Publications by authors named "Gamal El-Din A Abuo-Rahma"

51 Publications

A first-in-class anticancer dual HDAC2/FAK inhibitors bearing hydroxamates/benzamides capped by pyridinyl-1,2,4-triazoles.

Eur J Med Chem 2021 May 29;222:113569. Epub 2021 May 29.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt. Electronic address:

Novel 5-pyridinyl-1,2,4-triazoles were designed as dual inhibitors of histone deacetylase 2 (HDAC2) and focal adhesion kinase (FAK). Compounds 5d, 6a, 7c, and 11c were determined as potential inhibitors of both HDAC2 (IC = 0.09-1.40 μM) and FAK (IC = 12.59-36.11 nM); 6a revealed the highest activity with IC values of 0.09 μM and 12.59 nM for HDAC2 and FAK, respectively. Compound 6a was superior to reference drugs vorinostat and valproic acid in its ability to inhibit growth/proliferation of A-498 and Caki-1 renal cancer cells. Further investigation proved that 6a strongly arrests the cell cycle at the G2/M phase and triggers apoptosis in both A-498 and Caki-1 cells. Moreover, the enhanced Akt activity that is observed upon chronic application of HDAC inhibitors was effectively suppressed by the dual HDAC2/FAK inhibitor. Finally, the high potency and selectivity of 6a towards HDAC2 and FAK proteins were rationalized by molecular docking. Taken together, these findings highlight the potential of 6a as a promising dual-acting HDAC2/FAK inhibitor that could benefit from further optimization.
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http://dx.doi.org/10.1016/j.ejmech.2021.113569DOI Listing
May 2021

Novel 4-(piperazin-1-yl)quinolin-2(1H)-one bearing thiazoles with antiproliferative activity through VEGFR-2-TK inhibition.

Bioorg Med Chem 2021 Jun 22;40:116168. Epub 2021 Apr 22.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt; Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Deraya University, New Minia, Minia, Egypt. Electronic address:

A new series of 2-(4-(2-oxo-1,2-dihydroquinolin-4-yl)piperazin-1-yl)-N-(4-phenylthiazol-2-yl)acetamide derivatives were synthesized and evaluated for anticancer activity. All target compounds showed anticancer activity higher than that of their 2-oxo-4-piperazinyl-1,2-dihydroquinolin-2(1H)-one precursors. Multidose testing of target compounds was performed against breast cancer T-47D cell line. Five compounds showed higher cytotoxic activity than Staurosporine. The dihalogenated derivative showed the best cytotoxic activity with IC 2.73 ± 0.16 µM. In addition, the VEGFR-2 inhibitory activity of all synthetic compounds was evaluated. Two compounds of 6-fluoro-4-(piperazin-1-yl)quinolin-2(1H)-ones showed inhibitory activity comparable to sorafenib with IC 46.83 ± 2.4, 51.09 ± 2.6 and 51.41 ± 2.3 nM, respectively. The cell cycle analysis of two compounds namely, 2-(4-(6-fluoro-2-oxo-1,2-dihydroquinolin-4-yl)piperazin-1-yl)-N-(4-phenylthiazol-2-yl)acetamide and N-(4-(4-chlorophenyl)thiazol-2-yl)-2-(4-(2-oxo-1-phenyl-1,2-dihydroquinolin-4-yl)piperazin-1-yl)acetamide revealed that the arrest of cell cycle occurred at S phase. In apoptosis assay, the same two compounds were able to induce significant levels of early and late apoptosis. In a similar manner to Sorafenib, docking of target compounds with VEGFR-2 protein 4ASD showed HB with Cys919 in hinge region of enzyme and HB with both Glu885 and Asp1046 in gate area. Using SwissADME, all target compounds were predicted to be highly absorbed from gastrointestinal tract with no BBB permeability. It is clear that the two compounds are promising antiproliferative candidates that require further optimization.
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http://dx.doi.org/10.1016/j.bmc.2021.116168DOI Listing
June 2021

Modulation of Apoptosis and Epithelial-Mesenchymal Transition E-cadherin/TGF-β/Snail/TWIST Pathways by a New Ciprofloxacin Chalcone in Breast Cancer Cells.

Anticancer Res 2021 May;41(5):2383-2395

Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt.

Background/aim: This study aimed to investigate the effect of the new ciprofloxacin chalcone [7-(4-(N-substituted carbamoyl methyl) piperazin-1 yl)] on the proliferation, migration, and metastasis of MCF-7 and MDA-MB-231 breast cancer cell lines.

Materials And Methods: Cell viability, colony formation and cell migration abilities were analysed. Cell cycle distribution and apoptosis were examined by flow cytometry. The molecular mechanism underlying chalcone's activity was investigated using qRT-PCR and western blotting.

Results: This new ciprofloxacin chalcone significantly inhibited proliferation, colony formation, and cell migration abilities of both cancer cell lines. Furthermore, it initiated apoptosis and caused cell cycle arrest at G2/M and S phase in MCF-7 and MDA-MB-231 cell lines, respectively. In addition, it up-regulated the expression of pro-apoptotic factors, p53, PUMA and NOXA, and down-regulated the expression of anti-apoptotic factors, MDM2 and MDM4. At the same time, it inhibited epithelial-mesenchymal transition by increasing the expression of E-cadherin and decreasing the expression of TGF-β1, SNAI1, TWIST1, MMP2, and MMP9.

Conclusion: This new ciprofloxacin chalcone exhibited promising apoptotic and anti-metastatic activities against MCF-7 and MDA-MB-231 breast cancer cell lines, and, therefore, is an attractive molecule for drug development in the treatment of breast cancer.
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http://dx.doi.org/10.21873/anticanres.15013DOI Listing
May 2021

Novel 1,2,4-oxadiazole-chalcone/oxime hybrids as potential antibacterial DNA gyrase inhibitors: Design, synthesis, ADMET prediction and molecular docking study.

