Publications by authors named "Mahmoud M Elaasser"

23 Publications

  • Page 1 of 1

Development of isatin-thiazolo[3,2-a]benzimidazole hybrids as novel CDK2 inhibitors with potent in vitro apoptotic anti-proliferative activity: Synthesis, biological and molecular dynamics investigations.

Bioorg Chem 2021 05 18;110:104748. Epub 2021 Feb 18.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, 11795 Cairo, Egypt.

In the current medical era, human health is experiencing numerous challenges, particularly the human malignancies. Therefore, the therapeutic arsenal for these malignancies is to be inexorably enhanced with new treatments that target tumor cells in a selective manner. In this regard, the present work aims at developing a new set of small molecules featuring the privileged isatin scaffold conjugated with a thiazolo[3,2-a]benzimidazole (TBI) motif through a cleavable hydrazide linker (7a-e and 10a-i) as potential anticancer CDK2 inhibitors. The large tricyclic TBI motif is anticipated to achieve a plethora of hydrophobic interactions within the CDK2 binding site. The growth of the two examined cell lines was significantly inhibited by most the prepared hybrids with IC ranges; (2.60 ± 1.47-20.90 ± 1.17 µM, against MDA-MB-231) and (1.27 ± 0.06-16.83 ± 0.95 µM, against MCF-7). In particular, hybrids 7a, 7d and 10a displayed potent dual activity against the examined cell lines, and thus selected for further investigations. They exerted a significance alteration in the cell cycle progression, in addition to an apoptosis induction within both MDA-MB-231 and MCF-7 cells. Furthermore, 7a, 7d and 10a displayed potent CDK2 inhibitory action (IC = 96.46 ± 5.3, 26.24 ± 1.4 and 42.95 ± 2.3 nM, respectively). The docking simulations unveiled, as expected, the ability of the TBI ring to well-accommodate and establish several hydrophobic interactions within a hydrophobic pocket in the CDK2 binding site. Also, the docking simulations highlighted the significance of incorporation of the hydrazide linker and isatin unsubstituted (NH) functionality in the H-bonding interactions. Interestingly, the most potent CDK2 inhibitor 7d achieved the best binding score (-11.2 Kcal/mole) and formed the most stable complex with CDK2 enzyme (RMSD = 1.24 Å) in a 100 ns MD simulation. In addition, the MM-PBSA calculations ascribed the lowest binding free energy to the 7d-CDK2 complex (-323.69 ± 15.17 kJ/mol). This could be attributed to an incorporation of the 5-OCH group that was engaged in an extra hydrogen bonding with key THR14 amino acid residue. Finally, these results suggested hybrid 7d as a good candidate for further optimization as promising breast cancer antitumor agent and CDK2 inhibitor.
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http://dx.doi.org/10.1016/j.bioorg.2021.104748DOI Listing
May 2021

Thiazole-Based Thiosemicarbazones: Synthesis, Cytotoxicity Evaluation and Molecular Docking Study.

Drug Des Devel Ther 2021 17;15:659-677. Epub 2021 Feb 17.

Chemistry Department, Faculty of Science, University of Cairo, Giza, Egypt.

Introduction: Hybrid drug design has developed as a prime method for the development of novel anticancer therapies that can theoretically solve much of the pharmacokinetic disadvantages of traditional anticancer drugs. Thus a number of studies have indicated that thiazole-thiophene hybrids and their bis derivatives have important anticancer activity. Mammalian Rab7b protein is a member of the Rab GTPase protein family that controls the trafficking from endosomes to the TGN. Alteration in the Rab7b expression is implicated in differentiation of malignant cells, causing cancer.

