrogen synthesis in hormone-driven cancers. Inhibition of matrix metalloproteinases presents an opportunity to impede cancer cell invasion and metastasis. Additionally, their emerging role as histone deacetylase inhibitors offers promising prospects in epigenetic-based cancer therapies. These diverse roles underscore sulfonamides as invaluable tools for innovative anti-cancer treatments, warranting further exploration for enhanced clinical applications and patient outcomes. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel series of 1,2,3-triazole benzenesulfonamides containing chalcone, pyridine and pyrimidine scaffolds were designed and synthesized as carbonic anhydrase IX and XII inhibitors. • The most potent compounds were screened for their in vitro anticancer activity against MCF-7, Hep-3B and normal WI-38 cell lines. • Molecular modeling and MDS studies were assessed to predict the stability of binding for the most active derivatives inside h CAIX and h CA XII active sites. • Physicochemical properties were predicted through ADME study. Novel 1,2,3-triazole benzenesulfonamide derivatives were designed as inhibitors for the tumor- related h CA IX and XII isoforms. Most of the synthesized compounds showed good inhibitory activity against h CA IX and h CA XII isoforms. Compounds 4d , 5h and 6b , exhibited remarkable activity as h CA IX inhibitors, with K i values in the range of 0.03 to 0.06 µM, more potent than AAZ. Additionally, compounds 5b and 6d , efficiently inhibited h CA XII isoform, with K i value of 0.02 µM, respectively, similar to AAZ. Further investigation for those potent derivatives against MCF-7, Hep-3B and WI-38 cell lines was achieved. Compounds 4d and 6d exerted dual cytotoxic activity against MCF-7 and Hep-3B cell lines, with IC 50 values of 3.35 & 2.12 µM against MCF-7 cell line and 1.72 & 1.56 µM against Hep-3B cell line, with high SI values ranged from 8.92 to 17.38 on both of the cell lines. Besides, they showed a high safety profile against normal human cell line, WI-38. Moreover, compound 5h had better cytotoxic effect on MCF-7 than the reference, DOX, with IC 50 value of 4.02 µM. While, compounds 5b and 6b showed higher activity against Hep-3B if compared to the reference drug, 5-FU. From ADME study, compounds 4d, 5b, 6b and 6d obeyed Lipinski's rule of five, and they might be orally active derivatives, while, compound 5h exerted less oral bioavailability than the reference standard acetazolamide. Molecular docking and MDS studies predicted the binding mode and the stability of the target compounds inside h CA IX and h CA XII active sites, especially for compounds 5b and 6b. [ABSTRACT FROM AUTHOR]

[Display omitted] • New compounds harboring the privileged thienopyrimidine scaffold were designed and synthesized. • They were tested for their inhibitory activity against carbonic anhydrase isoforms. • Compound 5r exhibited activity against CA II, CA IX and CA XII with Ki values of 8.6, 13.8, and 19 nM , respectively. • Molecular docking study was carried out to predict binding modes in the binding pockets of the four carbonic anhydrase isoforms. Eighteen novel compounds harboring the privileged thienopyrimidine scaffold (5a-q, and 6a) , were designed based on molecular hybridization strategy. These compounds were synthesized and tested for their inhibitory activity against four different carbonic anhydrase isoforms: CA I, II, IX, and XII. Microwave and conventional techniques were applied for their synthesis. Compounds 5b, 5g, 5l, and 5p showed the highest inhibition activity against the four CA isoforms. Compound 5p exhibited promising inhibitory activity against CA II, CA IX and CA XII with K I values of 8.6, 13.8, and 19 nM , respectively, relative to AAZ, where K I s = 12, 25, and 5.7 nM , respectively. Also, compound 5 l showed significant activity against the tumor-associated isoform CA IX with K I = 16.1 nM. All the newly synthesized compounds were also screened for their anticancer activity against NCI 60 cancer cell lines at a 10 µM concentration. Compound 5n showed 80.38, 83.95, and 87.39 % growth inhibition against the leukemic cell lines CCRF-CEM, HL-60 (TB), and RPMI-8226, respectively. Also, 5 h showed 87.57 % growth inhibition against breast cancer cell line MDA-MB-468; and 66.58 and 60.95 % inhibition against renal cancer cell lines UO-31, and ACHN, respectively. A molecular docking study was carried out to predict binding modes of our synthesized compounds in the binding pockets of the four carbonic anhydrase isoforms, and results revealed that compounds 5b, 5g, 5l , and 5p succeeded in mimicking the binding mode of AAZ through metal coordination with Zn+2 ion and binding to the amino acids Thr199, His94, and His96 that are critical for activity. [ABSTRACT FROM AUTHOR]

[Display omitted] Over the last decades, the medicinal chemistry of boron-based compounds has been extensively explored, designing valuable small molecule drugs to tackle diseases and conditions, such as cancer, infections, inflammatory and neurological disorders. Notably, boron has proven to also be a valuable element for the development of inhibitors of the metalloenzymes carbonic anhydrases (CAs), a class of drug targets with significant potential in medicinal chemistry. Incorporating boron into carbonic anhydrase inhibitors (CAIs) can modulate the ligand ability to recognize the target and/or influence selectivity towards different CA isoforms, using the tail approach and boron-based tails. The electron-deficient nature of boron and its associated properties have also led to the discovery of novel zinc-binding CAIs, such as boronic acids and the benzoxaboroles, capable of inhibiting the CAs upon a Lewis acid-base mechanism of action. The present manuscript reviews the state-of-the-art of boron-based CAIs. As research in the applications of boron compounds in medicinal chemistry continues, it is anticipated that new boron-based CAIs will soon expand the current array of such compounds. However, further research is imperative to fully unlock the potential of boron-based CAIs and to advance them towards clinical applications. [ABSTRACT FROM AUTHOR]

