This study describes design and synthesis of new hybrids of N-substituted-N'-(4-(piperidin-1-... more This study describes design and synthesis of new hybrids of N-substituted-N'-(4-(piperidin-1-yl-sulfonyl)phenylthiourea and condensed thiourea derivatives (monocyclic, bicyclic, and tricyclic) via ...
Breast cancer is the most common malignancy worldwide; therefore, the development of new anticanc... more Breast cancer is the most common malignancy worldwide; therefore, the development of new anticancer agents is essential for improved tumor control. By adopting the pharmacophore hybridization approach, two series of 7-hydroxyl-4-methylcoumarin hybridized with thiosemicarbazone (V–VI) and thiazolidin-4-one moieties (VII–VIII) were prepared. The in vitro anticancer activity was assessed against MCF-7 cells adopting the MTT assay. Nine compounds showed significant cytotoxicity. The most promising compound, VIIb, induced remarkable cytotoxicity (IC50 of 1.03 + 0.05 µM). Further investigations were conducted to explore its pro-apoptotic activity demonstrating S-phase cell cycle arrest. Apoptosis rates following VIIb treatment revealed a 5-fold and 100-fold increase in early and late apoptotic cells, correspondingly. Moreover, our results showed caspase-9 dependent apoptosis induction as manifested by an 8-fold increase in caspase-9 level following VIIb treatment. Mechanistically, VIIb wa...
Background: Quinazolines and quinazolinones derivatives are well known for their important range ... more Background: Quinazolines and quinazolinones derivatives are well known for their important range of therapeutic activities. Objective: The study aims to carry out the synthesis of some derivatives of substituted fluoroquinazolinones based on structure-based design and evaluation of their antibacterial, antifungal, and anti-biofilm activities. Methods: Compounds were chemically synthesized by conventional methods. Structures were established on the basis of spectral and elemental analyses. The antimicrobial potential was tested against various microorganisms using the agar disc-diffusion method. MIC and MBC as well as anti-biofilm activity for the highly active compounds were assessed. Moreover, the computational studies were performed using Auto dock free software package (version 4.0) to explain the predicted mode of binding. Results: All derivatives (5-8), (10a-g), and (A-H) were biologically tested and showed significant antimicrobial activity comparable to the reference compound...
International journal of molecular sciences, Jan 11, 2018
A series of new fluoroquinazolinone ⁻ and ⁻ derivatives was designed, prepared and screened for t... more A series of new fluoroquinazolinone ⁻ and ⁻ derivatives was designed, prepared and screened for their in vitro cytotoxic activity against human cancer cell lines MCF-7 and MDA-MBA-231. Compounds (IC = 0.35 ± 0.01 µM), (IC = 0.71 ± 0.01 µM), (IC = 0.89 ± 0.02 µM) and (IC = 0.95 ± 0.01 µM) displayed broad spectrum anticancer activity better than the reference drug gefitinib (IC = 0.97 ± 0.02 µM) against MCF-7. Compounds (IC = 0.28 ± 0.02 µM), (IC = 0.38 ± 0.01 µM), (IC = 0.94 ± 0.07 µM) and (IC = 1.09 ± 0.01 µM) showed better activity than the reference gefitinib (IC = 1.30 ± 0.04 µM) against MDA-MBA-231. Moreover, EGFR and tubulin inhibition assays were performed for the highest active derivatives and showed remarkable results comparing to the reference drugs. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from mol...
Some fluoroquinazolinones (⁻) were designed, synthesized and biologically evaluated for their ant... more Some fluoroquinazolinones (⁻) were designed, synthesized and biologically evaluated for their antitumor activity against the two cell lines, MCF-7 and MDA-MBA-231. New derivative (IC = 0.44 ± 0.01 µM) showed antitumor activity, better than that of the reference drug erlotinib (IC = 1.14 ± 0.04 µM) against MCF-7. New derivative (IC = 0.43 ± 0.02 µM) showed higher activity than the reference drug erlotinib (IC = 2.55 ± 0.19 µM) against MDA-MBA-231. Furthermore, the EGFR (epidermal growth factor receptor) and tubulin inhibition assays were carried out for the highest active derivatives to reveal the expected mechanism of action. They exhibited significant results compared to the reference drugs. Molecular docking simulations were performed on EGFR and tubulin binding sites to rationalize the experimental results and describe their binding modes. The results of the molecular modeling study were correlated with that of the antitumor screening.
Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c w... more Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33-40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives...