Methods: 1-(4-Methyl-2-(2-(1-(thiophen-2-yl) ethylidene) hydrazinyl) thiazol-5-yl) ethanone was used as building block for synthesis of novel series of 5-(1-(2-(thiazol-2-yl) hydrazono) ethyl) thiazole derivatives. The bioactivities of the synthesized compounds were evaluated with respect to their antitumor activities against MCF-7 tumor cells using MTT assay. Computer-aided docking protocol was performed to study the possible molecular interactions between the newly synthetic thiazole compounds and the active binding site of the target protein Rab7b. Moreover, the in silico prediction of adsorption, distribution, metabolism, excretion (ADME) and toxicity (T) properties of synthesized compounds were carried out using admetSAR tool.

Results: The results obtained showed that derivatives and have promising activity (IC = 14.6 ± 0.8 and 28.3 ± 1.5 µM, respectively) compared to Cisplatin (IC = 13.6 ± 0.9 µM). The molecular docking analysis reveals that the synthesized compounds are predicted to be fit into the binding site of the target Rab7b. In summary, the synthetic thiazole compounds could be used as potent inhibitors as anticancer drugs.

Conclusion: Promising anticancer activity of compounds and compared with cisplatin reference drug suggests that these ligands may contribute as lead compounds in search of new anticancer agents to combat chemo-resistance.
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http://dx.doi.org/10.2147/DDDT.S291579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900779PMC
February 2021

Synthesis of Novel Chalcone-Based Phenothiazine Derivatives as Antioxidant and Anticancer Agents.

Molecules 2020 Oct 6;25(19). Epub 2020 Oct 6.

Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.

Based on reported results for the potential medicinal impact of phenothiazine core, as well as the chalcone skeleton that is widely present in many natural products, together with their reported bioactivities, the present work was aimed at combining both moieties in one molecular skeleton and to synthesize and characterize a novel series of chalone-based phenothiazine derivatives. For this purpose, 2-acetylphenothiazine was N-alkylated, followed by the Claisen-Schmidt reaction to produce the chalcones with good yield. Antioxidant activity, as evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, was assessed to determine if their antioxidant potential was comparable with ascorbic acid, and attributable to the phenothiazine core. Screening anticancer activities of the synthesized chalone-based phenothiazine derivatives against human breast cancer cell line MCF-7 cells, and human hepatocellular carcinoma HepG-2 cells, compared with standard drugs cisplatin and doxorubicin, was evaluated. The results revealed that compounds 4a 4b 4d 4h 4j 4k 4m 4o and 4p were good against human hepatocellular carcinoma HepG-2 cells, and among these compounds 4b and 4k were the most effective compounds, with IC values of 7.14 μg/mL and 7.6 1 μg/mL, respectively. On the other hand, compounds 4a 4b 4k and 4m were good against human breast cancer cell line MCF-7 cells and, among these compounds, 4k and 4b were the most effective compounds, with IC values of 12 μg/mL and 13. 8 μg/mL, respectively. The overall results suggest that these compounds could, potentially, be further modified for the formation of more potent antioxidant and anticancer agents.
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http://dx.doi.org/10.3390/molecules25194566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583060PMC
October 2020

Discovery of 3,6-disubstituted pyridazines as a novel class of anticancer agents targeting cyclin-dependent kinase 2: synthesis, biological evaluation and in silico insights.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1616-1630

Department of Applied Organic Chemistry, National Research Center, Giza, Egypt.

