Publications by authors named "Khaled El-Adl"

27 Publications

  • Page 1 of 1

Design, synthesis, molecular docking and in silico ADMET profile of pyrano[2,3-d]pyrimidine derivatives as antimicrobial and anticancer agents.

Bioorg Chem 2021 Jul 22;115:105186. Epub 2021 Jul 22.

Department of Biochemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt.

Pyrano[2,3-d]pyrimidine derivatives were synthesized by treating cyclic compounds containing active methylene group with aldehyde and malononitrile in butanol. The behavior of pyrano[2,3-d]pyrimidine towards some electrophlies namely triethylorthoformate followed by nitrogen nucleophiles as isobutylamine, urea, phenylthiourea, p-toluidine, o-phenylenediamine, o-aminophenol, 2-amino-4-methyl-pyridine and acetic acid with the aim of obtaining some interesting non-mixed heterocyclic compounds. All synthesized compounds to some extent have shown good antimicrobial activity against different microbial strains that had been extracted by inhibiting cell wall synthesis. Compound 5b showed the highest antibacterial activities against B. subtilis, S. aureus and E. coli. On the other hand compound 5 g exhibited the highest antibacterial and antifungal activities against P. aeruginosa and A. niger respectively. In addition, they explore cytotoxic potentialities against different cell lines via DNA intercalation and Top-II inhibition. The cytotoxic activities clarify the strong inhibitory activity of derivative 5a against HepG2 cells with IC = 2.09 μM, while HCT-116 cells were highly susceptible to derivative 5c with IC = 2.61 μM, in the meantime, derivative 5f showed pronounced negative impact against MCF-7 (IC = 2.43 μM) when compared with other prepared compounds. All derivatives exhibited higher anticancer activities than doxorubicin against the three cell lines except compound 2 against both HepG2 and MCF-7 and compound 5e against HepG2 cell lines. Compounds 5a, 5c and 5f potently intercalate DNA at IC values of 26.96, 27.13 and 29.86 µM respectively, which were more potent than doxorubicin (IC value of 31.27 µM). Moreover, compounds 5a, 5c and 5f exhibited very good Topoisomerase II inhibitory activities with IC values of 0.752, 0.791 and 0.776 µM respectively, that were more potent than that of doxorubicin (IC = 0.94 µM). For a great extent, the molecular modeling studies were in agreement with that of in vitro cytotoxicity activity, DNA binding and Top-II inhibition results.
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http://dx.doi.org/10.1016/j.bioorg.2021.105186DOI Listing
July 2021

Discovery of new quinoxaline-2(1H)-one-based anticancer agents targeting VEGFR-2 as inhibitors: Design, synthesis, and anti-proliferative evaluation.

Bioorg Chem 2021 Jun 18;114:105105. Epub 2021 Jun 18.

Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address:

VEGF/VEGFR2 pathway is the crucial therapeutic target in the treatment of cancer. So that, a new series of quinoxaline-2(1H)-one derivatives were designed and synthesized. The synthesized compounds were tested against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) aiming to evaluate its anti-proliferative activities. Doxorubicin as a universal anticancer drug and sorafenib as a potent VEGFR-2 inhibitor were used as positive controls. The data obtained from biological activity were found highly correlated with that obtained from molecular modeling studies. The most sensitive cell line to the influence of our new derivatives was HCT-116. Compounds 13, 15, 16 and 17 exert the highest cytotoxic activities against the tested cell lines. Overall, compound 15 was the most active member with IC values of 5.30, 2.20, 5.50 µM against HepG-2, MCF-7 and HCT-116, respectively. Compounds 15 and 17 showed better anti-proliferative activities than doxorubicin and sorafenib against the three cancer cell lines. Additionally, compound 16 showed better anti-proliferative activities than doxorubicin and sorafenib against HepG-2 and HCT-116 but exhibited lower activity against MCF-7 cell line. In addition, the most promising members were further evaluated for their inhibitory activities against VEGFR-2. Compounds 15 and 17 potently inhibited VEGFR-2 at lower IC values of 1.09 and 1.19 µM, respectively, compared to sorafenib (IC = 1.27 µM). Moreover, docking studies were conducted to investigate the binding pattern of the synthesized compounds against the prospective molecular target VEGFR-2.
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http://dx.doi.org/10.1016/j.bioorg.2021.105105DOI Listing
June 2021

Pyridine-derived VEGFR-2 inhibitors: Rational design, synthesis, anticancer evaluations, in silico ADMET profile, and molecular docking.

Arch Pharm (Weinheim) 2021 May 5:e2100085. Epub 2021 May 5.

Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Novel pyridine-derived compounds (5-19) were designed and synthesized, and their anticancer activities were evaluated against HepG2 and MCF-7 cells, targeting the VEGFR-2 enzyme. Compounds 10, 9, 8, and 15 were found to be the most potent derivatives against the two cancer cell lines, HepG2 and MCF-7, respectively, with IC  = 4.25 and 6.08 µM, 4.68 and 11.06 µM, 4.34 and 10.29 µM, and 6.37 and 12.83 µM. Compound 10 displayed higher activity against HepG2 cells than sorafenib (IC  = 9.18 and 5.47 µM, respectively) and doxorubicin (IC  = 7.94 and 8.07 µM, respectively). It also showed higher activity than doxorubicin against MCF-7 cells, but lower activity than sorafenib. Compounds 9, 8, and 15 displayed higher activities than sorafenib and doxorubicin against HepG2 cells but exhibited lower activities against MCF-7 cells. Compound 10 potently inhibited VEGFR-2 at an IC value of 0.12 µM, which is nearly equipotent to sorafenib (IC  = 0.10 µM). Compounds 8 and 9 exhibited very good activity with the same IC value of 0.13 µM. The six most potent derivatives, 6, 9, 8, 10, 15, and 18, were tested for their cytotoxicity against normal Vero cells. Compounds 6, 8, 9, 10, 15, and 18 are, respectively, 1.13, 3.74, 4.18, 3.64, 2.81, and 2.00 times more toxic to HepG2 and 2.06, 1.58, 1.76, 2.54, 1.40, and 2.69 times more toxic to MCF-7 breast cancer cells than in normal Vero cells.
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http://dx.doi.org/10.1002/ardp.202100085DOI Listing
May 2021

Design, synthesis, docking, ADMET profile, and anticancer evaluations of novel thiazolidine-2,4-dione derivatives as VEGFR-2 inhibitors.