A bioisosteric replacement approach was adopted to replace the 4-fluorophenyl tail of SLC-0111 with thiazole and thiadiazole ones, which were thereafter extended by lipophilic un/substituted phenyl moieties. • New series of thiazole and thiadiazole derivatives were synthesized as SLC-0111 congeners. • Inhibitory activities of such analogues were evaluated towards hCA I, II, IX and XII isoforms. • Compounds 11c and 12b–d showed superior inhibitory activity against hCA IX than SLC-0111. • 11a , 12a , 12b and 12d were found to be selective towards hCAIX and XII over hCA II. • A docking study was done for 12d within the hCA IX active site to justify its inhibitory activity. 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. [ABSTRACT FROM AUTHOR]

Compounds 15, 45, 47, and 26 exhibited potent selective inhibitory activity against human isoforms CA I, II, IX, and XII (K I s: 39.4, 0.73, 1.6, and 5.2 nM, respectively), comparable to that of acetazolamide (AAZ) as a standard inhibitor (K I : 250.0, 12.0, 25.0, and 5.7 nM respectively). • Quinazoline-linked benzensulfonamides with CA inhibitory activity were synthesized. • Newly synthesized compounds potently inhibit human isoforms CA I, II, IX and XII. • Inhibitory activity of new compounds was comparable to that of CA inhibitor AAZ. • Compounds 14–15, 17, 19–21, 24–25, 28–29, 31, 35, 45, 47, 49&51 inhibit hCA I (K I s: 39.4–354.7 nM). • Compounds 15, 20, 24, 28, 29, 45, and 47 inhibit hCA II (K I s: 0.73–16.5 nM). • Compounds 13–29, 31–32, and 45–51 inhibit hCA IX (K I s: 1.6–32.2 nM). Carbonic anhydrase (CA) inhibitory activities of newly synthesized quinazoline-linked benzensulfonamides 10 – 29 , 31 , 32 , 35 , 36, and 45 – 51 against human CA (hCA) isoforms I, II, IX, and XII were measured and compared to that of acetazolamide (AAZ) as a standard inhibitor. Potent selective inhibitory activity against hCA I was exerted by compounds 14 , 15 , 17 , 19 , 20 , 21 , 24 , 25 , 28 , 29 , 31 , 35 , 45 , 47 , 49, and 51 with inhibition constant (K I s) values of 39.4–354.7 nM that were nearly equivalent or even greater than that of AAZ (K I , 250.0 nM). Compounds 15 , 20 , 24 , 28 , 29 , 45 and 47 proved to have inhibitory activities against hCA II with (K I s, 0.73–16.5 nM) that were similar or improved to that of AAZ (K I , 12.0 nM). Compounds 13 – 29 , 31 – 32, and 45 – 51 displayed potent hCA IX inhibitory activities (K I s, 1.6–32.2 nM) that were more effective than or nearly equal to AAZ (K I , 25.0 nM). Compounds 14 , 15 , 20 , 21 , 26 , 45, and 47 exerted potent hCA XII inhibitory activities (K I s, 5.2–9.2 nM), indicating similar CAI activities as compared to that of AAZ (K I , 5.7 nM). [ABSTRACT FROM AUTHOR]

• A serie of novel pyrazole compounds (1–8 and 9a, b) was synthesised. • These precursors have been characterized by 1H and 13C NMR and FTIR spectroscopies. • Molecular docking studies of compounds (1 – 4) were obtained. • Their inhibition effects on hCA I, hCA II, and AChE enzymes were determined. A series of substituted pyrazole compounds (1 – 8 and 9a , b) were synthesized and their structure was characterized by IR, NMR, and Mass analysis. These obtained novel pyrazole derivatives (1 – 8 and 9a , b) were emerged as effective inhibitors of the cytosolic carbonic anhydrase I and II isoforms (hCA I and II) and acetylcholinesterase (AChE) enzymes with K i values in the range of 1.03 ± 0.23–22.65 ± 5.36 µM for hCA I, 1.82 ± 0.30–27.94 ± 4.74 µM for hCA II, and 48.94 ± 9.63–116.05 ± 14.95 µM for AChE, respectively. Docking studies were performed for the most active compounds, 2 and 5, and binding mode between the compounds and the receptors were determined. [ABSTRACT FROM AUTHOR]