Human health in the current medical era is facing numerous challenges, especially cancer. So, the therapeutic arsenal for cancer should be unremittingly enriched with novel small molecules that selectively target tumour cells with minimal toxicity towards normal cells. In this context, herein a new series of 3,6-disubstituted pyridazines has been synthesised and evaluated for anticancer activity. They possessed good anti-proliferative action towards human breast cancer T-47D (IC range: 0.43 ± 0.01 - 35.9 ± 1.18 µM) and MDA-MB-231 (IC range: 0.99 ± 0.03 - 34.59 ± 1.13 µM) cell lines, whereas they displayed weak activity against the tested ovarian cancer cell line SKOV-3. Among the studied compounds, the methyltetrahydropyran-bearing pyridazine emerged as the unique submicromolar growth inhibitor herein reported towards both T-47D (IC = 0.43 ± 0.01 µM) and MDA-MB-231 (IC = 0.99 ± 0.03 µM) cell lines. In addition, the biological results indicated that pyridazines and exerted an efficient alteration within the cell cycle progression as well as induction of apoptosis in both T-47D and MDA-MB-231 cells. Moreover, pyridazines and displayed good mean tumour S. I. values of 13.7 and 16.1 upon assessment of their cytotoxicity towards non-tumorigenic breast MCF-10A cells. Furthermore, an study proposed CDK2 as a probable enzymatic target for pyridazines , and explored their binding interactions within the vicinity of CDK2 binding site. Subsequently, pyridazines , , , and were selected to be evaluated for their ability to inhibit CDK2, where they exerted good inhibitory activity (IC = 151, 43.8, 55.6 and 20.1 nM, respectively). Finally, the study implied that target pyridazines exhibited not only an efficient anticancer activity but also an acceptable ADME, physicochemical and druglikeness properties, specifically pyridazines and . Overall the obtained results from this study quite sustained our strategy and gave us a robust opportunity for further development and optimisation of 3,6-disubstituted pyridazine scaffold to enrich therapeutic arsenal with efficient and safe anticancer CDK inhibitors.
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http://dx.doi.org/10.1080/14756366.2020.1806259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470104PMC
December 2020

Novel [(-alkyl-3-indolylmethylene)hydrazono]oxindoles arrest cell cycle and induce cell apoptosis by inhibiting CDK2 and Bcl-2: synthesis, biological evaluation and studies.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1300-1309

Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, Egypt.

As a continuation for our previous work, a novel set of -alkylindole-isatin conjugates (, , and ) is here designed and synthesised with the prime aim to develop more efficient isatin-based antitumor candidates. Utilising the SAR outputs from the previous study, our design here is based on appending four alkyl groups with different length (ethyl and n-propyl), bulkiness (iso-propyl) and unsaturation (allyl) on -1 of indole motif, with subsequent conjugation with different -unsubstituted isatin moieties to furnish the target conjugates. As planned, the adopted strategy achieved a substantial improvement in the growth inhibitory profile for the target conjugates in comparison to the reported lead . The best results were obtained with -propylindole -5-methylisatin hybrid which displayed broad spectrum anti-proliferative action with efficient sub-panel GI (MG-MID) range from 1.33 to 4.23 µM, and promising full-panel GI (MG-MID) equals 3.10 µM, at the NCI five-dose assay. Also, hybrid was able to provoke cell cycle disturbance and apoptosis in breast T-47D cells as evidenced by the DNA flow cytometry and Annexin V-FITC/PI assays. Furthermore, hybrid exhibited good inhibitory action against cell cycle regulator CDK2 protein kinase and the anti-apoptotic Bcl-2 protein (IC= 0.85 ± 0.03 and 0.46 ± 0.02 µM, respectively). Interestingly, molecular docking for hybrid in CDK2 and Bcl-2 active sites unveiled that -propyl group is involved in significant hydrophobic interactions. Taken together, the results suggested conjugate as a promising lead for further development and optimisation as an efficient antitumor drug.
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http://dx.doi.org/10.1080/14756366.2020.1773814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717600PMC
December 2020

3-Hydrazinoisatin-based benzenesulfonamides as novel carbonic anhydrase inhibitors endowed with anticancer activity: Synthesis, in vitro biological evaluation and in silico insights.

Eur J Med Chem 2019 Dec 8;184:111768. Epub 2019 Oct 8.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address:

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 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.
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http://dx.doi.org/10.1016/j.ejmech.2019.111768DOI Listing
December 2019

New thiobarbituric acid scaffold-based small molecules: Synthesis, cytotoxicity, 2D-QSAR, pharmacophore modelling and in-silico ADME screening.

Eur J Pharm Sci 2019 Mar 23;130:124-136. Epub 2019 Jan 23.

