Novel 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione was synthesized and recrystallize... more Novel 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione was synthesized and recrystallized from ethanol. The compound was characterized by 1H NMR, 13C NMR in CDCl3, DMSO-d6 and acetone-d6, elemental analysis and X-ray diffraction. The NMR data observed that the title compound exists in the enol tautomer rather than keto, and it stabilized by strong H-bond as observed form the NMR data at different temperatures. Theoretical calculations (DFT) were carried out using Gaussian09 program package and B3LYP correlation function. Full geometry optimization of the keto and enol forms were carried out using 6-311G++(d,p) basis set. The structure and energy of the transition state between these two tautomers were calculated. The frontier orbital energy and atomic net atomic charges of the tautomers were presented. The experimental results of the title compound have been compared with the theoretical results and it was found that the experimental data are in a good agreement with the ca...
The present work aimed to synthesize 2-methylthio-triazoloquinazoline derivatives and study their... more The present work aimed to synthesize 2-methylthio-triazoloquinazoline derivatives and study their X-ray, NMR, DFT and Hirshfeld characteristics. The cyclocondensation of dimethyl-N-cyanodithiocarbonate with 2-hydrazinobenzoic acid hydrochloride resulted in an intermediate, 2-methylthio-[1,2,4]triazolo[1,5-a]quinazolin-5-one (A), which upon treatment with phosphorus pentasulfide, transformed into the 2-methylthio-[1,2,4]triazolo[1,5-a]quinazolin-5-thione (B). Reaction of 2-methylthio-triazoloquinazolines (A&B) with alkyl halides (allyl bromide and ethyl iodide) in basic medium afforded 4-allyl-2-methylthio-[1,2,4]triazolo[1,5-a]quinazolin-5-one (1; N-alkylated) and 5-ethylthio-2-methylthio-[1,2,4]triazolo[1,5-a]quinazoline (2; S-alkylated), respectively. Their molecular and supramolecular structures were presented. Unambiguously, the molecular structures of 1 and 2 were confirmed via NMR and single-crystal X-ray diffraction. The resulting findings confirmed the structures of 1 and 2 ...
The pharmacological activities of thiazole and pyrazole moieties as antimicrobial and anticancer ... more The pharmacological activities of thiazole and pyrazole moieties as antimicrobial and anticancer agents have been thoroughly described in many literature reviews. In this study, a convenient synthesis of novel pyrazolo[5,1-b]thiazole-based heterocycles was carried out. The synthesized compounds were characterized by IR, 1H and 13C NMR spectroscopy and mass spectrometry. Some selected examples were screened and evaluated for their antimicrobial and anticancer activities and showed promising results. These products could serve as leading compounds in the future design of new drug molecules.
The target compound 3-amino-1-(2,5-d ichlorophenyl)-8-methoxy-1H-benzo[f]-chromene-2-carbonitrile... more The target compound 3-amino-1-(2,5-d ichlorophenyl)-8-methoxy-1H-benzo[f]-chromene-2-carbonitrile (4) was synthesized via a reaction of 6-methoxynaphthalen-2-ol (1), 2,5-dichlorobenzaldehyde (2), and malononitrile (3) in ethanolic piperidine solution under microwave irradiation. The newly synthesized β-enaminonitrile was characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy, elemental analysis and X-ray diffraction data. Its cytotoxic activity was evaluated against three different human cancer cell lines MDA-MB-231, A549, and MIA PaCa-2 in comparison to the positive controls etoposide and camptothecin employing the XTT cell viability assay. The analysis of the Hirshfeld surface was utilized to visualize the reliability of the crystal package. The obtained results confirmed that the tested molecule revealed promising cytotoxic activities against the three cancer cell lines. Furthermore, theoretical calculations (DFT) were carried out with the Becke3-Lee-Yang-parr (B3LYP) level u...
