Mahmoud M. Elaasser

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.

Synthesis and anticancer activity of arylazothiazoles and 1,3,4-thiadiazoles using chitosan-grafted-poly(4-vinylpyridine) as a novel copolymer basic catalyst

A novel series of 4-substituted 5-arylazo-2-[1-(pyrrol-3-yl)ethylidenehydrazinyl]thiazoles and 5-arylazo-2-[1-(pyrrol-3-yl)ethylidenehydrazinyl]-2,3-dihydrothiazol-3-amines was prepared by cyclocondensation of α-oxohydrazonoyl halides with 1-(pyrrol-3-yl)-ethylidenethiosemicarbazide and 1-(pyrrol-3-yl)ethylidenethiocarbohydrazide, respectively. These cyclocondensation reactions were achieved by using chitosan-grafted-poly(4-vinylpyridine) as a novel basic catalyst under microwave irradiation. Furthermore, the reaction of the above mentioned thiosemicarbazide and thiocarbohydrazide with N-phenylbenzenecarbohydrazonyl chlorides (bereft of the α-oxo group) using chitosan-grafted catalyst proceeded via a similar mechanism and afforded the same 2-hydrazono-1,3,4-thiadiazoles. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences as well as by their synthesis via alternative methods. Finally, the appraisal of the newly synthesized products for their anticancer activity against a colon carcinoma cell line (HCT-116) and liver carcinoma cell line (HEPG2-1) revealed promising activity, especially 4-phenyl- and 4-(thiophen-2-yl)-substituted 1,3-thiazole derivatives.

Anti-phosphorylcholine-opsonized low-density lipoprotein promotes rapid production of proinflammatory cytokines by dendritic cells and natural killer cells

BACKGROUND AND OBJECTIVE Epidemiological and animal studies suggest that periodontal infections increase atherosclerosis risk. Periodontitis patients have elevated levels of anti-phosphorylcholine (anti-PC) reactive not only with numerous periodontal organisms but also with minimally modified low-density lipoprotein (mmLDL). Dendritic cells (DCs) reside in arterial walls and accumulate in atherosclerotic lesions. The ability of anti-PC to bind mmLDL prompted the hypothesis that opsonized mmLDL would stimulate DCs and enhance the production of proinflammatory cytokines that promote atherogenic plaque development. MATERIAL AND METHODS Monocyte-derived DCs (mDCs) were generated using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, then stimulated with mmLDL or with anti-PC-opsonized mmLDL. The anti-PC effect was determined using flow cytometry, cofocal microscopy and cytokine assays. The production of CD83, IL-12p35 mRNA, IL-12p40 mRNA, IL-12p70 and IL-10 by DCs was monitored. RESULTS Dendritic cells stimulated with mmLDL expressed little CD83 and produced little IL-12p70. However, anti-PC-opsonized mmLDL enhanced DC maturation, as indicated by upregulated CD83 and rapid (≤ 48 h) production of IL-12p70 if a source of interferon-γ (IFN-γ) was available. In leukocyte cultures, natural killer (NK) cells rapidly produced IFN-γ (≤ 48 h) when interacting with IL-12-producing DCs activated by anti-PC-opsonized mmLDL. Moreover, IFN-γ promoted DC IL-12 responses that were further augmented when mmLDL was opsonized with anti-PC. CONCLUSION Minimally modified LDL-stimulated DCs and NK cells were mutually stimulatory, with DC IL-12p70 needed by NK cells and with NK cell IFN-γ needed by DCs. Moreover, production of these proinflammatory cytokines was markedly enhanced when LDL was opsonized by anti-PC. In short, the data suggest that the elevated anti-PC levels in periodontitis patients could promote a mechanism that facilitates atherosclerosis.

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.