Biomedical Sciences Program, Zewail City of Science and Technology, 12578 Cairo, Egypt. Electronic address:

A series of twenty five new thiobarbituric acid derivatives, viz. 3a-h, 4-7, 8a-c, 9, 10a-c, 11 and 12a-d, were designed and synthesized as potential cytotoxic agents. In-vitro screening of the new compounds against the three human cancer cell lines Caco-2, HepG-2 and MCF-7 was performed to assess their intrinsic activity. Compound 12d exhibited potent sub-micromolar activity against HepG-2 and MCF-7 (IC = 0.07 and 0.08 μM, respectively). In-silico pharmacophore modelling of this chemotype compounds disclosed a five features' pharmacophore model representing essential steric and electronic fingerprints essential for activity. Finally, a 2D-QSAR model was devised to quantitatively correlate the 2D molecular feature descriptors of this series of thiobarbiturates with their cytotoxic activity against MCF-7. Finally, in silico evaluation of the physicochemical and ADME properties of these derivatives was performed.
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http://dx.doi.org/10.1016/j.ejps.2019.01.023DOI Listing
March 2019

One-pot synthesis of spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitriles as p53-MDM2 interaction inhibitors.

Future Med Chem 2018 12 10;10(24):2771-2789. Epub 2018 Dec 10.

Department of Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt.

Aim: Inhibition of P53-mdm2 interaction will lead to cancer cell apoptosis. This strategy was achieved by reported spiro-oxindole derivatives.

Materials & Methods: Spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitrile derivatives (4a-i and 9a, b) were synthesized and screened for their in vitro anticancer activity. The most active compounds were subjected to P53-MDM2 inhibitory activity, apoptotic and molecular docking studies.

Results & Discussion: Compound 4d exhibited potent and broad spectrum of antiproliferative activity with full panel GI (MG-MID) value of 3.97 μM. Compounds 4d and 4i inhibited p53-MDM2 protein-protein interaction with IC = 52.1 and 95.2 nM, respectively. Compound 4d inhibits the expression of wild p53 in MCF-7 more than mutant p53 in MDA-MB231 at the molecular level. Molecular docking studies illustrated the possible interaction of the target spiro-oxindoles with the p53 binding site on MDM2.
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http://dx.doi.org/10.4155/fmc-2018-0288DOI Listing
December 2018

Novel indole-thiazolidinone conjugates: Design, synthesis and whole-cell phenotypic evaluation as a novel class of antimicrobial agents.

Eur J Med Chem 2018 Dec 4;160:49-60. Epub 2018 Oct 4.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.

In connection with our research program on the development of novel anti-tubercular candidates, herein we report the design and synthesis of two different sets of indole-thiazolidinone conjugates (8a,b; 11a-d) and (14a-k; 15a-h). The target compounds were evaluated for their in vitro antibacterial and antifungal activities against selected human pathogens viz. Staphylococcus aureus (Gram positiveve), Pseudomonas aeruginosa, Escherichia coli (Gram negative), Mycobacterium tuberculosis (Acid-fast bacteria), Aspergillus fumigates and Candida albicans (fungi). Moreover, eukaryotic cell-toxicity was tested via an integrated ex vivo drug screening model in order to evaluate the selective therapeutic index (SI) towards antimicrobial activity when microbes are growing inside primary immune cells. Also, the cytotoxicity towards a panel of cancer cell lines and human lung fibroblast normal cell line, WI-38 cells, was explored to assure their safety. Compound 15b emerged as a hit in this study with potent broad spectrum antibacterial (MIC: 0.39-0.98 μg/mL) and antifungal (MIC: 0.49-0.98 μg/mL) activities, in addition to its ability to kill mycobacteria M. aurum inside an infected macrophage model with good therapeutic window. Moreover, compound 15b displayed promising activity towards resistant bacteria strains MRSA and VRE with MIC values equal 3.90 and 7.81 μg/mL, respectively. These results suggest compound 15b as a new therapeutic lead with good selectivity for further optimization and development.
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http://dx.doi.org/10.1016/j.ejmech.2018.10.008DOI Listing
December 2018

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

Molecules 2018 06 12;23(6). Epub 2018 Jun 12.

Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt.

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 (⁻) and thiazolo[3,2-]benzimidazolone-isatin conjugates (⁻), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds and emerged as the most active congeners against MDA-MB-231 cells (IC = 7.6 ± 0.5 and 13.2 ± 1.1 µM, respectively). Compounds and 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 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 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 and 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.
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http://dx.doi.org/10.3390/molecules23061420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099623PMC
June 2018

Synthesis and biological evaluation of 2-aminothiazole-thiazolidinone conjugates as potential antitubercular agents.

Future Med Chem 2018 06 23;10(12):1405-1419. Epub 2018 May 23.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-AiniStreet, Cairo, P.O. Box 11562, Egypt.

Aim: Mycobacterium tuberculosis, which causes tuberculosis, continues to infect millions of the global population, resulting in 1.8 million deaths worldwide in 2015.

Methodology: Hybrids of 2-amino-4-methylthiazole bearing 5-acetyl/5-ethyl carboxylate functionality with 5-arylidene thiazolidinone moiety (6a-k and 9a-d) were synthesized and screened for antitubercular and antimicrobial activities.

Results & Discussion: 5-ethyl carboxylate derivative 6k revealed half antitubercular activity (minimal inhibitory concentration = 1.56 μg/ml) than the acetyl analog 6c (minimal inhibitory concentration = 0.78 μg/ml), however, it exhibited more potent broad spectrum antibacterial and antifungal activities in addition to its excellent safety profile with high selectivity toward M. tuberculosis over normal human lung cells. Collectively, these data suggested that compound 6k can be considered as an ideal lead compound for further optimization.
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http://dx.doi.org/10.4155/fmc-2017-0327DOI Listing
June 2018

Design, synthesis, anticancer screening, docking studies and in silico ADME prediction of some β-carboline derivatives.

Future Med Chem 2018 05 22;10(10):1159-1175. Epub 2018 May 22.

Regional Center for Mycology & Biotechnology, Al-Azhar University, Cairo, Egypt.

Background: Medicinal interest has focused on β-carbolines as anticancer agents.

Methodology/results: Several β-carbolines were designed, synthesized and evaluated for their cytotoxic activity against MCF-7 and A-549 cancer cell lines using MTT assay. Compounds 13a, 13c, 13d and 20a were the most promising showing high selectivity indices. Compounds 13c and 20a showed potent inhibition of topoisomerase (topo-I) and kinesin spindle protein (KSP/Eg5 ATPase) which was confirmed by their docking results into the active site of both enzymes. In silico physicochemical calculations predicted that compounds 13a, 13d and 20a obeyed Lipinski's rule of five.

Conclusion: Compounds 13c and 20a are multitarget anticancer leads that act as potent inhibitors for both topo-I and/or KSP ATPase.
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http://dx.doi.org/10.4155/fmc-2017-0206DOI Listing
May 2018

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

J Enzyme Inhib Med Chem 2018 Dec;33(1):686-700

f The Regional Center for Mycology and Biotechnology , Al-Azhar University , Cairo , Egypt.

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; IC=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.
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http://dx.doi.org/10.1080/14756366.2017.1421181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010103PMC
December 2018

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

Bioorg Chem 2018 02 2;76:332-342. Epub 2017 Dec 2.

The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt.

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.
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http://dx.doi.org/10.1016/j.bioorg.2017.11.019DOI Listing
February 2018

Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety.

Chem Cent J 2017 May 19;11(1):42. Epub 2017 May 19.

The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt.

Background: A series of novel N-(2, 6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido) benzenesulfonamides 3a-t was synthesized by the addition of N-(2,6-dimethoxypyrimidin-4-yl)-4-isothiocyanatobenzenesulfonamide 2 to the appropriate aromatic amine. The structures of the synthesized compounds were inspired from the second line antituberculosis pro-drugs.