Bioorg Chem 2021 Jun 1;111:104885. Epub 2021 Apr 1.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt. Electronic address:

New antibacterial drugs are urgently needed to tackle the rapid rise in multi-drug resistant bacteria. DNA gyrase is a validated target for the development of new antibacterial drugs. Thus, in the present investigation, a novel series of 1,2,4-oxadiazole-chalcone/oxime (6a-f) and (7a-f) were synthesized and characterized by IR, NMR (H and C) and elemental analyses. The title compounds were evaluated for their in-vitro antimicrobial activity by the modified agar diffusion method as well as their E. coli DNA gyrase inhibitory activity. The minimum inhibitory concentration (MIC) and the structure activity relationships (SARs) were evaluated. Among all, compounds 6a, 6c-e, 7b and 7e were the most potent and proved to possess broad spectrum activity against the tested Gram-positive and Gram-negative organisms. Additionally, compounds 6a (against S. aureus), 6c (against B. subtilis and E. hirae), 6e (against E. hirae), 6f, 7a and 7c (against E. coli) and 7d (against B. subtilis), with MIC value of 3.12 μM were two-fold more potent than the standard ciprofloxacin (MIC = 6.25 μM). Mechanistically, compounds 6c, 7c, 7e and 7b had good inhibitory activity against E. coli gyrase with IC values of 17.05, 13.4, 16.9, and 19.6 µM, respectively, in comparison with novobiocin (IC = 12.3 µM) and ciprofloxacin (IC = 10.5 µM). The molecular docking results at DNA gyrase active site revealed that the most potent compounds 6c and 7c have binding mode and docking scores comparable to that of ciprofloxacin and novobiocin suggesting their antibacterial activity via inhibition of DNA gyrase. Finally, the predicted parameters of Lipinski's rule of five and ADMET analysis showed that 6c and 7c had good drug-likeness and acceptable physicochemical properties. Therefore, the hybridization of the chalcone and oxadiazole moieties could be promising lead as antibacterial candidate which merit further future structural optimizations.
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http://dx.doi.org/10.1016/j.bioorg.2021.104885DOI Listing
June 2021

Discovery of antiproliferative and anti-FAK inhibitory activity of 1,2,4-triazole derivatives containing acetamido carboxylic acid skeleton.

Bioorg Med Chem Lett 2021 May 17;40:127965. Epub 2021 Mar 17.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, 71526, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Sphinx University, New Assiut, Egypt.

Small molecule inhibitors of the focal adhesion kinase are regarded as promising tools in our armamentarium for treating cancer. Here, we identified four 1,2,4-triazole derivatives that inhibit FAK kinase significantly and evaluated their therapeutic potential. Most tested compounds revealed potent antiproliferative activity in HepG2 and Hep3B liver cancer cells, in which 3c and 3d were the most potent (IC range; 2.88 ~ 4.83 µM). Compound 3d possessed significant FAK inhibitory activity with IC value of 18.10 nM better than the reference GSK-2256098 (IC = 22.14 nM). The preliminary mechanism investigation by Western blot analysis showed that both 3c and 3d repressed FAK phosphorylation comparable to GSK-2256098 in HepG2 cells. As a result of FAK inhibition, 3c and 3d inhibited the pro-survival pathways by decreasing the phosphorylation levels of PI3K, Akt, JNK, and STAT3 proteins. This effect led to apoptosis induction and cell cycle arrest. Taken together, these results indicate that 3d could serve as a potent preclinical candidate for the treatment of cancers.
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http://dx.doi.org/10.1016/j.bmcl.2021.127965DOI Listing
May 2021

3,7-bis-benzylidene hydrazide ciprofloxacin derivatives as promising antiproliferative dual TOP I & TOP II isomerases inhibitors.

Bioorg Chem 2021 May 15;110:104698. Epub 2021 Feb 15.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New Minia, Minia, Egypt. Electronic address:

We report herein design and synthesis of a new series of 3,7-bis-benzylidenes of ciprofloxacin. Most of the target compounds revealed good cytotoxic activity; the most potent 4e and 4i achieved strong broad spectrum antiproliferative activity with comparable activity to Doxorubicin with IC (M) of 1.21 ± 0.02, 0.87 ± 0.04, 1.21 ± 0.02; 0.41 ± 0.02, 0.57 ± 0.06, 1.31 ± 0.04 and 1.26 ± 0.01, 1.79 ± 0.04, 0.63 ± 0.01 against leukemia cancer cell line HL-60 (TB), colon cancer cell line HCT-116 and breast cancer cell line MCF7, respectively. Moreover, the most potent derivative 4i induced apoptosis at G2/M phase Investigating the mechanism of action of compounds 4e, 4 h and 4i exhibited promising dual TOP Iα and TOP IIB % inhibition comparable to Camptothecin and Etoposide; respectively. Docking of 4e, 4 h and 4i into the active site of topo I and II proteins compared to Camptothein and Etoposide revealed acceptable binding score and augmented enzyme assay data. Hence, 4e and 4i are promising targeted antiproliferative dual acting TOP Iα TOP IIB inhibitors that require further optimization.
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http://dx.doi.org/10.1016/j.bioorg.2021.104698DOI Listing
May 2021

Novel Mannich bases of ciprofloxacin with improved physicochemical properties, antibacterial, anticancer activities and caspase-3 mediated apoptosis.