Anticancer activities, molecular docking and structure–activity relationship of novel synthesized 4 H -chromene, and 5 H -chromeno[2,3- d ]pyrimidine candidates

In the present study, a series of 4H-chromene and 5H-chromeno[2,3-d]pyrimidine derivatives was synthesized and evaluated as potential cytotoxic agents. The cytotoxic activities of the target compounds were evaluated against four cancer cell lines MCF-7, HCT-116, HepG-2, and A549 in comparison with vinblastine and colchicine as reference drugs. We explored the structure–activity relationship of 4H-chromenes with modification at the 2-,4- or 7-position, and fused pyrimidine ring at 2,3-position. Most of the screened compounds showed marginal antitumor activity against the different cell lines in comparison to the standard drugs. The structure–activity relationship study revealed that the antitumor activity of the synthesized compounds was significantly affected by the lipophilicity of the substituent at the 2-,4- or 7-position for the 4H-chromenes, and 5,8-position or fused pyrimidine ring at 2,3-positions for 5H-chromeno[2,3-d]pyrimidines. Structure–activity relationship was elaborated with the help of molecular docking studies. The structures of the synthesized compounds were established on the basis of the spectral data, infrared, proton nuclear magnetic resonance, 13-Carbon nuclear magnetic resonance and mass spectroscopic data.

Design, synthesis, molecular docking of new lipophilic acetamide derivatives affording potential anticancer and antimicrobial agents

Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33-40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives were the most active compounds especially 5f and 6f ones. Further EGFR enzymatic investigation was carried out for these most active compounds 5f and 6f resulting in inhibitory activity by 1.89 and 2.05 µM respectively. Docking simulation was performed as a trial to study the mechanisms and binding modes of these compounds toward the enzyme target, EGFR protein kinase enzyme. The results revealed good compounds placement in the active sites and stable interactions similar to the co-crystallized reference ligand. Collectively, the analogs 5f and 6f could be further utilized and optimized as good cytotoxic agents.

Hydrazonoyl chlorides in the synthesis of pyrazolo[5,1- c ][1,2,4]triazole derivatives and their biological activities

A new series of 7-arylazopyrazolo[5,1-c][1,2,4]triazoles was synthesised via reaction of 3-amino-4-(arylhydrazono)-4,5-dihydropyrazol-5-ones with hydrazonoyl halides using triethylamine as a basic catalyst. The structure of all the synthesised compounds was confirmed on the basis of elemental and spectral analyses. Moreover, the antimicrobial and antitumour activities of these compounds were evaluated and the results obtained indicate the weak efficacy of some of them as antibacterial agents. However, the results of antitumour activity against HepG-2 liver cancer and HCT-116 colon cancer of some derivatives showed good activity in comparison with the reference drugs.

Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation

In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates (4a–n) and thiazolo[3,2-a]benzimidazolone-isatin conjugates (7a–d), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds 4m and 7b emerged as the most active congeners against MDA-MB-231 cells (IC50 = 7.6 ± 0.5 and 13.2 ± 1.1 µM, respectively). Compounds 4m and 7b were able to provoke apoptosis in MDA-MB-231 cells, evidenced by the up-regulation of Bax and down-regulation of Bcl-2, besides boosting caspase-3 levels. Hybrid 4m induced a fourfold increase in the percentage of cells at Sub-G1, with concurrent arrest in G2-M phase by 2.5-folds. Furthermore, hybrid 4m resulted in a sixfold increase in the percentage of annexin V-FITC positive apoptotic MDA-MB-231 cells as compared with the control. Moreover, the cytotoxic activities of the active conjugates were assessed towards two nontumorigenic cell lines (breast MCF-10A and lung WI-38) where both conjugates 4m and 7b displayed mean tumor selectivity index: 9.6 and 13.9, respectively. Finally, several ADME descriptors were predicted for the active conjugates via a theoretical kinetic study.

Fungitoxicity of organic extracts of Ocimum basilicum on growth and morphogenesis of Bipolaris species (teleomorph Cochliobolus)

This study aimed at evaluating the inhibitory effects of various organic extracts of Ocimum basilicum against some species of Bipolaris and Cochliobolus with GC‐MS and HPLC analysis.