Arch Pharm (Weinheim) 2021 Jul 31;354(7):e2000491. Epub 2021 Mar 31.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, Egypt.

The anticancer activity of novel thiazolidine-2,4-diones was evaluated against HepG2, HCT-116, and MCF-7 cells. Among the tested cancer cell lines, HCT-116 was the most sensitive one to the cytotoxic effect of the new derivatives. In particular, compounds 18, 11, and 10 were found to be the most potent derivatives among all the tested compounds against the HepG2, HCT-116, and MCF-7 cancer cell lines, with IC values ranging from 38.76 to 53.99 µM. The most active antiproliferative derivatives (7-14 and 15-19) were subjected to further biological studies to evaluate their inhibitory potentials against VEGFR-2. The tested compounds displayed a good-to-medium inhibitory activity, with IC values ranging from 0.26 to 0.72 µM. Among them, compounds 18, 11, and 10 potently inhibited VEGFR-2 at IC values in the range of 0.26-0.29 µM, which are nearly three times that of the sorafenib IC value (0.10 µM). Although our derivatives showed lower activities than the reference drug, they could be useful as a template for future design, optimization, adaptation, and investigation to produce more potent and selective VEGFR-2 inhibitors with higher anticancer analogs. The ADMET profile showed that compounds 18, 11, and 10 do not violate any of Lipinski's rules and have a comparable intestinal absorptivity in humans. Also, the new derivatives could not inhibit cytochrome P3A4. Unlike sorafenib and doxorubicin, compounds 18, 11, and 10 are expected to have prolonged dosing intervals. Moreover, compounds 10 and 18 displayed a wide therapeutic index and higher selectivity against cancer cells as compared with their cytotoxicity against normal cells.
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http://dx.doi.org/10.1002/ardp.202000491DOI Listing
July 2021

In vivo- and in silico-driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors.

Arch Pharm (Weinheim) 2021 May 9;354(5):e2000449. Epub 2021 Feb 9.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Shebin El-Koum, Egypt.

The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.
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http://dx.doi.org/10.1002/ardp.202000449DOI Listing
May 2021

Design, synthesis, molecular docking, in silico ADMET profile and anticancer evaluations of sulfonamide endowed with hydrazone-coupled derivatives as VEGFR-2 inhibitors.

Bioorg Chem 2021 Mar 21;108:104669. Epub 2021 Jan 21.

Department of Chemistry, Faculty of Science, Al-Azhar University (Girls Branch), PO Box 11754, Cairo, Egypt. Electronic address:

A new series of sulfonamide endowed with hydrazone coupled to dimethyl and/or diethyl malonates were prepared. Various sulfa drugs were diazotized and followed by coupling with active methylene of dimethyl and/or diethyl malonate to afford the new intermediates hydrazones 3 and 4. The reactivity of hydrazone derivatives towards hydrazines was investigated. Thus, a novel series of 3,5-dioxopyrazolidine7were obtained by treatment with hydrazine hydrate. When hydrazones were allowed to react with phenyl hydrazine, the alkyl 2-((4-(N-(substituted)sulfamoyl)phenyl)diazenyl)-3-oxo-3-(2-phenylhydrazinyl)propanoateswere obtained 8 and/or 10. Their anticancer activities were evaluated against HepG2, HCT-116 and MCF-7. HepG2 was the most sensitive one. In particular, compounds 7, 7 and 10 were found to be the most potent derivatives with IC = 6.43 ± 0.5, 9.66 ± 0.8, 10.57 ± 0.9 µM, 8.65 ± 0.7, 7.49 ± 0.6, 14.29 ± 1.3 µM and 8.97 ± 0.7, 10.13 ± 0.9, 13.82 ± 1.1 µM respectively. Sorafenib and doxorubicin were used as reference drugs. The most potent derivatives 7, 7, 7, 8 and 10 were tested for their cytotoxicity against normal VERO cell lines. Compounds 7, 7, 7, 8 and 10 are respectively, 2.41, 4.85, 4.08, 3.23 and 5.89 fold times more toxic in HCT116 than in VERO normal cells. Moreover, the most active anti-proliferative derivatives 7, 7, 7, 8 and 10 were subjected to further biological study to evaluate their inhibitory potentials against VEGFR-2. The tested compounds displayed high to good inhibitory activity with IC values ranging from 0.14 ± 0.02 to 0.23 ± 0.03 µM. Among them, compounds 7, 7 and 10 were found to be the most potent derivative that inhibited VEGFR-2 at IC values of 0.14 ± 0.02, 0.15 ± 0.02 and 0.15 ± 0.02 µM respectively. sorafenib was used as reference drug. Furthermore, ADMET profile was evaluated for the four most active compounds in comparison to doxorubicin as a reference drug. The data obtained from docking studies were highly correlated with that obtained from the biological screening.
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http://dx.doi.org/10.1016/j.bioorg.2021.104669DOI Listing
March 2021

[1,2,4]Triazolo[4,3-c]quinazoline and bis([1,2,4]triazolo)[4,3-a:4',3'-c]quinazoline derived DNA intercalators: Design, synthesis, in silico ADMET profile, molecular docking and anti-proliferative evaluation studies.

Bioorg Med Chem 2021 01 21;30:115958. Epub 2020 Dec 21.

Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt. Electronic address:

In view of their DNA intercalation activities as anticancer agents, novel fifteen [1,2,4]triazolo[4,3-c]quinazoline and bis([1,2,4]triazolo)[4,3-a:4',3'-c]quinazoline derivatives have been designed, synthesized and evaluated against HepG2 and HCT-116. The molecular design was performed to investigate the binding mode of the proposed compounds with DNA active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling studies. HCT-116 was found to be more sensitive cell lines to the influence of the new derivatives. In particular, compounds 16, 18, 11 and 5 were found to be the most potent derivatives with IC = 3.61, 6.72, 7.16 and 5.18 µM respectively against HepG2 cell line. Also, compounds 16, 18, 11 and 5 displayed IC = 2.85, 3.82, 4.97 and 6.40 µM respectively against HCT-116 cell line. These derivatives displayed higher activities than doxorubicin, (IC = 7.94 and 8.07 µM respectively) against the two HepG2 and HCT-116 cell lines. The most active anti-proliferative derivatives 5, 6, 10, 11, 13, 16, 18, 19 and 20 were further evaluated for their DNA-binding affinity which revealed the ability of these compounds to intercalate DNA. The tested compounds displayed very strong to moderate DNA-binding affinities. Compounds 16 and 18 potently intercalate DNA at IC values of 26.03 and 28.37 µM respectively which were lower than IC of Doxorubicin (IC = 31.27). This finding indicated that these derivatives exhibited higher DNA binding activities than Doxorubicin. Also, compounds 11 and 5 displayed very strong DNA binding at IC = 30.84 and 33.56 µM respectively, which were nearly equipotent to that of doxorubicin. Moreover, most of our derivatives exhibited good ADMET profile.
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http://dx.doi.org/10.1016/j.bmc.2020.115958DOI Listing
January 2021

Design, synthesis, and anti-proliferative evaluation of new quinazolin-4(3H)-ones as potential VEGFR-2 inhibitors.

Bioorg Med Chem 2021 01 12;29:115872. Epub 2020 Nov 12.

Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address:

Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. Thus, nineteen new quinazoline-4(3H)-one derivatives were designed and synthesized. Preliminary cytotoxicity studies of the synthesized compounds were evaluated against three human cancer cell lines (HepG-2, MCF-7 and HCT-116) using MTT assay method. Doxorubicin and sorafenib were used as positive controls. Five compounds were found to have promising cytotoxic activities against all cell lines. Compound 16, containing a 2-chloro-5-nitrophenyl group, has emerged as the most active member. It was approximately 4.39-, 5.73- and 1.96-fold more active than doxorubicin and 3.88-, 5.59- and 1.84-fold more active than sorafenib against HepG2, HCT-116 and MCF-7 cells, respectively. The most active cytotoxic agents were further evaluated in vitro for their VEGFR-2 inhibitory activities. The results of in vitro VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Molecular docking of these compounds into the kinase domain, moreover, supported the results.
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http://dx.doi.org/10.1016/j.bmc.2020.115872DOI Listing
January 2021

N-Substituted-4-phenylphthalazin-1-amine-derived VEGFR-2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluation studies.

Arch Pharm (Weinheim) 2021 Mar 16;354(3):e2000219. Epub 2020 Nov 16.

Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

In accordance with the significant impetus of the discovery of potent vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors, herein, we report the design, synthesis, and anticancer evaluation of 12 new N-substituted-4-phenylphthalazin-1-amine derivatives against HepG2, HCT-116, and MCF-7 cells as VEGFR-2 inhibitors. The results of the cytotoxicity investigation indicated that HCT-116 and MCF-7 were the most sensitive cell lines to the influence of the newly synthesized derivatives. In particular, compound 7a was found to be the most potent derivative among all the tested compounds against the three cancer cell lines, HepG2, HCT116, and MCF-7, with IC  = 13.67 ± 1.2, 5.48 ± 0.4, and 7.34 ± 0.6 µM, respectively, which is nearly equipotent to that of sorafenib (IC  = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively). All synthesized derivatives, 4a,b-8a-c, were evaluated for their inhibitory activities against VEGFR-2. The tested compounds displayed high to low inhibitory activity, with IC values ranging from 0.14 ± 0.02 to 9.54 ± 0.85 µM. Among them, compound 7a was found to be the most potent derivative that inhibited VEGFR-2 at an IC value of 0.14 ± 0.02 µM, which is nearly 72% of that of the sorafenib IC value (0.10 ± 0.02 µM). Compounds 7b, 8c, 8b, and 8a exhibited very good activity with IC values of 0.18 ± 0.02, 0.21 ± 0.03, 0.24 ± 0.02, and 0.35 ± 0.04 µM, respectively. Molecular modeling studies were carried out for all compounds against the VEGFR-2 active site. The data obtained from biological testing highly correlated with that obtained from molecular modeling studies. However, these modifications led to new phthalazine derivatives with higher VEGFR-2 inhibitory activities than vatalanib and which are nearly equipotent to sorafenib.
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http://dx.doi.org/10.1002/ardp.202000219DOI Listing
March 2021

Design, green synthesis, molecular docking and anticancer evaluations of diazepam bearing sulfonamide moieties as VEGFR-2 inhibitors.

Bioorg Chem 2020 11 8;104:104350. Epub 2020 Oct 8.

Department of Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.

Novel series of diazepam bearing sulfonamide moieties 5 and 7 were designed, synthesized and evaluated for anticancer activity against HepG2, HCT-116 and MCF-7 cell lines. MCF-7 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5 was found to be the most potent derivative overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC = 8.98 ± 0.1, 7.77 ± 0.1 and 6.99 ± 0.1 µM respectively. Compound 5 exhibited higher activity than sorafenib, (IC = 9.18 ± 0.6, 5.47 ± 0.3 and 7.26 ± 0.3 µM respectively), against HepG2 and MCF-7 but exhibited lower activity against HCT116 cancer cell lines respectively. Also, this compound displayed lower activity than doxorubicin, (IC = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and MCF-7 but higher activity against HCT116 cell lines respectively. Compounds 5, 5, 5, 5, 5 and 7 are respectively, 5.77, 8.58, 9.54, 5.71, 4.68 and 2.31 fold times more toxic in breast cancer cell lines (MCF-7, the most sensitive cells) than in VERO normal cells. All the synthesized compounds 5 and 7 were evaluated for their inhibitory activities against VEGFR-2. Among them, compound 5 was found to be the most potent derivative that inhibited VEGFR-2 at IC value of 0.10 ± 0.01 µM, which is equipotent to sorafenib IC value (0.10 ± 0.02 µM). Compound 5 exhibited excellent activity with IC value of 0.12 ± 0.01 µM which nearly equipotent to that of sorafenib. Compounds 5, 5 and 5 exhibited very good activity with the same IC value of 0.14 ± 0.02 µM. Also, compounds 7 and 7 possessed good VEGFR-2 inhibition with IC values of 0.16 ± 0.06 and 0.17 ± 0.06 µM respectively which are more than the half activity of that of sorafenib. The data obtained from docking studies were highly correlated with that obtained from the biological screening.
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http://dx.doi.org/10.1016/j.bioorg.2020.104350DOI Listing
November 2020

Discovery of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors: Design, synthesis, and anti-proliferative evaluation.