• There is an great need for new antibacterial agents to treat resistant infections. • Inhibition of CAs from resistance-showing bacteria was assessed with sulfonamides. • Comparison was made with α-class human ubiquitous isoforms. • Click-tailed benzenesulfonamides showed potency and selectivity. • A subnanomolar VchCAα inhibitor was indentified. A series of 1,2,3-triazole-bearing benzenesulfonamides was assessed for the inhibition of carbonic anhydrases (CA, EC 4.2.1.1) from bacteria Vibrio cholerae (VchCAα and VchCAβ) and Mycobacterium tuberculosis (β-mtCA3). Growing resistance phenomena against existing antimicrobial drugs are globally spreading and highlight a urgent need of agents endowed with alternative mechanisms of action. Two global WHO strategies aim to reduce cholera deaths by 90% and eradicate the tuberculosis epidemic by 2030. The derivatives here reported represent interesting leads towards the optimization of new antibiotic agents showing excellent inhibitory efficiency and selectivity for the target CAs over the human (h) off-target isoform hCA I. In detail, the first subset of derivatives potently inhibits VchCAα in a low nanomolar range (K I s between 0.72 and 22.6 nM). Compounds of a second subset, differing from the first one for the position of the spacer between benzenesulfonamide and triazole, preferentially inhibit VchCAβ (K I s in the range 54.8–102.4 nM) and β-mtCA3 (K I s in the range 28.2–192.5 nM) even more than the clinically used AAZ, used as the standard. [ABSTRACT FROM AUTHOR]

• Novel selenoderivatives CAIs of the β-CA from L. donovani chagasi are reported. • In vitro studies reported potent inhibition of the β-CA from L. donovani chagasi. • Leishmanicidal evaluation on L. infantum amastigotes and cytotoxicity in THP-1 cells. We report new organoselenium compounds bearing the sulfonamide moiety as effective inhibitors of the β-isoform of Carbonic Anhydrase from the unicellular parasitic protozoan L. donovani chagasi. All derivatives were evaluated in vitro for their leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells. Compounds 3e-g showed their activity in the low micromolar range with IC 50 values spanning from 0.72 to 0.81 µM and selectivity indexes (SI) > 8 (for 3g SI > 30), thus much higher than those observed for the reference drugs miltefosine and edelfosine. This is the first study which reports new selenoderivatives with promising leishmanicidal properties and acting as Carbonic Anhydrase inhibitors too thus paving the way to the development of innovative agents for the treatment of neglected diseases such as leishmaniasis. [ABSTRACT FROM AUTHOR]