In continuation of our endeavor towards the design and development of potent and effective antimi... more In continuation of our endeavor towards the design and development of potent and effective antimicrobial agents, three series of phthalimide derivatives (4a-i, 5a-f, and 6a-c) were synthesized, fully characterized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the discovery of nine compounds 4c, 4f, 4g, 4h, 4i, 5c, 5d, 5e, and 6c (MIC range from 0.49 to 31.5 μg/mL) with potent antibacterial, antifungal, and antimycobacterial activities. Ampicillin, ciprofloxacin, amphotericin B were used as references for antibacterial and antifungal screening respectively, while isoniazid was used as a reference for antimycobacterial testing. Furthermore, molecular modeling studies were done to explore the binding mode of the most active derivatives to M. tuberculosis enoyl reductase (InhA) and DNA gyrase B. Our study showed the importance of both hydrogen bonding and hydrophobic interactions as a key interaction with the target en...
Novel series of 7-substituted-benzopyran-2-ones was synthesized by incorporating heterocyclic rin... more Novel series of 7-substituted-benzopyran-2-ones was synthesized by incorporating heterocyclic rings as oxadiazole, triazole, pyrazole or pyrazolin-5-one to benzopyran-2-one nucleus at p-7 via methylene-oxy or acetoxy linker. In-vitro anticancer activity was evaluated for these hybrids; twelve compounds were selected by National Cancer Institute for anticancer screening. Among them, compound 9a exhibited broad spectrum antitumor activity showing full panel median growth inhibition (GI(50)) = 5.46 microM. According to docking results using Molsoft ICM 3.4-8c program, the target compounds may act through inhibition of topoismerase 1, where camptothecin is used as ligand.
Some new tetrahydropyrimidine-2-thione, octahydroquinazoline-2-thione and thiazolo[3,2-a]pyrimidi... more Some new tetrahydropyrimidine-2-thione, octahydroquinazoline-2-thione and thiazolo[3,2-a]pyrimidine derivatives have been synthesized and tested for their antihypertensive activity. Among them, compounds 1 and 2b can be considered more potent than the reference, nifedipine (CAS 21829-25-4), while compounds 3b and 10a are equipotent to it. In addition, compound 6 showed significant antihypertensive activity.
This study describes design and synthesis of new hybrids of N-substituted-N'-(4-(piperidin-1-... more This study describes design and synthesis of new hybrids of N-substituted-N'-(4-(piperidin-1-yl-sulfonyl)phenylthiourea and condensed thiourea derivatives (monocyclic, bicyclic, and tricyclic) via ...
Breast cancer is the most common malignancy worldwide; therefore, the development of new anticanc... more Breast cancer is the most common malignancy worldwide; therefore, the development of new anticancer agents is essential for improved tumor control. By adopting the pharmacophore hybridization approach, two series of 7-hydroxyl-4-methylcoumarin hybridized with thiosemicarbazone (V–VI) and thiazolidin-4-one moieties (VII–VIII) were prepared. The in vitro anticancer activity was assessed against MCF-7 cells adopting the MTT assay. Nine compounds showed significant cytotoxicity. The most promising compound, VIIb, induced remarkable cytotoxicity (IC50 of 1.03 + 0.05 µM). Further investigations were conducted to explore its pro-apoptotic activity demonstrating S-phase cell cycle arrest. Apoptosis rates following VIIb treatment revealed a 5-fold and 100-fold increase in early and late apoptotic cells, correspondingly. Moreover, our results showed caspase-9 dependent apoptosis induction as manifested by an 8-fold increase in caspase-9 level following VIIb treatment. Mechanistically, VIIb wa...
Background: Quinazolines and quinazolinones derivatives are well known for their important range ... more Background: Quinazolines and quinazolinones derivatives are well known for their important range of therapeutic activities. Objective: The study aims to carry out the synthesis of some derivatives of substituted fluoroquinazolinones based on structure-based design and evaluation of their antibacterial, antifungal, and anti-biofilm activities. Methods: Compounds were chemically synthesized by conventional methods. Structures were established on the basis of spectral and elemental analyses. The antimicrobial potential was tested against various microorganisms using the agar disc-diffusion method. MIC and MBC as well as anti-biofilm activity for the highly active compounds were assessed. Moreover, the computational studies were performed using Auto dock free software package (version 4.0) to explain the predicted mode of binding. Results: All derivatives (5-8), (10a-g), and (A-H) were biologically tested and showed significant antimicrobial activity comparable to the reference compound...