Bioorg Chem 2021 Feb 7;107:104629. Epub 2021 Jan 7.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New-Minia, 61519 Minia, Egypt; Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sphinx University, New-Assiut, Egypt. Electronic address:

The design, synthesis and identification of a novel series of Mannich bases of ciprofloxacin was reported. Naphthol derivatives 2a and 2b showed highly potent cytotoxic activity among the tested compounds. Compound 2a showed broad spectrum antiproliferative activity with GI of 2.5-6.79 µM with remarkable selectivity towards renal and prostate cancers with selectivity ratios ranging from 0.17 to 6.79. Independently, 2a showed outstanding activity against colon cancer HOP-92 cell lines with IC of 6.66 µM while 2b showed highly potent activity against ovarian cancer cell lines with IC of 0.97 µM. Results showed that 2b induced cell cycle arrest at G2/M phase and apoptosis; compound 2b showed over-expression of caspase-3 protein level (449.2 ± 7.95) compared to doxorubicin (578.7 ± 14.4 pg/mL). Meanwhile, compounds 2a and 2b experienced outstanding activity against both Gram-positive and Gram-negative microorganisms. Interestingly, compound 2j experienced high activity against Escherichia coli and Pseudomonas aeruginosa with MIC of 0.036 and 0.043, respectively. Compound 2d revealed 27 folds and 22 folds, respectively increasing of activity over ciprofloxacin against Staphylococcus aureus and MRSA(reference strain). Compound 2d showed high activity against Staphylococcus aureus, MRSA (reference strain) and MRSA (clinical strain) with MIC of 0.57, 0.52, 0.082 µg/mL, respectively. Interestingly, the most active tested compounds were found to have promising physicochemical and drug likeness properties. The Mannich bases 2j, 2d and 2g showed promising antibacterial activities, while naphthols 2a and 2b showed promising antiproliferative and antibacterial activities that require further optimization.
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http://dx.doi.org/10.1016/j.bioorg.2021.104629DOI Listing
February 2021

Synthesis, antitumor, antibacterial and urease inhibitory evaluation of new piperazinyl N-4 carbamoyl functionalized ciprofloxacin derivatives.

Pharmacol Rep 2021 Jun 3;73(3):891-906. Epub 2021 Jan 3.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt.

Background: Quinolones are well known antibacterial chemotherapeutics. Furthermore, they were reported for other activities such as anticancer and urease inhibitory potential. Modification at C7 of quinolones can direct these compounds preferentially toward target molecules.

Methods: Different derivatives of ciprofloxacin by functionalization at the piperazinyl N-4 position with arylidenehydrazinecarbonyl and saturated heterocyclic-carbonyl moieties have been synthesized and characterized using different spectral and analytical techniques. The synthesized compounds were evaluated for anticancer, antibacterial, and urease inhibitory activities.

Results: Among the synthesized compounds derivatives 3f and 3g experienced a potent antiproliferative activity against the breast cancer BT-549 cell line, recording growth percentages of 28.68% and 6.18%, respectively. Additionally, compound 3g revealed a remarkable antitumor potential toward the colon cancer HCT-116 cells (growth percentage 14.76%). Activity of compounds 3f and 3g against BT-549 cells was comparable to doxorubicin (IC = 1.84, 9.83, and 1.29 µM, respectively). Test compounds were less active than their parent drug, ciprofloxacin toward Klebsiella pneumoniae and Proteus mirabilis. However, derivative 4a showed activity better than chloramphenicol against Klebsiella pneumoniae (MIC = 100.64 and 217.08 µM, respectively). Meanwhile, many of the synthesized compounds revealed a urease inhibitory activity greater than their parent. Compound 3i was the most potent urease inhibitor with IC of 58.92 µM, greater than ciprofloxacin and standard inhibitor, thiourea (IC = 94.32 and 78.89 µM, respectively).

Conclusion: This study provided promising derivatives as lead compounds for development of anticancer agents against breast and colon cancers, and others for optimization of urease inhibitors.
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http://dx.doi.org/10.1007/s43440-020-00193-0DOI Listing
June 2021

Design, synthesis, and biological evaluation of new series of pyrrol-2(3H)-one and pyridazin-3(2H)-one derivatives as tubulin polymerization inhibitors.

Bioorg Chem 2021 Feb 1;107:104522. Epub 2020 Dec 1.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New Minia, Minia, Egypt. Electronic address:

A potential microtubule destabilizing series of new thirty-five Pyrrol-2-one, Pyridazin-3(2H)-one and Pyridazin-3(2H)-one/oxime derivatives has been synthesized and tested for their antiproliferative activity against a panel of 60 human cancer cell lines. Compounds IVc, IVg and IVf showed a broad spectrum of growth inhibitory activity against cancer cell lines representing renal, cancer of lung, colon, central nervous system, ovary, and kidney. Among them, compound IVg was found to have broad spectrum anti-tumor activity against the tested nine tumor subpanels with selectivity ratios ranging between 0.21 and 3.77 at the GI level. In vitro assaying revealed tubulin polymerization inhibition by all active compounds IVc, IVg and IVf. The results of the docking study revealed nice fitting of compounds IVc, IVf, and IVg into CA-4 binding site in tubulin. The three compounds exhibited high binding affinities (ΔG = -12.49 to -12.99 kcal/mol) toward tubulin compared to CA-4 (-8.87 kcal/mol). Investigation of the binding modes of the three compounds IVc, IVf, and IVg revealed that they interacted mainly hydrophobically with tubulin and similar binding orientations to that of CA-4. These observations suggest that tubulin is a possible target for these compounds.
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http://dx.doi.org/10.1016/j.bioorg.2020.104522DOI Listing
February 2021

Novel urea linked ciprofloxacin-chalcone hybrids having antiproliferative topoisomerases I/II inhibitory activities and caspases-mediated apoptosis.

Bioorg Chem 2021 Jan 22;106:104422. Epub 2020 Oct 22.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, 71526, Egypt.