N-(Anthracen-9-ylmethyl)-N-methyl-2-(phenylsulfonyl)ethanamine 3 has been synthesized via the aza... more N-(Anthracen-9-ylmethyl)-N-methyl-2-(phenylsulfonyl)ethanamine 3 has been synthesized via the aza-Michael addition approach by reaction of the corresponding amine with the vinyl sulfone derivative under microwave conditions. The structure of the aza-Michael product 3 is elucidated by X-ray crystallography. The study of molecular packing by employing the Hirshfeld analysis indicates that the percentages of O…H, C…H and H…H contacts are 16.8%, 34.1% and 48.6%, respectively, where the O...H hydrogen bonds have the characteristics of short and strong contacts while the C...H contacts are considered weak. Density functional theory (DFT) investigations show that the aza-Michael product 3 is polar with a net dipole moment of 5.2315 debye.
A series of triazolo-thiadiazepines 4a–k were synthesized with excellent yields using dehydrated ... more A series of triazolo-thiadiazepines 4a–k were synthesized with excellent yields using dehydrated PTSA as a catalyst in toluene. Two triazolo-thiadiazines were obtained; 8a was formed directly by reflux in ethanol, whereas, PTSA promoted the formation of 8b. The molecular structure of the formed triazolo-thiadiazepines is identical to the imine-form 4a–k and not the enamine-tautomer 6a–k. The structures of the newly synthesized triazolo-thiadiazepines 4a–k and triazolo-thiadiazines 8a–b were elucidated using NMR (1H, and 13C), 2D NMR, HRMS, and X-ray single crystal. Furthermore, 4a was deduced using X-ray single crystal diffraction analysis. These new thiadiazepine hits represent an optimized series of previously synthesized indole-triazole derivatives for the inhibition of EGFR. The cytotoxicity activity against two cancer cell lines including human liver cancer (HEPG-2) and breast cancer (MCF-7) was promising, with IC50 between 12.9 to 44.6 µg/mL and 14.7 to 48.7 µg/mL for the test...
A simple, cost-effective method under environmentally benign conditions is a very important conce... more A simple, cost-effective method under environmentally benign conditions is a very important concept for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. The present work describes an efficient and eco-friendly protocol for the synthesis of 2-amino-N-(2-substituted-ethyl)benzamide and 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives. The novel feature of this protocol is the use of 2-methyl tetrahydrofuran (2-MeTHF) as an eco-friendly alternative solvent to tetrahydrofuran (THF) in the first step. In the second step, methanol in the presence of potassium carbonate as a catalyst was used under conventional heating or microwave irradiation, which provided an eco-friendly method to afford the target products in excellent yields and purities. NMR (1H and 13C), elemental analysis, and LC-MS confirmed the structures of all compounds. X-ray crystallography further confirmed the structure of the intermediate 2-amino-N-(2-substituted-ethyl)benzamide 3a. The molecular s...
Certain Biginelli pyrimidines with ester substitution in C5 were subjected to unexpected ring ope... more Certain Biginelli pyrimidines with ester substitution in C5 were subjected to unexpected ring opening upon solvent-free reaction with hydrazine hydrate to give three products: pyrazole, arylidenehydrazines, and urea/thiourea, respectively. The nonisolable carbohydrazide intermediates are formed firstly followed by the intermolecular nucleophilic attack of terminal amino group of hydrazide function on sp2 C6 rather than the sp3 C4 to give the ring adduct which was produced as a final product.
The crystal structures of five new chalcones derived from N-ethyl-3-acetylindole with different s... more The crystal structures of five new chalcones derived from N-ethyl-3-acetylindole with different substituents were investigated: (E)-3-(4-bromophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one (3a); (E)-3-(3-bromophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one (3b); (E)-1-(1-ethyl-1H-indol-3-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (3c); (E)-1-(1-ethyl-1H-indol-3-yl)-3-mesitylprop-2-en-1-one (3d); and (E)-1-(1-ethyl-1H-indol-3-yl)-3-(furan-2-yl)prop-2-en-1-one (3e). The molecular packing of the studied compounds is controlled mainly by C–H⋅⋅⋅O hydrogen bonds, C–H⋅⋅⋅π interactions, and π···π stacking interactions, which were quantitatively analyzed using Hirshfeld topology analysis. Using density functional theory (DFT) calculations, the order of polarity (3b ˂ 3d ˂ 3e ˂ 3a ˂ 3c) was determined. Several chemical reactivity indices such as the ionization potential (I), electron affinity (A), chemical potential (μ), hardness (η), electrophilicity (ω) and nucleophilicity (N) indices were c...