Bioorg Chem 2020 12 15;105:104380. Epub 2020 Oct 15.

Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt. Electronic address:

Sixteen novel quinazoline-based derivatives were designed and synthesized via modification of the VEGFR-2 reported inhibitor 7 in order to increase the binding affinity of the designed compounds to the receptor active site. The designed compounds were evaluated for their VEGFR-2 inhibitory effects. Inhibiting VEGFR-2 has been set up as a therapeutic strategy for treatment of cancer. The bioactivity of the new compounds was performed against HepG-2, MCF-7 and HCT-116 cell lines. Doxorubicin and sorafenib were used as positive controls. Compound 18 was observed to have promising cytotoxic activity (IC = 3.74 ± 0.14, 5.00 ± 0.20 and 6.77 ± 0.27 µM) in comparison to the reference drug doxorubicin (IC = 8.28, 9.63 and 7.67 µM) and sorafenib (IC = 7.31, 9.40 and 7.21 µM). The most active compounds were tested for their in vitro VEGFR-2 inhibitory activities. Results of VEGFR-2 inhibition were consistent with that of the cytotoxicity data. Thus, compound 18 showed VEGFR-2 inhibitory activity (IC = 0.340 ± 0.04 µM) superior to that of the reference drug, sorafenib (IC = 0.588 ± 0.06 µM). Furthermore, docking study was performed in order to understand the binding pattern of the new compounds into VEGFR-2 active site. Docking results attributed the potent VEGFR-2 inhibitory effect of the new compounds as they bound to the key amino acids in the active site, Glu883 and Asp1044, as well as their hydrophobic interaction with the receptor hydrophobic pocket. Results of cytotoxic activities, in vitro VEGFR-2 inhibition together with docking study argument the advantages of the synthesized analogues as promising anti-angiogenic agents.
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http://dx.doi.org/10.1016/j.bioorg.2020.104380DOI Listing
December 2020

Design, synthesis, molecular docking and anti-proliferative evaluations of [1,2,4]triazolo[4,3-a]quinoxaline derivatives as DNA intercalators and Topoisomerase II inhibitors.

Bioorg Chem 2020 12 21;105:104399. Epub 2020 Oct 21.

Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt. Electronic address:

In view of their DNA intercalation activities as anticancer agents, novel twenty four [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized and evaluated against HepG2, HCT-116 and MCF-7 as DNA intercalators and Top II enzyme inhibitors. The data obtained from molecular modeling studies revealed that, our small aromatic molecules were concluded to act through two ways firstly, through non-covalent interaction with the directly bound proteins to DNA hence inhibit topoisomerase-II enzyme. The second is through non-covalently binding to double helical structures of DNA either by intercalating binder as in compounds 10 and 11 or by minor groove binding as in compounds 8 and 8. Cytotoxic activity indicated that MCF-7 and HepG2 were the most sensitive cell lines to the influence of the new derivatives respectively. In particular, compounds 10, 11 and 8 were found to be the most potent derivatives overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC = (4.55 ± 0.3, 6.18 ± 0.8 and 3.93 ± 0.6 µM), (5.61 ± 0.5, 6.49 ± 0.5and 3.71 ± 0.3 µM) and (4.66 ± 0.3, 8.08 ± 0.8 and 5.11 ± 0.7 µM) respectively. The three derivatives exhibited higher activities than doxorubicin, (IC = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and MCF-7 but 8 exhibited nearly the same activity against HCT116 cancer cell lines respectively. The most active derivatives 8, 10,, 11, 13 and 14 were evaluated for their DNA binding activities. The tested compounds displayed very good to moderate DNA-binding affinities. Compounds 10 11, 8, 8, 8 and 8 displayed the highest binding affinities. These compounds potently intercalate DNA at decreased IC values of 25.27 ± 1.2, 27.47 ± 2.1, 27.54 ± 3.2, 27.78 ± 1.3, 29.15 ± 1.8 and 30.23 ± 3.7 µM respectively, which were less than that of doxorubicin (31.27 ± 1.8). Furthermore, the most active cytotoxic compounds 8, 8, 8, 8, 10 and 11 were selected to evaluate their inhibitory activities against Topo II enzyme. All the tested compounds could interfere with the Topo II activity. They exhibited very good inhibitory activities with IC values ranging from 0.379 ± 0.07 to 0.813 ± 0.14 µM that were lower than that of doxorubicin (IC = 0.94 ± 0.4 µM). For a great extent, the reported results were in agreement with that of in vitro cytotoxicity activity, DNA binding and molecular modeling studies.
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http://dx.doi.org/10.1016/j.bioorg.2020.104399DOI Listing
December 2020

Synthesis, antimicrobial evaluation, DNA gyrase inhibition, and in silico pharmacokinetic studies of novel quinoline derivatives.

Arch Pharm (Weinheim) 2021 Feb 20;354(2):e2000277. Epub 2020 Oct 20.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.

Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram-positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66-5.29 μg/ml. Among them, compound 14 exhibited a particularly potent broad-spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66-3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC value (3.39 μM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.
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http://dx.doi.org/10.1002/ardp.202000277DOI Listing
February 2021

Design, synthesis, molecular docking, anticancer evaluations, and in silico pharmacokinetic studies of novel 5-[(4-chloro/2,4-dichloro)benzylidene]thiazolidine-2,4-dione derivatives as VEGFR-2 inhibitors.