A novel series of urea-linked ciprofloxacin (CP)-chalcone hybrids 3a-j were synthesized and screened by NCI-60 cancer cell lines as potential cytotoxic agents. Interestingly, compounds 3c and 3j showed remarkable antiproliferative activities against both colon HCT-116 and leukemia SR cancer cells compared to camptothecin, topotecan and staurosporine with IC = 2.53, 2.01, 17.36, 12.23 and 3.1 μM for HCT-116 cells, respectively and IC = 0.73, 0.64, 3.32, 13.72 and 1.17 μM for leukemia SR cells, respectively. Also, compounds 3c and 3j exhibited inhibitory activities against Topoisomerase (Topo) I with % inhibition = 51.19% and 56.72%, respectively, compared to camptothecin (% inhibition = 60.05%) and Topo IIβ with % inhibition = 60.81% and 60.06%, respectively, compared to topotecan (% inhibition = 71.09%). Furthermore, compound 3j arrested the cell cycle of leukemia SR cells at G2/M phase. It induced apoptosis both intrinsically and extrinsically via activation of proteolytic caspases cascade (caspases-3, -8, and -9), release of cytochrome C from mitochondria, upregulation of proapoptotic Bax and down-regulation of Bcl-2 protein level. Thus, the new ciprofloxacin derivative 3j could be considered as a potential lead for further optimization of antitumor agent against leukemia and colorectal carcinoma.
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http://dx.doi.org/10.1016/j.bioorg.2020.104422DOI Listing
January 2021

Design, synthesis and molecular modeling of novel aryl carboximidamides and 3-aryl-1,2,4-oxadiazoles derived from indomethacin as potent anti-inflammatory iNOS/PGE2 inhibitors.

Bioorg Chem 2020 12 28;105:104439. Epub 2020 Oct 28.

Department of Chemistry, Faculty of Science, Sohag University, Sohag 82524, Egypt.

The development of NSAIDs/iNOS inhibitor hybrids is a new strategy for the treatment of inflammatory diseases by suppression of the overproduction of PGE and NO. A novel series of aryl carboximidamides 4a-g and their cyclized 3-aryl-1,2,4-oxadiazoles 5a-g counterparts derived from indomethacin 1 were synthesized. Most of the target compounds displayed lower LPS-induced NO production IC in RAW 264.7 cells and potent in vitro iNOS and PGE2 inhibitory activity than indomethacin. Moreover, in carrageenan-induced rat paw oedema method, most of them exhibited higher in vivo anti-inflammatory activity than the reference drug indomethacin. Notably, 4 hrs after carrageenan injection, compound 4a proved to be the most potent anti-inflammatory agent in this study, with almost two- and eight-fold more active than the reference drugs indomethacin (1) and celecoxib, respectively. Compound 4a proved to be inhibitor to LPS-induced NO production, iNOS activity and PGE2 with IC of 10.70 μM, 2.31 μM, and 29 nM; respectively. Compounds 4a and 5b possessed the lowest ulcerogenic liabilities (35% and 38%, respectively) compared to 1. Histopathological analysis revealed that compounds 4a and 5b demonstrated reduced degeneration and healing of ulcers. Molecular docking studies into the catalytic binding pocket of the iNOS protein receptor (PDB ID: 1r35) showed good correlation with the obtained biological results. Parameters of Lipinski's rule of five and ADMET analysis were calculated where compound 4a had reasonable drug-likeness with acceptable physicochemical properties so it could be used as promising orally absorbed anti-inflammatory therapy and entitled to be used as future template for further investigations.
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http://dx.doi.org/10.1016/j.bioorg.2020.104439DOI Listing
December 2020

Comprehensive review for anticancer hybridized multitargeting HDAC inhibitors.

Eur J Med Chem 2021 Jan 8;209:112904. Epub 2020 Oct 8.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New Minia, Minia, Egypt. Electronic address:

Despite the encouraging clinical progress of chemotherapeutic agents in cancer treatment, innovation and development of new effective anticancer candidates still represents a challenging endeavor. With 15 million death every year in 2030 according to the estimates, cancer has increased rising of an alarm as a real crisis for public health and health systems worldwide. Therefore, scientist began to introduce innovative solutions to control the cancer global health problem. One of the promising strategies in this issue is the multitarget or smart hybrids having two or more pharmacophores targeting cancer. These rationalized hybrid molecules have gained great interests in cancer treatment as they are capable to simultaneously inhibit more than cancer pathway or target without drug-drug interactions and with less side effects. A prime important example of these hybrids, the HDAC hybrid inhibitors or referred as multitargeting HDAC inhibitors. The ability of HDAC inhibitors to synergistically improve the efficacy of other anti-cancer drugs and moreover, the ease of HDAC inhibitors cap group modification prompt many medicinal chemists to innovate and develop new generation of HDAC hybrid inhibitors. Notably, and during this short period, there are four HDAC inhibitor hybrids have entered different phases of clinical trials for treatment of different types of blood and solid tumors, namely; CUDC-101, CUDC-907, Tinostamustine, and Domatinostat. This review shed light on the most recent hybrids of HDACIs with one or more other cancer target pharmacophore. The designed multitarget hybrids include topoisomerase inhibitors, kinase inhibitors, nitric oxide releasers, antiandrogens, FLT3 and JAC-2 inhibitors, PDE5-inhibitors, NAMPT-inhibitors, Protease inhibitors, BRD4-inhibitors and other targets. This review may help researchers in development and discovery of new horizons in cancer treatment.
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http://dx.doi.org/10.1016/j.ejmech.2020.112904DOI Listing
January 2021

Synthesis and antimicrobial evaluation of new nitric oxide-donating fluoroquinolone/oxime hybrids.

Arch Pharm (Weinheim) 2021 Jan 21;354(1):e2000180. Epub 2020 Sep 21.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, Egypt.