Results: Most of the new compounds were screened for their activity against Mycobacterium tuberculosis. The results of the antimycobacterial assay showed that compound 3i exerted the highest activity (MIC = 3.13 µg/mL), followed by compound 3s (MIC = 6.25 µg/mL).

Conclusion: The structure-activity relationship (SAR) analysis revealed that the introduction of the benzo[1,3]dioxol moiety in 3i and the 4-morpholinyl-4-phenyl moiety in 3s has proven to give the most potent compounds in this study. Docking of the promising compounds inside the active site of M. tuberculosis enoyl reductase InhA was performed in order to emphasize the results. The compounds showed a similar orientation to that of GSK 625 inside the active site of 5JFO and bind to Met 98 in a way similar to that of the co-crystallized ligand.
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http://dx.doi.org/10.1186/s13065-017-0271-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438335PMC
May 2017

Antimicrobial and anticancer activity of some novel fluorinated thiourea derivatives carrying sulfonamide moieties: synthesis, biological evaluation and molecular docking.

Chem Cent J 2017 Apr 7;11(1):32. Epub 2017 Apr 7.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Background: Various thiourea derivatives have been used as starting materials for compounds with better biological activities. Molecular modeling tools are used to explore their mechanism of action.

Results: A new series of thioureas were synthesized. Fluorinated pyridine derivative 4a showed the highest antimicrobial activity (with MIC values ranged from 1.95 to 15.63 µg/mL). Interestingly, thiadiazole derivative 4c and coumarin derivative 4d exhibited selective antibacterial activities against Gram positive bacteria. Fluorinated pyridine derivative 4a was the most active against HepG2 with IC50 value of 4.8 μg/mL. Molecular docking was performed on the active site of MK-2 with good results.

Conclusion: Novel compounds were obtained with good anticancer and antibacterial activity especially fluorinated pyridine derivative 4a and molecular docking study suggest good activity as mitogen activated protein kinase-2 inhibitor. Graphical abstract Compound 4a in the active site of MK-2.
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http://dx.doi.org/10.1186/s13065-017-0258-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383913PMC
April 2017

Novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino) benzenesulfonamides: Synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular modelling studies.

Eur J Med Chem 2017 Oct 1;139:250-262. Epub 2017 Aug 1.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address:

Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino)benzenesulfonamides (4a-m and 7a-g). All the newly prepared sulfonamides were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO hydrase assay. In particular, hCA isoforms II and IX (tumor-associated) were more susceptible to inhibition by the synthesized derivatives, with Ks in the range of 2.6-598.2 nM for hCA II, and of 16.1-321 nM for hCA IX. All compounds (4a-m and 7a-g) were evaluated for their anti-proliferative activity against breast cancer MCF-7 and colorectal cancer Caco-2 cell lines. Compound 4c was found to be the most potent derivative against MCF-7 (IC = 3.96 ± 0.21 μM), while 4j was the most active member against Caco-2 cells (IC = 5.87 ± 0.37 μM). Compound 4c induced the intrinsic apoptotic mitochondrial pathway in MCF-7 cells; evidenced by the enhanced expression of the pro-apoptotic protein Bax and the reduced expression of the anti-apoptotic protein Bcl-2, and the up-regulated active caspase-9 and caspase-3 levels.
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http://dx.doi.org/10.1016/j.ejmech.2017.07.073DOI Listing
October 2017

Design, synthesis and 2D QSAR study of novel pyridine and quinolone hydrazone derivatives as potential antimicrobial and antitubercular agents.