Arch Pharm (Weinheim) 2021 Feb 19;354(2):e2000279. Epub 2020 Oct 19.

Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

The anticancer activity of novel thiazolidine-2,4-diones was evaluated against HepG2, HCT-116, and MCF-7 cells. MCF-7 was the most sensitive cell line to the cytotoxicity of the new derivatives. In particular, compounds 18, 12, 17, and 16 were found to be the most potent derivatives over all the tested compounds against the cancer cell lines HepG2, HCT116, and MCF-7, with IC  = 9.16 ± 0.9, 8.98 ± 0.7, 5.49 ± 0.5 µM; 9.19 ± 0.5, 8.40 ± 0.7, 6.10 ± 0.4 µM; 10.78 ± 1.2, 8.87 ± 1.5, 7.08 ± 1.6 µM; and 10.87 ± 0.8, 9.05 ± 0.7, 7.32 ± 0.4 µM, respectively. Compounds 18 and 12 have nearly the same activities as sorafenib (IC  = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively), against HepG2 cells, but slightly lower activity against HCT116 cells and slightly higher activity against the MCF-7 cancer cell line. Also, these compounds displayed lower activities than doxorubicin against HepG2 and HCT-116 cells but higher activity against MCF-7 cells (IC  = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively). In contrast, compounds 17 and 16 exhibited lower activities than sorafenib against HepG2 and HCT116 cells, but nearly equipotent activity against the MCF-7 cancer cell line. Also, these compounds displayed lower activities than doxorubicin against the three cell lines. All the synthesized derivatives 7-18 were evaluated for their inhibitory activities against VEGFR-2. The tested compounds displayed high to medium inhibitory activity, with IC values ranging from 0.17 ± 0.02 to 0.27 ± 0.03 µM. Compounds 18, 12, 17, and 16 potently inhibited VEGFR-2 at IC values of 0.17 ± 0.02, 0.17 ± 0.02, 0.18 ± 0.02, and 0.18 ± 0.02 µM, respectively, which are nearly more than half of that of the IC value for sorafenib (0.10 ± 0.02 µM).
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http://dx.doi.org/10.1002/ardp.202000279DOI Listing
February 2021

Design, synthesis, and biological evaluation of new challenging thalidomide analogs as potential anticancer immunomodulatory agents.

Bioorg Chem 2020 11 1;104:104218. Epub 2020 Sep 1.

Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address:

Thalidomide and its analogs are immunomodulatory drugs that inhibit the production of certain inflammatory mediators associated with cancer. In the present work, a new series of thalidomide analogs was designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against a panel of four cancer cell lines (HepG-2, HCT-116, PC3 and MCF-7). Compounds 33, 33, 42 and 42 showed strong potencies against all tested cell lines with IC values ranging from 14.63 to 49.90 µM comparable to that of thalidomide (IC values ranging from 32.12 to 76.91 µM). The most active compounds were further evaluated for their in vitro immunomodulatory activities via estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds 33 and 42 showed a significant reduction in TNF-α. Furthermore, compounds 33 and 42 exhibited significant elevation in CASP8 levels. Compounds 33 and 42 inhibited VEGF. In addition, compound 42 showed significant decrease in levels of NF-κB p65. Moreover, apoptosis and cell cycle tests of the most active compound 42, were performed. The results indicated that compound 42 significantly induce apoptosis in HCT-116 cells and arrest cell cycle at the G2/M phase.
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http://dx.doi.org/10.1016/j.bioorg.2020.104218DOI Listing
November 2020

Unravelling the anticancer potency of 1,2,4-triazole-N-arylamide hybrids through inhibition of STAT3: synthesis and in silico mechanistic studies.

Mol Divers 2021 Feb 23;25(1):403-420. Epub 2020 Aug 23.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, 11884, Egypt.

The discovery of potent STAT3 inhibitors has gained noteworthy impetus in the last decade. In line with this trend, considering the proven biological importance of 1,2,4-triazoles, herein, we are reporting the design, synthesis, pharmacokinetic profiles, and in vitro anticancer activity of novel C3-linked 1,2,4-triazole-N-arylamide hybrids and their in silico proposed mechanism of action via inhibition of STAT3. The 1,2,4-triazole scaffold was selected as a privilege ring system that is embedded in core structures of a variety of anticancer drugs which are either in clinical use or still under clinical trials. The designed 1,2,4-triazole derivatives were synthesized by linking the triazole-thione moiety through amide hydrophilic linkers with diverse lipophilic fragments. In silico study to predict cytotoxicity of the new hybrids against different kinds of human cancer cell lines as well as the non-tumor cells was conducted. The multidrug-resistant human breast adenocarcinoma cells (MDA-MB-231) was found most susceptible to the cytotoxic effect of synthesized compounds and hence were selected to evaluate the in vitro anticancer activity. Four of the designed derivatives showed promising cytotoxicity effects against selected cancer cells, among which compound 12 showed the highest potency (IC = 3.61 µM), followed by 21 which displayed IC value of 3.93 µM. Also, compounds 14 and 23 revealed equipotent activity with the reference cytotoxic agent doxorubicin. To reinforce these observations, the obtained data of in vitro cytotoxicity have been validated in terms of ligand-protein interaction and new compounds were analyzed for ADMET properties to evaluate their potential to build up as good drug candidates. This study led us to identify two novel C3-linked 1,2,4-triazole-N-arylamide hybrids of interesting antiproliferative potentials as probable lead inhibitors of STAT3 with promising pharmacokinetic profiles.
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http://dx.doi.org/10.1007/s11030-020-10131-0DOI Listing
February 2021

Design, synthesis, molecular docking and anticancer evaluations of 5-benzylidenethiazolidine-2,4-dione derivatives targeting VEGFR-2 enzyme.

Bioorg Chem 2020 09 30;102:104059. Epub 2020 Jun 30.

MD in Clinical Pathology, Blood Bank Specialist, Blood Bank Directorate Manager, Ministry of Health, Cairo, Egypt.