• Hybrid pharmacophore containing sulfonamide, amide and amine designed and synthesized. • All the derivatives 4a-4m showed better inhibition than acetazolamide, with 4l exhibiting momentous inhibition. • The chemo-informatics and ligands-protein binding analyses carried out. Selective inhibition of carbonic anhydrase (CA) enzyme is an active area of research for medicinal chemists. In the current account, a hybrid pharmacophore approach was employed to design sulfonamide, amide and amine containing new series of potent carbonic anhydrase II inhibitors. The aromatic fragment associated with pharmacophore was altered suitably in order to find effective inhibitors of CA-II. All the derivatives 4a-4m showed better inhibition compared to the standard acetazolamide. In particular, compound 4l exhibited significant inhibition with IC 50 value of 0.01796 ± 0.00036 µM. The chemo-informatics analysis justified that all the designed compounds possess <10 HBA and <5 HBD. The ligands-protein binding analyses showed that 4l confined in the active binding pocket with three hydrogen bonds observed with His63, Asn66 and Thr197 residues. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of trimellitimides incorporating benzenesulfonamides and carboxylates. • Anti-inflammatory, ulcerogenic and cyctotoxic activities were studied. • The derivatives were investigated as COX-1/2 inhibitors. • The derivatives were elucidated as hCA I, II, IV and IX inhibitors. • Sulfonamide derivatives exhibited the best inhibitory activity against COX-2 and CA. Abstract Trimellitimides 6 – 21 were prepared and investigated in vivo for anti-inflammatory and ulcerogenic effects and in vitro for cytotoxicity. They were subjected to in vitro cyclooxygenase (COX-1/2) and carbonic anhydrase inhibition protocols. Compounds 6 – 11 and 18 exhibited anti-inflammatory activities and had median effective doses (ED 50) of 34.3–49.8 mg kg−1 and 63.6–86.6% edema inhibition relative to the reference drug celecoxib (ED 50 : 33.9 mg kg−1 and 85.2% edema inhibition). Compounds 6 – 11 and 18 were weakly cytotoxic at 10 μM against 59 cell lines compared with the reference standard 5-fluorouracil (5-FU). Compounds 6 – 11 had optimal selectivity against COX-2. The selectivity index (SI) range was >200–490 and was comparable to that for celecoxib [COX-2 (SI) > 416.7]. In contrast, compounds 12 , 13 , and 16 – 18 were nonselective COX inhibitors with a selectivity index range of 0.92–0.25. The carbonic anhydrase inhibition assay showed that sulfonamide incorporating trimellitimides 6 – 11 inhibited the cytosolic isoforms hCA I and hCA II, and tumor-associated isoform hCA IX. They were relatively more susceptible to inhibition by compounds 8 , 9 , and 11. The K I ranges were 54.1–81.9 nM for hCA I, 25.9–55.1 nM for hCA II, and 46.0–348.3 nM for hCA IX. © 2018 Elsevier Science. All rights reserved. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Benzotriazole mediated dipeptide synthesis. • Thirty new dipeptide-primary sulfonamide conjugates. • 4-(2-Aminoethyl)benzenesulfonamide-dipeptide Conjugates. • Potent carbonic anhydrase (hCA I, II, IV and XII) inhibitors. Abstract Thirty novel sulfonamide derivatives incorporating dipeptide were synthesized by facile acylation through benzotriazole mediated reactions and their structures were identified by 1H NMR, 13C NMR, MS and FT-IR spectroscopic techniques and elemental analysis. The carbonic anhydrase (CA, 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 XII. Most of the synthesized compounds showed excellent in vitro carbonic anhydrase inhibitory properties comparable to those of the clinically used drug acetazolamide (AAZ). The new unprotected dipeptide-sulfonamide conjugates showed very effective inhibitory activity, in the low nanomolar range against II and XII, being less effective as hCA I and IV inhibitors. Four of the thirty compounds also showed strong inhibitory activity against hCA XII compared to AAZ. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Novel 1,2,4-triazole-5-on derivatives were synthesized. • Evaluated for in vitro Carbonic anhydrase II inhibition. • Compound 7c emerged as the most active compound. • Docking studies were performed for the most active compound (7c). • ADME analysis. Abstract Carbonic anhydrase (CA) II plays major roles in pH regulation of body, protection of electrolyte balance, transportation of water and some metabolic pathways. Therefore, CA II inhibitors are very important molecules for drug design and have many pharmacological applications. CA II as a target molecule is also important for eliminating some pathological conditions such as glaucoma, cancer, epilepsy, ulcer and obesity. In this study, some 1,2,4-triazole derivatives were synthesized and CA II inhibition potentials of these molecules were examined. It has been found that molecule 7c was the most potent inhibitor with the lowest IC 50 value at micromolar level among the examined molecules. The inhibition in the range of 18.41–64.97% was seen in the presence of newly synthesized molecules at their reachable maximum concentration in the reaction mixtures. Kinetic studies showed that the inhibition mechanism of compound 7c on carbonic anhydrase activity was reversible and uncompetitive. Molecular docking studies also indicated that compound 7c could bind to the active site of the enzyme by weakly interacting with especially Gln102, Leu240, Ala241 and Trp243. ADME properties of these newly synthesized (3a-e , 6 , 7a-e) were also studied and showed good oral drug candidate like properties. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Twenty 1,2,4-trisubstituted imidazolin-5-one derivatives were synthesized. • Target compounds were evaluated as dual p38αMAPK/CA enzyme inhibitors. • The best p38αMAPK inhibition results were for compounds 3c, 3g, 3h, 4a, 6c and 6d. • The best hCA inhibition result was for compound 4a. • 4a was discovered as a potent dual p38αMAPK/CA inhibitor in this work. Abstract Various 1,2,4 trisubstituted imidazolin-5-one derivatives were synthesized and evaluated for their inhibitory activity against p38 mitogen-activated protein kinase (p38MAPK) and carbonic anhydrase (CA) enzymes aiming to explore potential dual inhibitors. Results revealed that compounds 3c, 3g, 3h, 4a, 6c and 6d were the most effective derivatives against p38αMAPK (IC 50 = 0.14, 0.14, 0.056, 0.14, 0.13 and 0.14 μM, respectively) compared to sorafenib (IC 50 = 1.58 μM) as standard drug. On the other hand, compound 4a revealed the best inhibitory activity against all the tested carbonic anhydrase isoforms CA I, II, IV and IX with K i values of 95.0, 0.83, 6.90 and 12.4 nM, respectively compared to acetazolamide with K i values 250, 12.1, 74 and 12.8 nM, respectively. Therefore, compound 4a can be considered as a potent dual p38αMAPK/CA inhibitor. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The synthesis of a series of novel ureido benzenesulfonamides incorporating 1,3,5-triazine moieties was reported. • The ureido benzenesulfonamides incorporating 1,3,5-triazine derivatives were investigated as hCA I, II, IX and XII inhibitors. • The derivatives showed to be subnanomolar to nanomolar inhibitors of hCA IX isozyme with K i s in the range of 0.91–126.2 nM. • These derivatives showed some selectivity for hCA IX over hCA I, II and XII isoforms. Abstract A series of novel ureido benzenesulfonamides incorporating 1,3,5-triazine moieties were obtained by reacting 4-isocyanato-benzenesulfonamide (2) with 2-amino-4,6-dicholoro-1,3,5-triazine (4). The 4-(3-(4,6-dichloro-1,3,5-triazin-2-yl)ureido) benzenesulfonamide (5) was subsequently derivatized by reaction with various nucleophiles such as, morpholine, ammonia, methyl amine, dimethyl amine, and piperidine. The ureido benzenesulfonamides incorporating triazinyl moieties were investigated as inhibitors of four selected physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, namely, hCA I, II, IX, and XII which are involved in various diseases such as glaucoma, epilepsy, obesity and cancer. The membrane-bound tumor-associated isoform hCA IX was potently inhibited with these compounds with K i s in the range of 0.91–126.2 nM. Specifically, compound 7j showed great potency against hCA IX with sub-nanomolar K i of 0.91 nM. Since hCA IX is a validated drug target for anticancer agents, these isoform-selective and potent inhibitors may be considered of interest for further medicinal/pharmacologic studies. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Inhibitory activity of isatin-based sulfonamides was evaluated toward hCA IX and XII isoforms. • All sulfonamides inhibited hCA IX with K I s spanning in the nanomolar range (6.2–64.8 nM). • hCA XII was highly inhibited by all sulfonamides with K I s in the range of 7.1–55.6 nM. • Anti-proliferative activity against MCF-7 and HCT-116 cancer cell lines was examined. • Sulphonamide 9e induced the intrinsic apoptotic mitochondrial pathway in HCT-116 cells. Abstract Three series of indolinone-based sulfonamides (3a–f, 6a–f and 9a–f) were in vitro evaluated as inhibitors of the tumor-associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA IX and XII, using a stopped-flow CO 2 hydrase assay. All the investigated sulfonamides displayed single- or double-digit nanomolar inhibitory activities towards both hCA IX (K I s: 6.2–64.8 nM) and XII (K I s: 7.1–55.6 nM) isoforms. All sulfonamides (3a–f, 6a–f and 9a–f) were in vitro examined for their potential anticancer activity against colorectal cancer HCT-116 and breast cancer MCF-7 cell lines. Sulfonamide 9e was found to be the most potent counterpart against HCT-116 (IC 50 = 3.67 ± 0.33 µM). Sulfonamide 9e displayed good selectivity profile for inhibition of the tumor-associated isoforms (CAs IX & XII) over the off-target cytosolic CAs I and II. 9e was screened for cell cycle disturbance and apoptosis induction in HCT-116 cells. It was found to persuade cell cycle arrest at G 2 -M stage as well as alter the Sub-G 1 phase. Also, 9e induced the intrinsic apoptotic mitochondrial pathway in HCT-116 cells via down-regulation of the anti-apoptotic protein Bcl-2 level with concurrent boosting the pro-apoptotic Bax, caspase-9, caspase-3, cytochrome C and p53 levels. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • 24 New dipeptides-sulfonamide derivatives. • Potent carbonic anhydrase (hCA I, II and IX) inhibitors. • Peptide synthesis. Abstract Twenty-four novel sulfonamide derivatives incorporating dipeptide tails were synthesized by facile acylation reactions of homosulfanilamide through benzotriazole or dicyclohexyl carbodiimide (DCC) mediated coupling reactions. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against four human (h) isoforms, hCA I, hCA II, hCA IX and hCA XII. Most of the synthesized compounds showed good in vitro carbonic anhydrase inhibitory properties, with inhibition constants in the low nanomolar range. Particularly, the new dipeptide-sulfonamide conjugates incorporating Ala, Phe and Met in the dipeptide sequence, showed the most effective inhibitory activity against to CA IX and XII. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesis of novel N -cyano- N -acyl-4-aminobenzenesulfonamides via acylation of potassium (4-sulfamoylphenyl)cyanamide. • Biochemical characterization as inhibitors of carbonic anhydrases and two cathepsins was performed. • Dual-active compounds against enzymes involved in neuropathic pain are reported. A set of novel N -cyano- N -substituted 4-aminobenzenesulfonamide derivatives were synthesized and investigated for their inhibitory activity against four cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, II, VII and XIII) and two cathepsins (S and B). N -alkyl/benzyl-substituted derivatives were revealed to be very potent inhibitors against brain-associated hCA VII, but inactive against both cathepsins. On the other hand, N -acyl-substituted derivatives displayed significant inhibitory activities against cathepsin S, but only moderate to poor inhibitory potency against hCA VII. Both hCA VII and cathepsin S have recently been validated as therapeutic targets in neuropathic pain. This study provided an excellent starting point for further structural optimization of this class of bifunctional compounds to enhance their inhibitory activity and selectivity against hCA VII and cathepsin S and to achieve new compounds with an attractive dual mechanism of action as anti-neuropathic agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • Substituted furan sulfonamides as carbonic anhydrase inhibitors. • Synthesis of substituted furan sulfonamides. • Biological evaluation- Carbonic Anhydrise inhibitory activity. • Molecular Docking Studies. • ADME properties. • Drug-Likeness and Bioavailability score. Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several of biological processes, such as respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show wide diversity in tissue distribution and in their subcellular localization. Fifteen novel furyl sulfonamides were designed, synthesized and evaluated against four human isoforms: hCA I, hCA II, hCA IV and hCA IX. Compounds appeared to be very active mostly against hCAI (8) and hCA IV (11) isoforms being more potent than reference drug acetazolamide (AAZ). It should be mentioned that four compounds were more active than AAZ against hCA IX isoform, with compound 13d to be selective against hCA I (SI 70), hCA II (SI 13.5) and hCA IV (SI 20). Furthermore, docking was performed for some of these compounds on all isoforms I order to understand the possible interactions with the active site. The most active compounds showed good bioavailability and drug likeness scores. [ABSTRACT FROM AUTHOR]