A new series of nitric oxide-donating fluoroquinolone/oximes was prepared in this study. The nitric oxide release from the prepared compounds was measured using a modified Griess colorimetric method. The antitubercular evaluation of the synthesized compounds indicated that ketone derivatives 2b and 2e and oximes 3b and 3d exhibited somewhat higher activity than their respective parent fluoroquinolones. Mycobacterial DNA cleavage studies and molecular modeling of Mycobacterium tuberculosis DNA gyrase were pursued to explain the observed bioactivity. More important, antibacterial evaluation showed that oximes 3c-e are highly potent against Klebsiella pneumoniae, with minimum inhibitory concentration (MIC) values of 0.06, 0.08, and 0.034 µM, respectively, whereas ketone 2c and oxime 4c are more active against Staphylococcus aureus than ciprofloxacin (MIC values: 0.7, 0.38, and 1.6 µM, respectively). Notably, the antipseudomonal activities of compounds 2a and 4c were much higher than those of their respective parent fluoroquinolones.
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http://dx.doi.org/10.1002/ardp.202000180DOI Listing
January 2021

A New Ciprofloxacin-derivative Inhibits Proliferation and Suppresses the Migration Ability of HeLa Cells.

Anticancer Res 2020 Sep;40(9):5025-5033

Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

Background/aim: This study aimed to investigate the effect of a new 7-(4-(N-substituted carbamoylmethyl) piperazin-1-yl) ciprofloxacin-derivative on the proliferation and migration abilities of HeLa cells.

Materials And Methods: Cell viability and morphological alterations were examined. Changes in migration were detected using wound healing and colony formation assays. Flow cytometry and western blotting were used to investigate the molecular mechanisms underlying this ciprofloxacin-derivative's action in HeLa cells.

Results: The examined ciprofloxacin-derivative reduced viability of HeLa cells in a concentration-dependent manner and altered cellular morphology, indicating cell death. Furthermore, it significantly inhibited wound closure, even in a non-cytotoxic concentration, and reduced HeLa cell colony formation. In addition, apoptosis was increased probably through significant up-regulation of Bax protein expression and the generation of active cleaved caspase-3 protein.

Conclusion: Our new derivative inhibits proliferation and induces apoptosis of HeLa cells. Furthermore, it suppressed the migration and colony formation abilities of HeLa cells. Therefore, it represents an attractive agent for drug development against cervical cancer based on its anti-metastatic effect.
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http://dx.doi.org/10.21873/anticanres.14505DOI Listing
September 2020

Cell Cycle Arrest and Apoptotic Effect of 7-(4-(N-substituted carbamoylmethyl) piperazin-1-yl) Ciprofloxacin-derivative on HCT 116 and A549 Cancer Cells.

Anticancer Res 2020 May;40(5):2739-2749

Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt

Background/aim: Ciprofloxacin has been used as an antibiotic in the clinic for decades. Recently, ciprofloxacin and its derivatives have shown promising anti-proliferative and cytotoxic activities against several malignant cells. The aim of this study was to investigate the effect of a new derivative of ciprofloxacin on colorectal cancer (HCT116) and non-small lung carcinoma (A549) cells.

Materials And Methods: Cell viability was detected by the MTT assay. Flow cytometry was used to examine the cell cycle and apoptosis. Expression of bax, bcl2, p53 and p21 was investigated by qRT-PCR and western blotting.

Results: Ciprofloxacin-derivative had an anti-proliferative effect on both cell lines in a concentration-dependent manner and caused cell cycle arrest at the G/M phase and apoptosis. p53 and Bax proteins were overexpressed, while p21 and bcl2 gene expression was decreased after treatment with the ciprofloxacin derivative.

Conclusion: This new ciprofloxacin derivative can be potentially used for the treatment of colorectal cancer and non-small lung carcinoma.
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http://dx.doi.org/10.21873/anticanres.14245DOI Listing
May 2020

Design, synthesis and anticancer activity of novel valproic acid conjugates with improved histone deacetylase (HDAC) inhibitory activity.

Bioorg Chem 2020 06 30;99:103797. Epub 2020 Mar 30.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt. Electronic address:

Twenty-five valproic acid conjugates have been designed and synthesized. All target compounds were explored for their in vitro anti-proliferative activities using the MTT-based assay against four human cancer cell lines includingliver (HePG2), colon (HCT116), breast (MCF7) and cervical (HeLa) carcinoma cell lines. Out of six valproic acid-amino acid conjugates 2a-f. Only cysteine containing conjugate 2f showed the significant activity (IC 9.10 µM against HePG2 and 6.81 µM against HCT116). However conjugate 2j showed broad-spectrum antitumor activity against all cell lines tested. In addition, conjugates 4j and 4k which contains phenyl hydrazide and hydroxamic acid group, respectively, also showed broad spectrum activity. Furthermore, six compounds were screened for HDAC 1-9 isozymes inhibitory activities. Compounds 2j, 4j and 4k manifested a higher inhibitory activity more than valproic acid but less than SAHA. In addition, the in vivo antitumor screening of 2j, 4j and 4k was done and the results have shown that 2j, 4j and 4k, particularly 4j, showed a significant decrease in tumor size and presented a considerable decrease in viable EAC count. Docking study of selectedcompound 4j revealed that it can bind nicely to the binding pocket of HDAC 1, 2, 3, 4 and HDAC 8. The results suggest that compounds 2j, 4j and 4k, particularly 4j, may be promising lead candidates for the development of novel targeted anti-tumor drug potentially via inhibiting HDACs.
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http://dx.doi.org/10.1016/j.bioorg.2020.103797DOI Listing
June 2020

New nicotinic acid-based 3,5-diphenylpyrazoles: design, synthesis and antihyperlipidemic activity with potential NPC1L1 inhibitory activity.