Novel series of 5-benzylidenethiazolidine-2,4-dione derivatives 4-8 were designed, synthesized and evaluated for anticancer activity against HepG2, HCT-116 and MCF-7 cell lines. MCF-7 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 8 was found to be the most potent derivative overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC = 11.19 ± 0.8, 8.99 ± 0.7 and 7.10 ± 0.4 µM respectively. Compound 8 exhibited lower activity than sorafenib, (IC = 9.18 ± 0.6, 8.37 ± 0.7 and 5.10 ± 0.4 µM respectively), against HepG2 and HCT116 but exhibited nearly the same activity against MCF-7 cancer cell lines respectively. Also, this compound displayed lower activity than doxorubicin, (IC = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and HCT116 but nearly the same activity against MCF-7cell lines respectively. The most active derivatives 6 and 8 were evaluated for their inhibitory activities against VEGFR-2. The elongation of the structures to have distal moieties enhanced anticancer and VEGFR-2 inhibitory activities as in compounds 8. Among them, compounds 8 was found to be the most potent derivative that inhibited VEGFR-2 at IC value of 0.22 ± 0.02 µM, which is nearly the half as that of sorafenib IC value (0.10 ± 0.02 µM). Furthermore, molecular design was performed to investigate their binding mode and affinities towards VEGFR-2 receptor. The data obtained from docking studies were highly correlated with that obtained from the biological screening.
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http://dx.doi.org/10.1016/j.bioorg.2020.104059DOI Listing
September 2020

5-(4-Methoxybenzylidene)thiazolidine-2,4-dione-derived VEGFR-2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluations.

Arch Pharm (Weinheim) 2020 Sep 9;353(9):e2000079. Epub 2020 Jun 9.

Department of Clinical Pathology, Blood Bank Specialist, Blood Bank Directorate, Ministry of Health, Al-Azhar University, Cairo, Egypt.

A novel series of 5-(4-methoxybenzylidene)thiazolidine-2,4-dione derivatives, 5a-g and 7a-f, was designed, synthesized, and evaluated for their anticancer activity against HepG2, HCT116, and MCF-7 cells. HepG2 and HCT116 were the most sensitive cell lines to the influence of the new derivatives. In particular, compounds 7f, 7e, 7d, and 7c were found to be the most potent derivatives of all the tested compounds against the HepG2, HCT116, and MCF-7 cancer cell lines. Compound 7f (IC  = 6.19 ± 0.5, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively) exhibited a higher activity than sorafenib (IC  = 9.18 ± 0.6, 8.37 ± 0.7, and 5.10 ± 0.4 µM, respectively) against HepG2 and MCF-7, cells but a lower activity against HCT116 cancer cells, respectively. Also, this compound displayed a higher activity than doxorubicin (IC  = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively) against HepG2 and MCF-7 cells, but nearly the same activity against HCT116 cells, respectively. All derivatives, 5a-g and 7a-f, were evaluated for their inhibitory activities against vascular endothelial growth factor receptor-2 (VEGFR-2). Among them, compound 7f was found to be the most potent derivative that inhibited VEGFR-2 at an IC value of 0.12 ± 0.02 µM, which is nearly the same as that of sorafenib (IC  = 0.10 ± 0.02 µM). Compounds 7e, 7d, 7c, and 7b exhibited the highest activity, with IC values of 0.13 ± 0.02, 0.14 ± 0.02, 0.14 ± 0.02, and 0.18 ± 0.03 µM, respectively, which are more than the half of that of sorafenib. Furthermore, molecular docking was performed to investigate their binding mode and affinities toward the VEGFR-2 receptor. The data obtained from the docking studies highly correlated with those obtained from the biological screening.
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http://dx.doi.org/10.1002/ardp.202000079DOI Listing
September 2020

Design, synthesis, molecular docking, and anticancer evaluations of 1-benzylquinazoline-2,4(1H,3H)-dione bearing different moieties as VEGFR-2 inhibitors.

Arch Pharm (Weinheim) 2020 Aug 8;353(8):e2000068. Epub 2020 Jun 8.

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

A novel series of 1-benzylquinazoline-2,4(1H,3H)-dione derivatives, 6a,b to 11a-e, was designed, synthesized, and evaluated for their anticancer activity against HepG2, HCT-116, and MCF-7 cells. Compounds 11b, 11e, and 11c were found to be the most potent derivatives of all tested compounds against the HepG2, HCT-116, and MCF-7 cancer cell lines, with GI  = 9.16 ± 0.8, 5.69 ± 0.4, 5.27 ± 0.2 µM, 9.32 ± 0.9, 6.37 ± 0.7, 5.67 ± 0.5 µM, and 9.39 ± 0.5, 6.87 ± 0.7, 5.80 ± 0.4 µM, respectively. These compounds exhibited nearly the same activity as sorafenib against HepG2 and HCT-116 cells and a higher activity against MCF-7 cells (GI  = 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively). Also, these compounds displayed a lower activity than doxorubicin against HepG2 cells and a higher activity against HCT-116 and MCF-7 cells (GI  = 7.94 ± 0.6, 8.07 ± 0.8, and 6.75 ± 0.4 µM, respectively). The most active antiproliferative derivatives, 6a,b, 8, 9, and 11a-e, were selected to evaluate their enzymatic inhibitory activity against VEGFR-2. Compounds 11b, 11e, and 11c potently inhibited VEGFR-2 at IC values of 0.12 ± 0.02, 0.12 ± 0.02, and 0.13 ± 0.02 µM, respectively, which are nearly equipotent as sorafenib IC value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.
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http://dx.doi.org/10.1002/ardp.202000068DOI Listing
August 2020

Benzoxazole/benzothiazole-derived VEGFR-2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluations.

Arch Pharm (Weinheim) 2019 Dec 9;352(12):e1900178. Epub 2019 Oct 9.