One of the most successful approaches for designing carbonic anhydrase (CA, EC 4.2.1.1) inhibitors was denominated ‘the sugar approach’. The sugar approach consists in attaching different carbohydrates to CA inhibiting pharmacophores for modulating the physicochemical properties of these pharmacological agents. In line with this approach, in this paper, we present a new class of C -glycosides incorporating the sulfamoylphenyl moiety. These compounds have been prepared by sulfamoylation of C-glycosyl phenols, which have been synthetized by aldol reaction of glycosyl ketones with the appropriate aromatic aldehydes. The inhibition profile of the new glycomimetics was determined against four human (h) CA isozymes, comprising hCAs I and II (cytosolic, ubiquitous isozymes), hCA IV and hCA IX (tumor associated isozyme). Peracetylated and deprotected C -glycosyl sulfamates showed better inhibition selectivity compared to structurally related phenylsulfamates. In this study, deprotected compound 12 was identified as selective inhibitor of hCA IX. These results confirm that attaching carbohydrate moieties to CA sulfamoylphenyl pharmacophore improves its inhibitory activity. [ABSTRACT FROM AUTHOR]

A series of novel aromatic primary sulfonamides decorated with diversely substituted 1,2,4-oxadiazole periphery groups has been prepared using a parallel chemistry approach. The compounds displayed a potent inhibition of cytosolic h CA II and membrane-bound h CA IX isoforms. Due to a different cellular localization of the two target enzymes, the compounds can be viewed as selective inhibition tools for either isoform, depending on the cellular permeability profile. The SAR findings revealed in this study has been well rationalized by docking simulation of the key compounds against the crystal structures of the relevant h CA isoforms. [ABSTRACT FROM AUTHOR]

4-Chloro-3-nitrobenzenesulfonamide reacted cleanly at room-temperature with a range of bis-electrophilic phenols bearing an NH-acidic functionality (secondary carboxamide or pyrazole) in the ortho -position. This produced a novel class of [1,4]oxazepine-based primary sulfonamides which exhibited strong inhibition of therapeutically relevant human carbonic anhydrases. 2-Chloronitrobenzene did not enter a similar cyclocondensation process, even under prolonged heating. Thus, the primary sulfonamide functionality plays a dual role by enabling the [1,4]oxazepine ring construction and acting as a enzyme prosthetic zinc-binding group when the resulting [1,4]oxazepine sulfonamides are employed as carbonic anhydrase inhibitors. [ABSTRACT FROM AUTHOR]

Curcumin is a multi-functional pharmacologically safe natural agent with proven cytoprotective effects to healthy human cells. In this study, a new series of sulfonamides with curcumin scaffold were synthesized, characterized and investigated for their carbonic anhydrase isoenzyme I (human) and II (bovine) isoforms. The structures of newly synthesized compounds were described by IR, 1 H NMR and 13 C NMR spectral data. Compound 14 showed the K i value of 0.99 µM with highest inhibitory activity among all other synthesized compounds against hCA-I enzyme. Similarly enzyme kinetic studies of compound 14, 16 and 30 against bCAII enzyme showed Ki values of 0.71, 0.67 and 0.71 µM respectively. Our biological assays results showed that most of active compounds have similar inhibitory activities compared to standard acetazolamide drug. The molecular docking predicted binding modes showed that these compounds bind with hCA-1 enzyme in similar fashion. [ABSTRACT FROM AUTHOR]

A series of N -substituted and N , N -disubstituted β-amino acids and their derivatives bearing benzenesulfonamide moiety were designed and synthesized in search of compounds that would be high-affinity and selective inhibitors of human carbonic anhydrases (CA). There are 12 catalytically active human CA isoforms, the cytosolic CA I, CA II, CA III, CA VII, and CA XIII, secreted CA VI, the mitochondrial CA VA and CA VB, membrane-associated CA IV, and transmembrane CA IX, CA XII, and CA XIV. The di-bromo meta-substituted compounds exhibited low nanomolar dissociation constants and over 10-fold selectivity for mitochondrial isozyme CA VB, implicated in diseases of the central nervous system and obesity. These compounds can be used for further development as inhibitors of significant binding affinity and selectivity towards CA VB isozyme. [ABSTRACT FROM AUTHOR]

[Display omitted] Rational of the design based on duail-tail approach resulting compound 4g with promising biological activity with detailed molecular simulations to justify this activity. • Arylidine-extended pyrazole benzenesulfonamides were designed based on tail approach. • In vitro evaluation for the synthesized compounds took place against hCA I, II, IV and IX. • Compounds 4g and 8a were tested for their cytotoxic activities against MCF-7 and MBA-MB231. • Compound 4g were subjected to cell cycle and apoptotic studies. • Molecular modeling simulations were performed for compounds 4g and 8a to assess their mechanism of action. Several pyrazole-benzene sulfonamides were reported as human carbonic anhydrase inhibitors. In this research work, a design of Arylidine-extented 5-oxo-pyrazole benzenesulfonamides (4a-i), (8a-d) and (10a-e) were reported based on tail-approach design. Beside the reported synthetic procedures and confirmation by different analytical procedures, a DFT study was employed to confirm the Z- conformer of the synthesized compounds. In vitro biological assay against four different human carbonic anhydrases took place and based on the results, SAR study was illustrated and selectivity indexes were discussed. Compounds 4g and 8a exhibited the best inhibitory activity among the target compounds with values (hCAIX: K I = 71.2 nM, hCAXII: K I = 22.5 nM), (hCAIX: K I = 34.3 nM, hCAXII: K I = 74.3 nM); respectively. Both of them were subjected to cellular assay against two different cancer cell lines with expressing nature to hCA isoforms under both normoxic and hypoxic conditions. Compound 4g showed the highest cytotoxic activity against MCF-7 cancer cell line (IC 50 = 4.15 µM under hypoxic conditions and IC 50 = 8.59 µM under normoxic conditions) compared to the reference drug doxorubicin under normoxic, (IC 50 = 4.34 µM), and hypoxic, (IC 50 = 2.23 µM), conditions. Further cellular investigations were employed to study the effect of this compound on the cell cycle of the affected cell line. Finally, molecular docking supported by molecular dynamic simulation was utilized to understand the mechanism of the inhibitory activity of two of these compounds – as representative examples- based on the designed rational. [ABSTRACT FROM AUTHOR]