Mol Divers 2021 May 17;25(2):673-686. Epub 2020 Feb 17.

Department of Chemistry, Sohag University, Sohâg, 82524, Egypt.

Nicotinic acid hydrazide was incorporated into new 4,5-dihydro-5-hydroxy-3,5-diphenylpyrazol-1-yl derivatives. Compounds 6a-h were synthesized, and their antihyperlipidemic activity was evaluated in high cholesterol diet-fed rat model. Compounds 6e, 6f were found to decrease the levels of serum total cholesterol by 14-19% compared to control group. Total triglycerides were also reduced by 24-28% and LDL cholesterol by 16%. As expected from parent niacin, compounds 6e and 6f caused an elevation of HDL cholesterol by 33-41%. Docking study supported the ability of designed compounds to block NPC1L1 active site in a manner similar to that observed with ezetimibe.
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http://dx.doi.org/10.1007/s11030-020-10039-9DOI Listing
May 2021

Arylidenes of Quinolin-2-one scaffold as Erlotinib analogues with activities against leukemia through inhibition of EGFR TK/ STAT-3 pathways.

Bioorg Chem 2020 03 27;96:103628. Epub 2020 Jan 27.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt. Electronic address:

A new series of 6-substiuted-4-(2-(4-substituted-benzylidene)hydrazinyl)quinolin-2(1H)-one derivatives have been designed and synthesized. The structure of the synthesized compounds was proved by H NMR, C NMR, 2D NMR, mass and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, the most active compounds were further examined against the most sensitive leukemia RPMI-8226 and on healthy cell lines. 6-Chloro-derivative was the most active one; with IC = 15.72 ± 1.21 and 46.05 ± 2.36 μM against RPMI-8226 and normal cell lines, respectively. Also, it showed a remarkable inhibitory activity compared to gefitinib on the EGFR TK mutant, wild and on H-RAS in addition to STAT-3 with IC = 695.49 ± 21.8, 263.15 ± 15.13, 10.61 ± 0.27 and 1.753 ± 0.81 nM, respectively. Cell cycle analysis of RPMI-8226 cells treated with the 6-chloro-derivative showed cell cycle arrest at G2/M phase (supported by Caspases-3,8, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking studies ROCS analysis and Tanimoto scores supported the results. The study illustrated the effect of several factors on compounds activity.
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http://dx.doi.org/10.1016/j.bioorg.2020.103628DOI Listing
March 2020

HSP70 induction by bleomycin metal core analogs.

Bioorg Med Chem Lett 2020 04 31;30(7):127002. Epub 2020 Jan 31.

Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, Kumamoto 862-0973, Japan. Electronic address:

Induction of heat shock protein 70 (HSP70) is known to be effective against various diseases. We are interested in HSP70 induction capability of an antitumor antibiotic bleomycin which produces oxidative stress by iron chelate formation and oxygen activation in a cell. The HSP70 induction activity of bleomycin and its six metal core analogs was examined, and a compound HPH-1Trt of 10 μM was found to induce this protein in a pheochromocytoma cell line and some T cell and monocytic cell lines. Its mechanism is increase of HSP70 mRNA, but higher concentration of this compound showed toxicity. Two new derivatives were then synthesized, and one of them named DHPH-1Trt was shown to have less toxicity and higher HSP70 induction activity. This study would lead to a clue for new HSP70 inducer clinically used in near future.
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http://dx.doi.org/10.1016/j.bmcl.2020.127002DOI Listing
April 2020

Identification and molecular modeling of new quinolin-2-one thiosemicarbazide scaffold with antimicrobial urease inhibitory activity.

Mol Divers 2021 Feb 8;25(1):13-27. Epub 2020 Jan 8.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, El-Minia, 61519, Egypt.

A new series of 6-substituted quinolin-2-one thiosemicarbazides 6a-j has been synthesized. The structure of the target compounds was proved by different spectroscopic and elemental analyses. All the designed final compounds were evaluated for their in vitro activity against the urease-producing R. mucilaginosa and Proteus mirabilis bacteria as fungal and bacterial pathogens, respectively. Moreover, all compounds were in vitro tested as potential urease inhibitors using the cup-plate diffusion method. Compounds 6a and 6b were the most active with (IC = 0.58 ± 0.15 and 0.43 ± 0.09 µM), respectively, in comparison with lead compound I (IC = 1.13 ± 0.00 µM). Also, the designed compounds were docked into urease proteins (ID: 3LA4 and ID: 4UBP) using Open Eye software to understand correctly about ligand-receptor interactions. The docking results revealed that the designed compounds can interact with the active site of the enzyme through multiple strong hydrogen bonds. Moreover, rapid overlay of chemical structures' analysis was described to understand the 3D QSAR of synthesized compounds as urease inhibitors. The results emphasize the importance of polar thiosemicarbazide directly linked to 6-substituted quinolone moieties as promising antimicrobial urease inhibitors.
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http://dx.doi.org/10.1007/s11030-019-10021-0DOI Listing
February 2021

Utilization of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinone as a cap moiety in design of novel histone deacetylase inhibitors.

Bioorg Chem 2019 10 18;91:103127. Epub 2019 Jul 18.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt. Electronic address:

A series of novel 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives bearing a hydroxamic acid, 2-aminoanilide and hydrazide moieties as zinc-binding group (ZBG) were designed, synthesized and evaluated for the HDAC inhibition activity and antiproliferative activity. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds IVa, IVb, IXa and IXb exhibited significant anti-proliferative activity against the three cell lines tested compared to SAHA as a reference. Compound IVb is equipotent inhibitor for HDAC1 and HDAC2 as SAHA. It is evident that the presence of free hydroxamic acid group is essential for Zn binding affinity with maximal activity with a linker of aliphatic 6 carbons. Docking study results revealed that compound IVb could occupy the HDAC2 binding site and had the potential to exhibit antitumor activity through HDAC inhibition, which merits further investigation.
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http://dx.doi.org/10.1016/j.bioorg.2019.103127DOI Listing
October 2019

Towards anticancer fluoroquinolones: A review article.