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

A novel series of benzoxazole/benzothiazole derivatives 4a-c-11a-e were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT-116, and MCF-7 cells. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 4c was found to be the most potent derivative against HepG2, HCT-116, and MCF-7 cells, with IC values = 9.45 ± 0.8, 5.76 ± 0.4, and 7.36 ± 0.5 µM, respectively. Compounds 4b, 9f, and 9c showed the highest anticancer activities against HepG2 cells with IC values of 9.97 ± 0.8, 9.99 ± 0.8, and 11.02 ± 1.0 µM, respectively, HCT-116 cells with IC values of 6.99 ± 0.5, 7.44 ± 0.4, and 8.15 ± 0.8 µM, respectively, and MCF-7 cells with IC values of 7.89 ± 0.7, 8.24 ± 0.7, and 9.32 ± 0.7 µM, respectively, in comparison with sorafenib as reference drug with IC  values of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 4a-c, 9b,c,e,f,h, and 11c,e were further evaluated for their VEGFR-2 inhibition. Compounds 4c and 4b potently inhibited VEGFR-2 at IC values of 0.12 ± 0.01 and 0.13 ± 0.02 µM, respectively, which are nearly equipotent to the sorafenib IC value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.
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http://dx.doi.org/10.1002/ardp.201900178DOI Listing
December 2019

Discovery and antiproliferative evaluation of new quinoxalines as potential DNA intercalators and topoisomerase II inhibitors.

Arch Pharm (Weinheim) 2019 Nov 29;352(11):e1900123. Epub 2019 Aug 29.

National Center for Natural Products Research, University of Mississippi, Mississippi.

In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G-2, Hep-2, and Caco-2). Compounds 18b, 19b, 23, 25b, and 26 showed strong potencies against all tested cell lines with IC values ranging from 0.26 ± 0.1 to 2.91 ± 0.1 µM, comparable with those of doxorubicin (IC values ranging from 0.65 ± 0.1 to 0.81 ± 0.1 µM). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC = 0.97 ± 0.1 and 1.10 ± 0.1 µM, respectively) and bound the DNA at concentrations of 43.51 ± 2.0 and 49.11 ± 1.8 µM, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC value of 37.06 ± 1.8 µM. Moreover, apoptosis and cell-cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G-2 cells. It has revealed cell-cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl-2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA-Topo II complex to examine the binding patterns of the synthesized compounds.
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http://dx.doi.org/10.1002/ardp.201900123DOI Listing
November 2019

Design, synthesis, molecular docking, and anticancer activity of benzoxazole derivatives as VEGFR-2 inhibitors.

Arch Pharm (Weinheim) 2019 Oct 25;352(10):e1900113. Epub 2019 Aug 25.

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

Novel series of benzoxazoles 4 -16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT-116, and MCF-7 cells. HCT-116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5 was found to be the most potent against HepG2, HCT-116, and MCF-7 with IC  = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 µM, respectively. Compounds 5 , 5 , 6 , 5 , and 6 showed the highest anticancer activities against HepG2 cells with IC of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 µM, respectively; HCT-116 cells with IC of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 µM, respectively; and MCF-7 cells with IC of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 µM, respectively, compared with sorafenib as a reference drug with IC of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 5 and 6 were further evaluated for their vascular endothelial growth factor receptor-2 (VEGFR-2) inhibition. Compounds 5 and 5 potently inhibited VEGFR-2 at lower IC values of 0.07 ± 0.01 and 0.08 ± 0.01 µM, respectively, compared with sorafenib (IC  = 0.1 ± 0.02 µM). Compound 5 potently inhibited VEGFR-2 at low IC value (0.10 ± 0.02 µM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR-2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR-2 active site.
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http://dx.doi.org/10.1002/ardp.201900113DOI Listing
October 2019

Design, synthesis, in silico ADMET profile and GABA-A docking of novel phthalazines as potent anticonvulsants.

Arch Pharm (Weinheim) 2019 May 15;352(5):e1800387. Epub 2019 Apr 15.

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

A new series of 2-substituted-2,3-dihydrophthalazine-1,4-diones (2- 9) were designed and synthesized to evaluate their anticonvulsant activity. The neurotoxicity was assessed using the rotarod test. Molecular docking was performed for the synthesized compounds to assess their binding affinities as γ-aminobutyric acid A (GABA-A) receptor agonists as a possible mechanism of their anticonvulsant action, to rationalize their anticonvulsant activity in a qualitative way. The data obtained from the molecular modeling was strongly matched with that obtained from the biological screening, which revealed that compounds 5 , 9 , and 9 showed the highest binding affinities toward the GABA-A receptor and also showed the highest anticonvulsant activities with relative potencies of 1.66, 1.63, and 1.61, respectively, compared with diazepam. The most active compounds 5 , 9 , and 9 were further tested against maximal electroshock seizures. Compounds 5 and 9 showed 100% protection at a dose level of 125 µg/kg, while compound 9 exhibited 83.33% protection at the same dose level. A GABA enzymatic assay was performed for these highly active compounds to confirm the obtained results and to explain the possible mechanism for their anticonvulsant action. These agents exerted low neurotoxicity and a high safety margin compared with valproate as a reference drug. Most of our designed compounds exhibited a good ADMET profile.
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http://dx.doi.org/10.1002/ardp.201800387DOI Listing
May 2019

Phthalazine-1,4-dione derivatives as non-competitive AMPA receptor antagonists: design, synthesis, anticonvulsant evaluation, ADMET profile and molecular docking.

Mol Divers 2019 May 30;23(2):283-298. Epub 2018 Aug 30.

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

In view of the anticonvulsant activity reported for phthalazine derivatives as non-competitive AMPA receptor antagonists, a new series of phthalazine-1,4-diones (2-12) were designed and synthesized. The neurotoxicity was assessed using rotarod test. The molecular docking was performed for the synthesized compounds to assess their binding affinities toward AMPA receptor as non-competitive antagonists. The molecular modeling data were strongly interrelated to biological screening data. Compounds 8, 7, 7, 10 and 3 exhibited the highest binding affinities as non-competitive AMPA receptor antagonists and also showed the highest relative potencies of 1.78, 1.66, 1.60, 1.59 and 1.29, respectively, as anticonvulsants in comparison with diazepam. The most active compounds 8, 7, 7, 10 and 3 were further tested against maximal electroshock seizure (MES). Compounds 8 and 7 and 3 showed 100% protection at a dose level of 125 µgm/kg, while compounds 7 and 10 exhibited 83.33% protection at the same dose level. These agents exerted low neurotoxicity and high safety margin in comparison with valproate as a reference drug. Most of our designed compounds exhibited good ADMET profile.
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http://dx.doi.org/10.1007/s11030-018-9871-yDOI Listing
May 2019

Design, Synthesis, In Vitro Anti-cancer Activity, ADMET Profile and Molecular Docking of Novel Triazolo[3,4-a]phthalazine Derivatives Targeting VEGFR-2 Enzyme.