1056 Most sickle cell anemia patients (HBB glu6val homozygotes) indigenous to the Eastern Provinc... more 1056 Most sickle cell anemia patients (HBB glu6val homozygotes) indigenous to the Eastern Province of Saudi Arabia have a fetal hemoglobin (HbF) level of about 20% that is associated with a mild clinical phenotype. Their HbS gene is on the Saudi-Indian (SI) haplotype characterized by an Xmn1 restriction site at position −158 5' to HBG2 (rs7482144), a Hinc2 site 5' to HBE (rs3834466) and other polymorphisms in the HBB gene-like cluster. However, the functional elements within the HBB gene-like cluster and elsewhere in the genome causing high HbF are yet to be determined. In a previous study we found that Saudi HbS homozygotes with the SI haplotype had a common region of autozygosity that spanned about 126 kb and included the complete HBB cluster. We have sequenced 13.6 kb in the HBD-HBG1 intergenic region (chr11:5255683-5269326, HG19), the region of the Corfu deletion. We found a SNP at position −68 bp 5' to HBD (c.-118 C>T) only in individuals with a SI haplotype. Thi...
Life-threatening fungal infections accounts for a major global health burden especially for indiv... more Life-threatening fungal infections accounts for a major global health burden especially for individuals suffering from cancer, acquired immune deficiency syndrome (AIDS), or autoimmune diseases. (2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(2-chlorophenyl)hydrazinecarboxamide has been synthesized and characterized using various spectroscopic tools to be evaluated as a new antifungal agent. The (E)-configuration of the imine moiety of the title molecule has been unequivocally identified with the aid of single crystal X-ray analysis. The molecular structure of compound 4 was crystallized in the monoclinic, P21/c, a = 8.7780 (6) Å, b = 20.5417 (15) Å, c = 11.0793 (9) Å, β = 100.774 (2)°, V = 1962.5 (3) Å3, and Z = 4. Density functional theory computations have thoroughly explored the electronic characteristics of the title molecule. Moreover, molecular docking studies and Hirshfeld surface analysis were also executed on the title compound 4. The in vitro antifung...
The search for a simple and efficient method for the synthesis of sulfonamide and sulfonate deriv... more The search for a simple and efficient method for the synthesis of sulfonamide and sulfonate derivatives under mild and eco-friendly conditions is of continuing interest. Sulfonyl chlorides are still the best choice as starting materials for the preparation of target products. Here, we report a simple, efficient and eco-friendly method for the synthesis of sulfonamide and sulfonate carboxylic acid derivatives under green conditions using water and sodium carbonate as HCl scavengers to produce the products with high yields and purities. Two derivatives, 4-(tosyloxy)benzoic acid (5a) and 4-((4-methylphenyl)sulfonamido)benzoic acid (5b), were reacted with 2-morpholinoethan-1-amine under green conditions, where OxymaPure/diisopropylcarbodiimide (DIC) was used as a coupling reagent and 2-MeTHF as a solvent to give the target product with high yield and purity. nuclear magnetic resonance (NMR) and elemental analysis confirmed the structures of all obtained products. X-ray crystallography c...
The development of drug-resistance and high morbidity rates due to life-threatening fungal infect... more The development of drug-resistance and high morbidity rates due to life-threatening fungal infections account for a major global health problem. A new antifungal imidazole-based oximino ester 5 has been prepared and characterized with the aid of different spectroscopic tools. Single crystal X-ray analysis doubtlessly identified the (E)-configuration of the imine fragment of the title compound. Compound 5, C18H15N3O5, was crystallized in the monoclinic, P21/c, a = 10.4067 (5) Å, b = 6.8534 (3) Å, c = 23.2437 (12) Å, β = 94.627 (2)°, V = 1652.37 (14) Å3, Z = 4. Spectral and electronic features of compound 5 have been thoroughly explored with the aid of density function theory (DFT) simulations and the data were compared with the experimental results. In addition, Hirshfeld surface analysis and molecular docking simulations were executed on the target compound. Molecular docking results are fairly consistent with the experimental in vitro antifungal potential of the oximino ester 5.