Eur J Med Chem 2017 Sep 4;138:698-714. Epub 2017 Jul 4.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, P.O. Box 11471, Egypt. Electronic address:

The increased development of highly resistant bacterial strains and tuberculosis, constitute a serious public health threat, highlighting the urgent need of novel antibacterial agents. In this work, two novel series of nicotinic acid hydrazone derivatives (6a-r) and quinolone hydrazide derivatives (12a-l) were synthesized and evaluated as antimicrobial and antitubercular agents. The synthesized compounds were evaluated in vitro for their antibacterial, antifungal and antimycobacterial activities. Compounds 6f and 6p bearing the 3,4,5- (OCH3)3 and 2,5-(OCH3)2 benzylidene motifs were the most potent and as antibacterial, antifungal (MIC: 0.49-1.95 μg/mL) and (MIC: 0.49-0.98 μg/mL) respectively and antimycobacterial activity (MIC = 0.76 and 0.39 μg/mL) respectively. Besides, several derivatives, 6e, 6h, 6l-6o, 6q, 6r, 12a, 12b, 12e, 12h, 12k and 12l, exhibited significant antibacterial and antifungal activities with MIC values ranging from 1.95 to 7.81 μg/mL, they also displayed excellent to good activity against Mycobacterium tuberculosis with MIC range from 0.39 to 3.12 μg/mL. In addition, some of the most active compounds were tested for cytotoxic activities against human lung fibroblast normal cells (WI-38) and displayed low toxicity. Moreover, 2D-QSAR models to characterize the descriptors controlling the observed activities, were generated and validated.
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http://dx.doi.org/10.1016/j.ejmech.2017.07.004DOI Listing
September 2017

Biological evaluation of some new N-(2,6-dimethoxypyrimidinyl) thioureido benzenesulfonamide derivatives as potential antimicrobial and anticancer agents.

Eur J Med Chem 2016 Nov 30;124:299-310. Epub 2016 Aug 30.

Department of Drug Radiation Research, National Center for Radiation Research and Technology, Atomic Energy Authority, Cairo, Egypt.

A series of novel heterocyclic thioureas 3a-u containing sulfonamide moiety have been synthesized by the condensation of isothiocyanatobenzenesulfonamide 2 with a variety of heterocyclic amines. The newly synthesized heterocyclic thioureas were investigated for their antimicrobial and anticancer activity. The in vitro antibacterial and antifungal activity were done using well diffusion method. Interestingly, compounds 3j and 3m, showed similar or better activity compared with the reference drug against the tested microorganisms. Although, 3j was less active among its analogues to inhibit the breast carcinoma cells, it exhibit strong broad spectrum antimicrobial activities. However, The results of the cytotoxic activity revealed that compound 3p was the most active against the breast carcinoma cell line (MCF-7) giving promising IC value of 1.72 μg/mL, compared with reference drug (5-flourouracil) with IC value of 4.8 μg/mL. The most potent compounds in cytotoxic activity 3b and 3p were further docked inside the active site of CAIX and were found to exhibit a proper binding with the active site amino acids according to their bond lengths, angles and conformational energy.
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http://dx.doi.org/10.1016/j.ejmech.2016.08.060DOI Listing
November 2016

Bis-isatin hydrazones with novel linkers: Synthesis and biological evaluation as cytotoxic agents.

Eur J Med Chem 2016 Jan 2;108:415-422. Epub 2015 Dec 2.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejmech.2015.11.047DOI Listing
January 2016

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

Eur J Med Chem 2015 Oct 16;103:583-93. Epub 2015 Sep 16.

Neurofarba Department, Sezione di Scienze Farmaceutiche, Università degli di Studi di Firenze, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejmech.2015.09.021DOI Listing
October 2015

Improvement of antibacterial activity of some sulfa drugs through linkage to certain phthalazin-1(2H)-one scaffolds.

Eur J Med Chem 2014 Oct 7;85:480-6. Epub 2014 Aug 7.

The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt.

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.
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http://dx.doi.org/10.1016/j.ejmech.2014.08.016DOI Listing
October 2014

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

Arch Pharm (Weinheim) 2013 Sep 23;346(9):688-98. Epub 2013 Aug 23.

Faculty of Pharmacy, Pharmaceutical Chemistry Department, Taif University, Taif, Saudi Arabia.

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.
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http://dx.doi.org/10.1002/ardp.201300193DOI Listing
September 2013
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