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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.)

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.)

Herein we report the design and synthesis of three different sets of novel benzenesulfonamides (5a-e, 7a-e and 10a-d) incorporating hydrophilic/hydrophobic tails by hydrazido or hydrazino linkers. The newly synthesized benzenesulfonamides were examined in vitro for their inhibitory activity towards four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII using a stopped-flow CO 2 hydrase assay. All these isoforms were inhibited by the sulfonamides (5a-e, 7a-e and 10a-d) with variable degrees in the following K I ranges: 76.8-357.4 nM for hCA I, 8.2-94.6 nM for hCA II, 2.0-46.3 nM for hCA XI, and 8.3-88.3 nM for hCA XII. The sulfonamide 7d exhibited potent anti-proliferative activity against breast MCF-7 cancer cell line under both normoxic and hypoxic conditions with IC 50 values equal 3.32 ± 0.06 and 8.53 ± 0.32 μM, respectively, which are comparable to the reference drug doxorubicin (IC 50  = 2.36 ± 0.04 and 8.39 ± 0.25 μM, respectively). Furthermore, 7d was screened for cell cycle disturbance and apoptosis induction in MCF-7 cells. It was found to persuade cell cycle arrest at G2-M stage as well as to alter the Sub-G1 phase, also, 7d resulted in a significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Molecular docking study was carried out for 7d within the hCA IX and hCA XII active sites to rationalize the obtained inhibition results., (Copyright © 2019 Elsevier Masson SAS. 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.)

The synthesis and characterization of two new sets of arylsulfonehydrazone benzenesulfonamides (4a-4i with phenyl tail and 4j-4q with tolyl tail) are reported. The compounds were designed according to a dual-tails approach to modulate the interactions of the ligands portions at the outer rim of both hydrophobic and hydrophilic active site halves of human isoforms of carbonic anhydrase (CA, EC 4.2.1.1). The synthesized sulfonamides were evaluated in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IV and IX. With the latter being a validated anticancer drug target and a marker of tumor hypoxia, attractive results arose from the Compounds' inhibitory screening in terms of potency and selectivity. Indeed, whereas the first subset of compounds 4a-4i exhibited great efficacy in inhibiting both the ubiquitous, off-target hCA II (K I s 9.5-172.0 nM) and hCA IX (K I s 7.5-131.5 nM), the second subset of tolyl-bearing derivatives 4j-4q were shown to possess a selective hCA IX inhibitory action over isoforms I, II and IV. The most selective compounds 4l and 4n were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under hypoxic conditions. The selective IX/II inhibitory trend of 4j-4q compared to those of compounds 4a-4i was unveiled by docking studies. Further exploration of these molecules could be useful for the development of novel antitumor agents with a selective CA inhibitory mechanism., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Isatin is a well acknowledged pharmacophore in many clinically approved drugs used for treatment of cancer. 3-Hydrazinoindolin-2-one, as a derivative of isatin, represents a pharmacophore of an important class of biologically active pharmaceutical agents by virtue of their diverse biological activities. In this review, anticancer activity will be on focus for compounds derived from 3-hydrazinoindolin-2-one. They are classified according to their chemical structure into nine different classes. In each class, different compounds were browsed, showing their anticancer activity and their potential targets. Moreover, crystallographic data or docking studies were highlighted for some compounds, when available, to provide a deep understanding of their mechanisms of action., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Many bis-isatins and isatins with hydrazide extension were reported to have a potential anti-proliferative effects against different cancer cell lines and cancer targets. In this study, four series of bis-isatins with hydrazide linkers were synthesized. These compounds were investigated for their antitumor activity by assessing their cytotoxic potency against HepG2, MCF-7 and HCT-116 cancer cell lines. Compound 21c possessed significant cytotoxic activity against MCF-7 (IC50 = 1.84 μM) and HCT-116 (IC50 = 3.31 μM) that surpasses the activity of doxorubicin against both cell lines (MCF-7; IC50 = 2.57 μM and HCT-116; IC50 = 3.70 μM). Cell cycle analysis and annexin V-FITC staining of MCF-7 cells treated with 21c suggested that the cytotoxic effect of the compound could be attributed to its pro-apoptotic activity., (Copyright © 2015 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.)