Arch Pharm (Weinheim) 2019 Jul 19;352(7):e1800376. Epub 2019 Jun 19.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, Egypt.

Different studies about the anticancer potential of several medically used antibacterial fluoroquinolones have been established. Fluoroquinolone derivatives, like some anti-cancer drugs, such as doxorubicin, can achieve antitumor activity via poisoning of type II human DNA topoisomerases. Interestingly, structural features required for the anticancer activity of quinolones have been determined. Most of the chemical modifications required to convert antibacterially acting fluoroquinolones into their anticancer analogs were at position 7 and the carboxylic group at position 3. This review highlights the antitumor potential of fluoroquinolones in general and summarizes the chemical modifications carried out on fluoroquinolones to become anticancer agents. Moreover, the review gives a quick recap on metal ion chelates with fluoroquinolones and their substantial role in topoisomerase poisoning and antitumor potential improvement. Hence, it should be highly interesting for researchers attempting to design and synthesize novel anticancer fluoroquinolone candidates.
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http://dx.doi.org/10.1002/ardp.201800376DOI Listing
July 2019

Novel Pyrazoloquinolin-2-ones: Design, synthesis, docking studies, and biological evaluation as antiproliferative EGFR-TK inhibitors.

Bioorg Chem 2019 09 8;90:103045. Epub 2019 Jun 8.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt. Electronic address:

Two new series of diethyl 2-[2-(substituted-2-oxo-1,2-dihydroquinolin-4-yl)hydrazono]-succinates 6a-g and 1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazoles 7a-f have been designed and synthesized. The structures of the synthesized compounds were proved by IR, mass, NMR (2D) spectra and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, seven compounds were further examined against the most sensitive cell lines, leukemia CCRF-CEM, and MOLT-4. 5-Amino-1-(6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazole-3,4-dicarbonitrile (7f) was the most active product, with IC = 1.35 uM and 2.42 uM against MOLT-4 and CCRF-CEM, respectively. Also, it showed a remarkable inhibitory activity compared to erlotinib on the EGFR TK with IC = 247.14 nM and 208.42 nM, respectively. Cell cycle analysis of MOLT-4 cells treated with 7f showed cell cycle arrest at G2/M phase (supported by Caspases, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking study indicated that both the pyrazole moiety and the quinolin-2-one ring showed good fitting into EGFR (PDB code: 1M17). In order to interpret SAR of the designed compounds, and provide a basis for further optimization, molecular docking of the synthesized compounds to known EGFR inhibitors was performed. The study illustrated the effect of several factors on the compounds' activity.
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http://dx.doi.org/10.1016/j.bioorg.2019.103045DOI Listing
September 2019

Design, synthesis and molecular docking of new N-4-piperazinyl ciprofloxacin-triazole hybrids with potential antimicrobial activity.

Bioorg Chem 2019 07 25;88:102952. Epub 2019 Apr 25.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt. Electronic address:

New N-4-piperazinyl ciprofloxacin-triazole hybrids 6a-o were prepared and characterized. The in vitro antimycobacterial activity revealed that compound 6a experienced promising antimycobacterial activity against Mycobactrium smegmatis compared with the reference isoniazide (INH). Additionally, compound 6a exhibited broad spectrum antibacterial activity against all the tested strains either Gram-positive or Gram-negative bacteria compared with the reference ciprofloxacin. Also, compounds 6g and 6i displayed considerable antifungal activity compared with the reference ketoconazole. DNA cleavage assay of the highly active compounds 6c and 6h showed a good correlation between the Mycobactrium cleaved DNA gyrase assay and their in vitro antimycobactrial activity. Moreover, molecular modeling studies were done for the designed ciprofloxacin derivatives to predict their binding modes towards Topoisomerase II enzyme (PDB: 5bs8).
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http://dx.doi.org/10.1016/j.bioorg.2019.102952DOI Listing
July 2019

Discovery of novel thienoquinoline-2-carboxamide chalcone derivatives as antiproliferative EGFR tyrosine kinase inhibitors.

Bioorg Med Chem 2019 03 5;27(6):1076-1086. Epub 2019 Feb 5.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt. Electronic address:

Novel thienoquinoline carboxamide-chalcone derivatives were prepared via the cyclization of acylated chalcones and 2-mercaptoquinoline-3-carbaldehyde in DMF with KCO. Thienoquinolines 9a-f, h exhibited promising antiproliferative effect against all the tested cell lines and gave a significant activity as EGFR inhibitors, with IC values ranging from 0.5 and 3.2 µM, and compounds 9e and 9f being the most active of the series. They also showed better activity than Erlotinib against melanoma cancer cell line A375. Moreover, compound 9f influenced pre G1 apoptosis and cell cycle arrest at G2/M phase. The binding mode of the best EGFR inhibitor 9e in the EGFR active site revealed that the thienoquinoline ring occupied the ATP-binding site while the chalcone moiety is located in the allosteric site and is responsible for the enhanced activity of these compounds.
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http://dx.doi.org/10.1016/j.bmc.2019.02.012DOI Listing
March 2019

Novel quinoline derivatives carrying nitrones/oximes nitric oxide donors: Design, synthesis, antiproliferative and caspase-3 activation activities.

Arch Pharm (Weinheim) 2019 Jan 30;352(1):e1800270. Epub 2018 Nov 30.

Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Assiut University, Assiut, Egypt.