In this study, a series of novel bromophenols were synthesized from benzoic acids and methoxylated bromophenols. The synthesized compounds were evaluated by using different bioanalytical antioxidant assays including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS + ) radical scavenging assays. Also, reducing power of novel bromophenols were evaluated by Cu 2+ -Cu + reducing, Fe 3+ -Fe 2+ reducing and [Fe 3+ -(TPTZ) 2 ] 3+ -[Fe 2+ -(TPTZ) 2 ] 2 + reducing and ferrous ions (Fe 2+ ) chelating abilities. The compounds demonstrate powerful antioxidant activities when compared to standard antioxidant molecules of α-tocopherol, trolox, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT). Also in the last part of this studies novel bromophenols were tested against some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE) enzymes and carbonic anhydrase I, and II (hCA I and hCA II) isoenzymes. The newly synthesized bromophenols showed Ki values in a range of 6.78 ± 0.68 to 126.07 ± 35.6 nM against hCA I, 4.32 ± 0.23 to 72.25 ± 12.94 nM against hCA II, 4.60 ± 1.15 to 38.13 ± 5.91 nM against AChE and 7.36 ± 1.31 to 29.38 ± 3.68 nM against BChE. [ABSTRACT FROM AUTHOR]

In the present study, a series of new hybrid compounds containing chalcone and methanoisoindole units 7a-n ((3a R ,4 S ,7 R ,7a S )-2-(4-(( E )-3-(3-aryl)acryloyl) phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione) were synthesized, characterized and investigated for their anticancer activity against C6 gliocarcinoma cell in rats, and antimicrobial activity against some human pathogen microorganisms. The compounds 7e , 7h , 7j , 7k , 7L and 7n showed very high anticancer activity with the inhibition range of 80.51–97.02% compared to 5-FU. Some of the compounds exhibited anti-microbial activity. Also, they evaluated for inhibition effects against human carbonic anhydrase I, and II isoenzymes (hCA I and II) with Ki values in the range of 405.26–635.68 pM for hCA I, and 245.40–489.60 pM for hCA II, respectively. These results demonstrated that 3a R ,4 S ,7 R ,7a S )-2-(4-(( E )-3-(3-aryl)acryloyl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives could be used in different biomedical applications. [ABSTRACT FROM AUTHOR]

In this study, 45 bisindolylmethanes having sulfonamide moiety had been synthesized through 3 steps. In vitro assay for inhibition of carbonic anhydrase showed that some of the compounds having sulfonamide moiety are capable of inhibiting carbonic anhydrase II. Bisindoles having halogens at fifth position showed better inhibitory activity as compared to unsubstituted bisindoles. The results obtained from in vitro inhibitory activity were subjected through 3D QSAR and docking studies to identify important features contributing to the activity and further improve the structure. Pharmacophore studies suggest that bisindolylmethane moiety is contributing significantly towards the inhibition activity. Docking studies showed that compounds having nitro substituent ( 5g and 5i ) were found to be able interact with Zn 2+ ion, Thr199, His94, His96, and His119, which interferes with the Zn OH Thr199 Glu106 hydrogen bond network. Bulky nitro substituent at ortho position for compound 5g prevents the compound from interacting with other residues like Thr199 and Thr200. Methyl substituent at ortho position for Compound 5i induces less steric hindrance effect, thus allowing second oxygen atom of sulfonamide to interact with Thr199 (2.51 Å). Hydrogen bonding between NH on indole ring with Glu69 might have increased stability of ligand-receptor complex. [ABSTRACT FROM AUTHOR]

Elevated levels of carbonic anhydrase II (CA II) have been shown to be associated with cardiac hypertrophy and heart failure. Although arjunolic acid (AA) has a diverse range of therapeutic applications including cardio-protection, there have been no reports on the effect of AA on CA II. The present study describes for the first time, the novel zinc independent inhibition of CA II by AA. The molecular docking studies of AA indicated that the hydroxyl group at C 2 of the A-ring, which hydrogen bonds with the catalytic site residues (His64, Asn62 and Asn67), along with the gem -dimethyl group at C 20 of the E-ring, greatly influences the inhibitory activity, independent of the catalytic zinc, unlike the inhibition observed with most CA II inhibitors. Among the triterpenoids tested viz. arjunolic acid, arjunic acid, asiatic acid, oleanolic acid and ursolic acid, AA was the most potent in inhibiting CA II in vitro with an IC 50 of 9 μM. It was interesting to note, that in spite of exhibiting very little differences in their structures, these triterpenoids exhibited vast differences in their inhibitory activities, with IC 50 values ranging from 9 μM to as high as 333 μM. Furthermore, AA also inhibited the cytosolic activity of CA in H9c2 cardiomyocytes, as reflected by the decrease in acidification of the intracellular pH (pH i ). The decreased acidification reduced the intracellular calcium levels, which further prevented the mitochondrial membrane depolarization. Thus, these studies provide a better understanding for establishing the novel molecular mechanism involved in CA II inhibition by the non-zinc binding inhibitor AA. [ABSTRACT FROM AUTHOR]