European journal of medicinal chemistry, Jan 15, 2018
Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for it... more Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for its significant role in the progression of different types of malignant tumors, where development of small molecules targeting EGFR is well known strategy for design of antitumor agents. Herein, we report the design and synthesis of two series of 6-(2-substitutedacetamido)-4-anilinoquinazolines (6a-x and 13a-d) as EGFR inhibitors. All the newly synthesized quinazoline derivatives were in vitro evaluated for their anti-proliferative activity towards MCF-7 (Breast Cancer) and HepG2 (Hepatocellular carcinoma) cell lines. In particular, compound 6n showed significant inhibitory activity against MCF-7 and HepG2 cell lines (IC = 3 and 16 μM, respectively), compared to that of Erlotinib (IC = 20 and 25 μM, respectively). Western blotting of 6n at MCF-7 cell line revealed the dual inhibitory activity of 6n towards diminishing the phosphorylated levels for EGFR and ERK. Also, ELISA assay confirmed ...
Enaminones, 4-methyl-1-[4-(piperazin/morpholin-1-yl) phenyl] pent-2-en-1-one (⁻) were synthesized... more Enaminones, 4-methyl-1-[4-(piperazin/morpholin-1-yl) phenyl] pent-2-en-1-one (⁻) were synthesized by refluxing 1-[4-(piperazin/morpholin-1-yl) phenyl] ethan-1-one (⁻) with dimethylformamide dimethylacetal (DMF⁻DMA) without any solvent. The three dimensional structure of enaminone () containing morpholine moiety was confirmed by single crystal X-ray crystallography. Finally, the dihydropyrimidinone derivatives (⁻) were obtained by reacting enaminones (⁻) with urea and different substituted benzaldehydes in the presence of glacial acetic acid. Dihydropyrimidinone derivatives containing piperazine/morpholine moiety were synthesized in a good yield by means of simple and efficient method.
Journal of enzyme inhibition and medicinal chemistry, 2018
On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindo... more On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindolin-2-one scaffolds is a logic tactic for designing pro-apoptotic agents. Consequently, 27 hybrids (6a-r, 9a-f and 11a-c) were synthesised and evaluated for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines. SAR studies unravelled that N-propylindole derivatives were the most active compounds such as 6n (MCF-7; IC=1.04 µM), which displayed a significant decrease of cell population in the G2/M phase and significant increase in the early and late apoptosis by 19-folds in Annexin-V-FTIC assay. Also, 6n increased the expression of caspase-3, caspase-9, cytochrome C and Bax and decreased the expression of Bcl-2. Moreover, compounds 6i, 6j, 6n and 6q generated ROS by significant increase in the level of SOD and depletion of the levels of CAT and GSH-Px in MCF-7.
International journal of molecular sciences, Jan 25, 2017
The development of low-cost catalytic systems that mimic the activity of tyrosinase enzymes (Cate... more The development of low-cost catalytic systems that mimic the activity of tyrosinase enzymes (Catechol oxidase) is of great promise for future biochemistry technologic demands. Herein, we report the synthesis of new biomolecules systems based on hydrazone derivatives containing a pyrazole moiety (L1-L6) with superior catecholase activity. Crystal structures of L1 and L2 biomolecules were determined by X-ray single crystal diffraction (XRD). Optimized geometrical parameters were calculated by density functional theory (DFT) at B3LYP/6-31G (d, p) level and were found to be in good agreement with single crystal XRD data. Copper (II) complexes of the compounds (L1-L6), generated in-situ, were investigated for their catalytic activities towards the oxidation reaction of catechol to ortho-quinone with the atmospheric dioxygen, in an attempt to model the activity of the copper containing enzyme tyrosinase. The studies showed that the activities depend on four parameters: the nature of the l...