Novel quinoline derivatives carrying nitrones and oxime as nitric oxide donors were prepared and characterized using different spectroscopic techniques. Nitrones can release nitric oxide in larger amounts compared to corresponding oximes. Antiproliferative screening results showed that the 2-benzylthioquinoline nitrones 6e and 6f and the 2-methylthio analogues 6g and 6h exhibited promising antiproliferative activity especially against leukemia and colon cancer cell lines. Compounds 6c, 6e, and 6f exhibited higher potency as anticancer agents compared to doxorubicin, with IC ranging from 0.45 to 0.91 μM. A remarkable overexpression of caspase-3 protein levels was observed in cells treated with the tested compounds. Compound 6e exhibited more pre-G1 apoptosis and cell cycle arrest at the G2/M phase than in other phases. These results revealed that the tested compounds can cause programmed cell death through overexpression of caspase 3, which may be attributed to the release of nitric oxide.
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http://dx.doi.org/10.1002/ardp.201800270DOI Listing
January 2019

Recent updates of fluoroquinolones as antibacterial agents.

Arch Pharm (Weinheim) 2018 Sep 26;351(9):e1800141. Epub 2018 Jul 26.

Faculty of Pharmacy, Department of Medicinal Chemistry, Minia University, Minia, Egypt.

Fluoroquinolones remain one of the most important kind of antibacterial agents used nowadays. The emergence of more virulent and resistant strains of bacteria by the development of either mutated DNA-binding proteins or efflux pump mechanism for drugs is considered the main problem associated with the therapeutic use of these drugs. This situation participated in pushing researchers to design new fluoroquinolone derivatives, mainly with different substituents at C-7 to withstand these resistant strains of bacteria and to obtain a wider spectrum of activity including activity against anaerobic organisms. Conjugation of fluoroquinolones with substitutions such as 1,2,4-triazoles, alkyl oximes, flavonoids, aryl furans, benzofuroxans, metronidazoles or even other antibiotics such as neomycin-B produced derivatives that have a superior and wider spectrum of activity and better resistance than the classical fluoroquinolone agents. Addition of a hydroxamic acid moiety to fluoroquinolones also increased the activity against Proteus mirabilis, which represents one of the most resistant strains of bacteria in urinary tract infections. This review aims to highlight the recent updates made for fluoroquinolones for broadening the spectrum of activity to become active not only against resistant strains of bacteria but also against anaerobic pathogens.
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http://dx.doi.org/10.1002/ardp.201800141DOI Listing
September 2018

Novel pyrrol-2(3H)-ones and pyridazin-3(2H)-ones carrying quinoline scaffold as anti-proliferative tubulin polymerization inhibitors.

Bioorg Chem 2018 10 5;80:151-163. Epub 2018 Jun 5.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.

A novel quinolinyl pyrrolone and quinolinyl pyridazinone derivatives has been synthesized and characterized using different spectroscopic and elemental analysis techniques. Most of the target compounds displayed promising antiproliferative activity; In general, the pyrrolone derivatives 4a-f exhibited higher antiproliferative activity than their corresponding pyridazinone. The pyrrolone 4f showed outstanding antiproliferative activity with moderate selectivity against CNS and renal cancer with selectivity ratio of 3.49 and 3.56, respectively. Compound 4e and 5d experienced tubulin polymerization inhibitory activity comparable to that of vincristine while 4c, 4e and 4d showed good BRAF kinase inhibition compared to Erlotinib. Docking of compound 4e into colchicine binding site and biological assay results revealed that these compounds act mainly through tubulin polymerization inhibitory mechanism and can exhibit pre G1 apoptosis and cell cycle arrest at G2/M phase.
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http://dx.doi.org/10.1016/j.bioorg.2018.06.003DOI Listing
October 2018

Current Trends and Future Directions of Fluoroquinolones.

Curr Med Chem 2019 ;26(17):3132-3149

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.

Fluoroquinolones represent an interesting synthetic class of antimicrobial agents with broad spectrum and potent activity. Since the discovery of nalidixic acid, the prototype of quinolones, several structural modifications to the quinolone nucleus have been carried out for improvement of potency, spectrum of activity, and to understand their structure activity relationship (SAR). The C-7 substituent was reported to have a major impact on the activity. Accordingly, Substitution at C-7 or its N-4-piperazinyl moiety was found to affect potency, bioavailability, and physicochemical properties. Also, it can increase the affinity towards mammalian topoisomerases that may shift quinolones from antibacterial to anticancer candidates. Moreover, the presence of DNA topoisomerases in both eukaryotic and prokaryotic cells makes them excellent targets for chemotherapeutic intervention in antibacterial and anticancer therapies. Based on this concept, several fluoroquionolones derivatives have been synthesized and biologically evaluated as antibacterial, antituberculosis, antiproliferative, antiviral and antifungal agents. This review is an attempt to focus on the therapeutic prospects of fluoroquinolones with an updated account on their atypical applications such as antitubercular and anticancer activities.
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http://dx.doi.org/10.2174/0929867325666180214122944DOI Listing
October 2019

Design, synthesis, docking studies and biological evaluation of novel chalcone derivatives as potential histone deacetylase inhibitors.

Bioorg Chem 2017 06 19;72:32-41. Epub 2017 Mar 19.

Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt. Electronic address:

A group of novel chalcone derivatives comprising hydroxamic acid or 2-aminobenzamide group as zinc binding groups (ZBG) were synthesized. The structure of the prepared compounds was fully characterized by IR, NMR and elemental microanalyses. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds 4a and 4b exhibited significant anti-proliferative activity against the three cell lines compared to SAHA as reference drug and displayed promising profile as anti-tumor candidates. The results indicated that these chalcone derivatives could serve as a promising lead compounds for further optimization as antitumor agents.
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http://dx.doi.org/10.1016/j.bioorg.2017.03.005DOI Listing
June 2017