Hany S. Ibrahim

Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII

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.

Design, synthesis and in vitro antitumor activity of novel N-substituted-4-phenyl/benzylphthalazin-1-ones.

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).

Synthesis of Diarylpyrazoles Containing a Phenylsulphone or Carbonitrile Moiety and their Chalcones as Possible Anti-Inflammatory Agents.

A series of chalcone-based diarylpyrazoles containing a phenylsulphone or carbonitrile moiety was synthesized. Thus, 3-acetylpyrazoles 6a–c and 10a–c were used as useful substrates in facile synthesis of functional pyrazoles 7a–f and 11a–f, respectively. The anti-inflammatory activity and ulcerogenic effect were evaluated and some of the obtained products possessed a significant anti-inflammatory activity. 1-[1-(3-Methylphenyl)-5-phenyl-4-(phenylsulfonyl)-1H-pyrazol-3-yl]ethanone (6b) showed a high activity when compared with indomethacin as reference drug with lower gastrointestinal (GI) profile. Furthermore, molecular docking studies were performed in order to rationalize the obtained biological results.

3-Hydrazinoindolin-2-one derivatives: Chemical classification and investigation of their targets as anticancer agents.

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.

One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a–p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents.

Synthesis and biological evaluation of some N-arylpyrazoles and pyrazolo[3,4-d]pyridazines as anti-inflammatory agents.

A series of 3,4‐bis‐chalcone‐N‐arylpyrazoles 3a–k was prepared from diacetyl pyrazoles 2a–e. The reaction of 2d and 2e with hydrazine hydrate gave pyrazolo[3,4‐d]pyridazine derivatives 4a–b. Furthermore, the reaction of 2a–e with thiosemicarbazide afforded pyrazolo[3,4‐d]pyridazine thiocyanate salts 5a–e. The synthesized compounds were subjected to in vivo anti‐inflammatory and ulcerogenic activity measurements, in addition to determination of their in vitro COX selectivity, to give a full profile about their anti‐inflammatory activities. Compounds 3c, 3f, 3i, and 3e showed significant anti‐inflammatory activity among the synthesized compounds. Moreover, docking studies were performed to give an explanation for their anti‐inflammatory activity through COX selectivity.

Novel [(3-indolylmethylene)hydrazono]indolin-2-ones as apoptotic anti-proliferative agents: design, synthesis and in vitro biological evaluation

Abstract On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindolin-2-one scaffolds is a logic tactic for designing pro-apoptotic agents. Consequently, 27 hybrids (6a–r, 9a–f and 11a–c) were synthesised and evaluated for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines. SAR studies unravelled that N-propylindole derivatives were the most active compounds such as 6n (MCF-7; IC50=1.04 µM), which displayed a significant decrease of cell population in the G2/M phase and significant increase in the early and late apoptosis by 19-folds in Annexin-V-FTIC assay. Also, 6n increased the expression of caspase-3, caspase-9, cytochrome C and Bax and decreased the expression of Bcl-2. Moreover, compounds 6i, 6j, 6n and 6q generated ROS by significant increase in the level of SOD and depletion of the levels of CAT and GSH-Px in MCF-7.

Hydrolysis and Hydrazinolysis of Isatin-Based Ald- and Ketazines

The hydrolysis of isatin aldazine 4a–d afforded the unexpected 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) and 1,2-di(arylidene)hydrazines 6a–d through dual hydrolysis of 4a–d. A mechanism to explain the formation of 5 and 6a–d was proposed. In addition, the hydrazinolysis of 4a–d yielded 3-hydrazonoindolin-2-one (2) and 1,2-di(arylidene)hydrazines 6a–d instead of hydrazones 17a–d, while hydrazinolysis of isatin ketazine 5 gave the expected 3-hydrazonoindolin-2-one (2). These results indicated the ability of the title compounds for unusual hydrolysis and hydrazinolysis reactions.

Pyridine-Ureas as Potential Anticancer Agents: Synthesis and In Vitro Biological Evaluation

In our endeavor towards the development of effective anticancer agents, a novel series of pyridine-ureas 8a–n were synthesized. All the newly prepared derivatives were evaluated in vitro for their growth inhibitory activity towards the proliferation of breast cancer MCF-7 cell line. Compounds 8e and 8n were found to be the most active congeners against MCF-7 cells (IC50 = 0.22 and 1.88 µM after 48 h treatment; 0.11 and 0.80 µM after 72 h treatment, respectively) with increased activity compared to the reference drug doxorubicin (IC50 = 1.93 µM). Moreover, eight selected pyridines 8b, 8d, 8e, 8i, 8j and 8l–n were evaluated for their in vitro anticancer activity according to the US-NCI protocol. Pyridines 8b and 8e proved to be the most effective anticancer agents in the NCI assay with mean inhibition = 43 and 49%, respectively. Both 8b and 8e exhibited anti-proliferative activity against all tested cancer cell lines from all subpanels growth inhibition (GI for 8b; 12–78%, GI for 8e; 15–91%). Pyridines 8b and 8e were screened in vitro for their inhibitory activity against VEGFR-2. Both compounds inhibited VEGFR-2 at micromolar IC50 values 5.0 ± 1.91 and 3.93 ± 0.73 µM, respectively. The most active pyridines were filtered according to the Lipinski and Veber rules and all of them passed these filters. Finally, several ADME descriptors were predicted for the active pyridines through a theoretical kinetic study.