In our effort to develop potent and effective agents with anti-proliferative activity towards HepG2 hepatocellular carcinoma cells with potential inhibitory activity against VEGFR-2, a novel series of 1-(4-((2-oxoindolin-3-ylidene)amino)phenyl)-3-arylureas was designed and synthesized. All the newly prepared ureas 9a-x were evaluated in vitro for their anti-proliferative activity against HepG2 hepatocellular carcinoma cell line. Compounds 9a-c, 9e, 9f, 9j, 9m-o, 9t-v and 9x exhibited good activity against HepG2 cancer cells (IC50 = 1.22 ± 0.11-8.37 ± 0.85 μM) comparable to that of doxorubicin and sorafinib (IC50 = 2.90 ± 0.36 and 3.40 ± 0.25 μM, respectively). These thirteen compounds were further evaluated for their inhibitory activity against VEGFR-2. Compound 9x emerged as the most active counterpart against VEGFR-2 with IC50 value of 0.31 ± 0.04 μM. Furthermore, a molecular docking of the tested compounds was carried out in order to investigate their binding pattern with the prospective target, VEGFR-2 (PDB-code: 4ASD)., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

A novel series of N-substituted-4-phenylphthalazin-1-ones 14a-g bearing different anilines at the N-2 of phthalazin-1-one scaffold via acetyl-flexible linker was designed and synthesized for the development of potential anticancer agents. Compounds 19a-g were synthesized by insertion of methylene (CH2) bridge at C4-position of 14a-g to provide a flexibility for the phenyl group. The newly synthesized compounds 14a-g and 19a-g were evaluated for their anti-proliferative activity against three human tumor cell lines HepG2 hepatocellular carcinoma, HT-29 colon cancer and MCF-7 breast cancer. In particular, HepG2 and HT-29 cancer cell lines were more susceptible to the synthesized derivatives. Compound 19d (IC50 = 1.2 ± 0.09 μM) was found to be the most potent derivative against HepG2 as it was 2.9 times more active than doxorubicin (IC50 = 3.45 ± 0.54) and sorafenib (IC50 = 3.5 ± 1.04 μM). Compounds 14e, 14g, 19d and 19g with IC50 = (3.29 ± 0.45), (3.50 ± 0.846), (1.20 ± 0.09) and (3.52 ± 0.70) μM, respectively, were found to be active candidates against HepG2 cancer cells. Compounds 14e, 14g, 19d and 19g were able to induce apoptosis in HepG2, this was assured by; the significant increase in the percentage of annexin V-FITC-positive apoptotic cells (UR + LR), the down-regulation of the anti-apoptotic protein Bcl-2 and the up-regulation of the pro-apoptotic protein Bax, in addition to boosting caspase-3 levels. Moreover, cytotoxicity evaluation of the newly synthesized compounds in HT-29 revealed that compounds 14e, 14f, 19e and 19f (IC50 = 3.05 ± 0.78, 4.02 ± 1.18, 3.68 ± 0.79 and 2.98 ± 0.47 μM, respectively) were more potent than doxorubicin (IC50 = 7.70 ± 1.78 μM)., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

RAB1 5 is a lead antibacterial agent in which trimethoprim is linked to phthalazine moiety. Similarly, our strategy in this research depends on the interconnection between some sulfa drugs and certain phthalazin-1(2H)-one scaffolds in an attempt to enhance their antibacterial activity. This approach was achieved through the combination of 4-substituted phthalazin-1(2H)-ones 9a, b or 14a, b with sulfanilamide 1a, sulfathiazole 1b or sulfadiazine 1c through amide linkers 6a, b to produce the target compounds 10a-d and 15a-e, respectively. The antibacterial activity of the newly synthesized compounds showed that all tested compounds have antibacterial activity higher than that of their reference sulfa drugs 1a-c. Compound 10c represented the highest antibacterial activity against Gram-positive bacteria Streptococcus pneumonia and Staphylococcus aureus with MIC = 0.39 μmol/mL. Moreover, compound 10d displayed excellent antibacterial activity against Gram-negative bacteria Escherichia coli and Salmonella typhimurium with MIC = 0.39 and 0.78 μmol/mL, respectively., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

The docking studies on CDK2 and GSK-3β inspired us to synthesis a series of indoline-2,3-dione hydrazones 10a-l. Treatment of indoline-2,3-dione derivatives 7a-d with hydrazine gave 3-hydrazonoindolin-2-ones 8a-d which were reacted with the appropriate aldehydes 9a-c to yield 3-substituted-(methylenehydrazono)indolin-2-ones 10a-l. Compounds 10a-l showed a significant anticancer activity against human breast cell line MCF-7. Compounds 10c, f, i exhibited the highest activity almost the same of doxorubicin (IC50 = 6.10 μM) with IC50 = 7.75, 6.75, 6.25 μM, respectively., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)