Anticancer Agents Med Chem 2018 ;18(8):1184-1196

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

Background: Extensive studies were reported in the synthesis of several phthalazine derivatives as promising anticancer agents as potent VEGFR-2 inhibitors. Vatalanib (PTK787) was the first anilinophthalazine published derivative as a potent inhibitor of VEGFR. The discovery of vatalanib as a clinical candidate led to the design and synthesis of different anilinophthalazine derivatives as potent inhibitors for VEGFR-2. The objective of present research work is the synthesis of new agents with the same essential pharmacophoric features of the reported and clinically used VEGFR-2 inhibitors (e.g vatalanib and sorafenib). The main core of our molecular design rationale comprised bioisosteric modification strategies of VEGFR-2 inhibitors at four different positions.

Material And Methods: A correlation between structure and biological activity of our designed phthalazines was established using molecular docking and VEGFR-2 kinase assay.

Results And Discussion: In view of their expected anticancer activity, novel triazolo[3,4-a]phthalazine derivatives 5-6a-o and 3-substituted-bis([1,2,4]triazolo)[3,4-a:4',3'-c]phthalazines 9a-b were designed, synthesized and evaluated for their anti-proliferative activity against two human tumor cell lines HCT-116 human colon adenocarcinoma and MCF-7 breast cancer. It was found that, compound 6o the most potent derivative against both HCT116 and MCF-7 cancer cell lines. Compounds 6o, 6m, 6d and 9b showed the highest anticancer activities against HCT116 human colon adenocarcinoma with IC50 of 7±0.06, 13±0.11, 15±0.14 and 23±0.22 µM respectively while compounds 6o, 6d, 6a and 6n showed the highest anticancer activities against MCF-7 breast cancer with IC50 of 16.98±0.15, 18.2±0.17, 57.54±0.53 and 66.45±0.67 µM respectively. Sorafenib as a highly potent VEGFR-2 inhibitor was used as a reference drug with IC50 of 5.47±0.3 and 7.26±0.3 µM respectively. Nine compounds were further evaluated for their VEGFR-2 inhibitory activity. Compounds 6o, 6m, 6d and 9b emerged as the most active counterparts against VEGFR-2 with IC50 values of 0.1±0.01, 0.15±0.02, 0.28±0.03 and 0.38±0.04 µM, respectively comparable to that of sorafenib (IC50 = 0.1±0.02) µM. Furthermore, molecular docking studies were carried out for all synthesized compounds to investigate their binding pattern and predict their binding affinities towards VEGFR-2 active site. In silico ADMET studies were calculated for the tested compounds. Most of our designed compounds exhibited good ADMET profile.

Conclusion: The obtained results showed that, the most active compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective VEGFR-2 inhibitors with higher anticancer analogs.
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http://dx.doi.org/10.2174/1871520618666180412123833DOI Listing
July 2019

Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR-2 Inhibitors.

Arch Pharm (Weinheim) 2017 Dec 13;350(12). Epub 2017 Nov 13.

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

Novel series of phthalazine derivatives 6-11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT-116 human colon adenocarcinoma and MCF-7 breast cancer cells, targeting the VEGFR-2 enzyme. Compounds 7a,b and 8b,c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC of 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 μM, respectively, and MCF-7 breast cancer cells with IC of 8.8 ± 0.45, 17.9 ± 0.50, 25.2 ± 0.55, and 44.3 ± 0.49 μM, respectively, in comparison to sorafenib as reference drug with IC of 5.47 ± 0.3 and 7.26 ± 0.3 μM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR-2, where compounds 7a, 7b, 8c, and 8b also showed the highest VEGFR-2 inhibition with IC of 0.11 ± 0.01, 0.31 ± 0.03, 0.72 ± 0.08, and 0.91 ± 0.08 μM, respectively, in comparison to sorafenib as reference ligand with IC of 0.1 ± 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict their binding pattern and affinity towards the VEGFR-2 active site, in order to rationalize their anticancer activity in a qualitative way.
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http://dx.doi.org/10.1002/ardp.201700240DOI Listing
December 2017

Synthesis, Modelling, and Anticonvulsant Studies of New Quinazolines Showing Three Highly Active Compounds with Low Toxicity and High Affinity to the GABA-A Receptor.

Molecules 2017 Jan 24;22(2). Epub 2017 Jan 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.

Some novel fluorinated quinazolines (-) were designed and synthesized to be evaluated for their anticonvulsant activity and their neurotoxicity. Structures of all newly synthesized compounds were confirmed by their infrared (IR), mass spectrometry (MS) spectra, ¹H nuclear magnetic resonance (NMR), C-NMR, and elemental analysis (CHN). The anticonvulsant activity was evaluated by a subcutaneous pentylenetetrazole (scPTZ) test and maximal electroshock (MES)-induced seizure test, while neurotoxicity was evaluated by a rotorod test. The molecular docking was performed for all newly-synthesized compounds to assess their binding affinities to the GABA-A receptor in order to rationalize their anticonvulsant activities in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticonvulsant activity for all newly-synthesized compounds. Compounds , , and showed the highest binding affinities toward the GABA-A receptor, along with the highest anticonvulsant activities in experimental mice. These compounds also showed low neurotoxicity and low toxicity in the median lethal dose test compared to the reference drugs. A GABA enzymatic assay was performed for these highly active compounds to confirm the obtained results and explain the possible mechanism for anticonvulsant action. The most active compounds might be used as leads for future modification and optimization.
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http://dx.doi.org/10.3390/molecules22020188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155771PMC
January 2017
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