International journal of molecular sciences, Jan 11, 2018
A series of new fluoroquinazolinone ⁻ and ⁻ derivatives was designed, prepared and screened for t... more A series of new fluoroquinazolinone ⁻ and ⁻ derivatives was designed, prepared and screened for their in vitro cytotoxic activity against human cancer cell lines MCF-7 and MDA-MBA-231. Compounds (IC = 0.35 ± 0.01 µM), (IC = 0.71 ± 0.01 µM), (IC = 0.89 ± 0.02 µM) and (IC = 0.95 ± 0.01 µM) displayed broad spectrum anticancer activity better than the reference drug gefitinib (IC = 0.97 ± 0.02 µM) against MCF-7. Compounds (IC = 0.28 ± 0.02 µM), (IC = 0.38 ± 0.01 µM), (IC = 0.94 ± 0.07 µM) and (IC = 1.09 ± 0.01 µM) showed better activity than the reference gefitinib (IC = 1.30 ± 0.04 µM) against MDA-MBA-231. Moreover, EGFR and tubulin inhibition assays were performed for the highest active derivatives and showed remarkable results comparing to the reference drugs. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from mol...
Some fluoroquinazolinones (⁻) were designed, synthesized and biologically evaluated for their ant... more Some fluoroquinazolinones (⁻) were designed, synthesized and biologically evaluated for their antitumor activity against the two cell lines, MCF-7 and MDA-MBA-231. New derivative (IC = 0.44 ± 0.01 µM) showed antitumor activity, better than that of the reference drug erlotinib (IC = 1.14 ± 0.04 µM) against MCF-7. New derivative (IC = 0.43 ± 0.02 µM) showed higher activity than the reference drug erlotinib (IC = 2.55 ± 0.19 µM) against MDA-MBA-231. Furthermore, the EGFR (epidermal growth factor receptor) and tubulin inhibition assays were carried out for the highest active derivatives to reveal the expected mechanism of action. They exhibited significant results compared to the reference drugs. Molecular docking simulations were performed on EGFR and tubulin binding sites to rationalize the experimental results and describe their binding modes. The results of the molecular modeling study were correlated with that of the antitumor screening.
Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c w... more Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33-40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives...
In continuation of our endeavor towards the design and development of potent and effective antimi... more In continuation of our endeavor towards the design and development of potent and effective antimicrobial agents, three series of phthalimide derivatives (4a-i, 5a-f, and 6a-c) were synthesized, fully characterized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the discovery of nine compounds 4c, 4f, 4g, 4h, 4i, 5c, 5d, 5e, and 6c (MIC range from 0.49 to 31.5 μg/mL) with potent antibacterial, antifungal, and antimycobacterial activities. Ampicillin, ciprofloxacin, amphotericin B were used as references for antibacterial and antifungal screening respectively, while isoniazid was used as a reference for antimycobacterial testing. Furthermore, molecular modeling studies were done to explore the binding mode of the most active derivatives to M. tuberculosis enoyl reductase (InhA) and DNA gyrase B. Our study showed the importance of both hydrogen bonding and hydrophobic interactions as a key interaction with the target en...
Novel series of 7-substituted-benzopyran-2-ones was synthesized by incorporating heterocyclic rin... more Novel series of 7-substituted-benzopyran-2-ones was synthesized by incorporating heterocyclic rings as oxadiazole, triazole, pyrazole or pyrazolin-5-one to benzopyran-2-one nucleus at p-7 via methylene-oxy or acetoxy linker. In-vitro anticancer activity was evaluated for these hybrids; twelve compounds were selected by National Cancer Institute for anticancer screening. Among them, compound 9a exhibited broad spectrum antitumor activity showing full panel median growth inhibition (GI(50)) = 5.46 microM. According to docking results using Molsoft ICM 3.4-8c program, the target compounds may act through inhibition of topoismerase 1, where camptothecin is used as ligand.
Some new tetrahydropyrimidine-2-thione, octahydroquinazoline-2-thione and thiazolo[3,2-a]pyrimidi... more Some new tetrahydropyrimidine-2-thione, octahydroquinazoline-2-thione and thiazolo[3,2-a]pyrimidine derivatives have been synthesized and tested for their antihypertensive activity. Among them, compounds 1 and 2b can be considered more potent than the reference, nifedipine (CAS 21829-25-4), while compounds 3b and 10a are equipotent to it. In addition, compound 6 showed significant antihypertensive activity.
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