A series of acyl selenoureido benzensulfonamides was evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors against two Vibrio cholerae such enzymes (VchCAα over VchCAβ) belonging to the α- and β-classes, potential novel targets for anti-infective drugs development. These compounds showed strong inhibitory action against VchCAα over VchCAβ and excellent selectivity over the human (h) off-target isoforms hCA I and II. Identification of potent and possibly selective inhibitors of VchCAα and/or VchCAβ over the human counterparts may lead to pharmacological tools useful for understanding the physiological role(s) of these under-investigated proteins, possibly involved in the virulence of the bacterium and colonization of the host in bicarbonate rich regions of the gastro-intestinal tract. [ABSTRACT FROM AUTHOR]

[Display omitted] • Compounds 19, 22, 26, 27 were more potent and selective inhibitors of cancer-associated hCA IX isoenzyme over hCA I. • Compounds 22 and 26 were more selective hCA IX inhibitors over hCA II isoenzyme. • Compounds 19, 22, 23, 24 and 26 showed higher cytotoxicity against OSCC with IC50 in the range of 1.6–1.7 μM. • Lead compounds showed significant dose-dependent cytotoxic effects. Pyrazole-based carbohydrazone hybrids have been considered to be a remarkable class of compounds in pharmaceutical chemistry. Here, we reported bioactivities of 4-(3-(2-(arylidene)hydrazin-1-carbonyl)-5-phenyl-1 H -pyrazol-1-yl)benzenesulfonamides (1 – 27) towards CA isoenzymes (hCA I, hCA II, hCA IX) and human oral squamous cell carcinoma cell line. Compounds 19 (Ki = 10.1 nM, hCA I/hCA IX = 749.6), 22 (Ki = 18.5 nM, hCA I/hCA IX = 429.2), 26 (Ki = 14.5 nM, hCA I/hCA IX = 596.9), 27 (Ki = 21.5 nM, hCA I/hCA IX = 413.1) were more potent and selective inhibitors of cancer-associated hCA IX isoenzyme. Compounds 22 and 26 were also found to be approximately three times more selective hCA IX inhibitors over off-target hCA II at low nanomolar. Compounds 19 , 22 , 23 , 24, and 26 with IC 50 of 1.6–1.7 μM showed potent cytotoxicity against human oral squamous cell carcinoma cell line as compared with human gingival fibroblast, producing the tumor-specificity value over 100. This was due to its cytostatic growth inhibition accompanied by a slight but significant dose-dependent increase in cell shrinkage and subG1 cell accumulation and marginal activation of caspase 3 substrates. Bioassay results showed that carbohydrazone-based hybrids could be useful candidates to design novel anticancer compounds and selective carbonic anhydrase inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] • Summative view of tail-approach based selective as well as potent hCA IX and XII inhibitors reported in the last decade. • Listing of the most promising molecules in terms of selectivity and potency from the available 181 research papers. • One stop solution to tailor the tail-approach based rational design of novel libraries of carbonic anhydrase inhibitors. Human carbonic anhydrase (hCA) isoforms hCA IX and hCA XII are well established anticancer drug targets and their selective inhibition is highly desired for the proper treatment of cancer. Lack of isoform-selectivity in current clinically used CA inhibitors (CAIs) is a major concern as it leads to undesired side effects, associated with off-target inhibition. Thus, there is need to explore alternative approaches for the design of isoform-selective inhibitors and the leading promising approach for the design of isoform-selective CAIs is "the tail-approach". Virtually, most drug design studies in the last decade were done by considering the tail-approach reported in 1999. The past decade of 2010–2020 witnessed progressive maturation of this approach as a large number of CAIs have been designed and synthesised based on it, many of which turned out to be effective as well as selective hCA IX and hCA XII inhibitors. This review covers the past decade (2010–2020) research, considering selective as well as potent inhibitors of tumor associated isoforms, hCA IX and hCA XII, which include newer generation inhibitors containing sulfonamides or their bioisosteres, non-classical inhibitors (including carboxylic acid/ester, coumarin and sulfocoumarin classes) and various other novel classes of inhibitors belonging to newly identified chemotypes/scaffolds. [ABSTRACT FROM AUTHOR]

[Display omitted] • - Different sets of coumarin-sulfonamide, coumarin-carboxylic acid and coumarin derivatives were synthesized. • - Inhibitory activities of all derivatives were evaluated toward hCA I, II, IX and XII isoforms. • - Coumarin-sulfonamides displayed superior hCA IX/XII inhibitory activities (K I s: 3.4–59 nM). • - Coumarins 9a - b exhibited excellent hCA IX/XII selectivity (SIs > 1000) over hCA I and II. • - Coumarin 9a showed promising anticancer activities against and MCF-7 cancer cell lines. 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 h CA 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. [ABSTRACT FROM AUTHOR]