In our ongoing efforts to develop potent antitubercular agents based on the 6-phenylnicotinohydra... more In our ongoing efforts to develop potent antitubercular agents based on the 6-phenylnicotinohydrazide, herein we report the design, synthesis and biological evaluation of three sets of 6-phenylnicotinohydrazide derivatives 8a-g, 12 and 16a, b. The designed compounds were synthesized and in vitro evaluated for their antitubercular activity. In addition, their antifungal and antibacterial activities were evaluated as well. The nicotinohydrazide class displayed different levels of antimicrobial activity and possessed a distinctive pattern of selectivity against the tested microorganisms. However, the 2,6-dichlorobenzylidene counterpart 8b emerged as the most active one in this study, with superior antimycobacterial activity (minimum inhibitory concentration (MIC)=3.90 µg/mL) and potent broad-spectrum antimicrobial activities with MIC range of 0.24-1.95 µg/mL. The structure-activity relationship for such nicotinohydrazides has been established. Further, the cytotoxicity of the most acti...
Journal of enzyme inhibition and medicinal chemistry, 2018
Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment opt... more Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a-p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated th...
Novel 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione was synthesized and recrystallize... more Novel 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione was synthesized and recrystallized from ethanol. The compound was characterized by 1H NMR, 13C NMR in CDCl3, DMSO-d6 and acetone-d6, elemental analysis and X-ray diffraction. The NMR data observed that the title compound exists in the enol tautomer rather than keto, and it stabilized by strong H-bond as observed form the NMR data at different temperatures. Theoretical calculations (DFT) were carried out using Gaussian09 program package and B3LYP correlation function. Full geometry optimization of the keto and enol forms were carried out using 6-311G++(d,p) basis set. The structure and energy of the transition state between these two tautomers were calculated. The frontier orbital energy and atomic net atomic charges of the tautomers were presented. The experimental results of the title compound have been compared with the theoretical results and it was found that the experimental data are in a good agreement with the ca...
The present work aimed to synthesize 2-methylthio-triazoloquinazoline derivatives and study their... more The present work aimed to synthesize 2-methylthio-triazoloquinazoline derivatives and study their X-ray, NMR, DFT and Hirshfeld characteristics. The cyclocondensation of dimethyl-N-cyanodithiocarbonate with 2-hydrazinobenzoic acid hydrochloride resulted in an intermediate, 2-methylthio-[1,2,4]triazolo[1,5-a]quinazolin-5-one (A), which upon treatment with phosphorus pentasulfide, transformed into the 2-methylthio-[1,2,4]triazolo[1,5-a]quinazolin-5-thione (B). Reaction of 2-methylthio-triazoloquinazolines (A&B) with alkyl halides (allyl bromide and ethyl iodide) in basic medium afforded 4-allyl-2-methylthio-[1,2,4]triazolo[1,5-a]quinazolin-5-one (1; N-alkylated) and 5-ethylthio-2-methylthio-[1,2,4]triazolo[1,5-a]quinazoline (2; S-alkylated), respectively. Their molecular and supramolecular structures were presented. Unambiguously, the molecular structures of 1 and 2 were confirmed via NMR and single-crystal X-ray diffraction. The resulting findings confirmed the structures of 1 and 2 ...
The pharmacological activities of thiazole and pyrazole moieties as antimicrobial and anticancer ... more The pharmacological activities of thiazole and pyrazole moieties as antimicrobial and anticancer agents have been thoroughly described in many literature reviews. In this study, a convenient synthesis of novel pyrazolo[5,1-b]thiazole-based heterocycles was carried out. The synthesized compounds were characterized by IR, 1H and 13C NMR spectroscopy and mass spectrometry. Some selected examples were screened and evaluated for their antimicrobial and anticancer activities and showed promising results. These products could serve as leading compounds in the future design of new drug molecules.
The target compound 3-amino-1-(2,5-d ichlorophenyl)-8-methoxy-1H-benzo[f]-chromene-2-carbonitrile... more The target compound 3-amino-1-(2,5-d ichlorophenyl)-8-methoxy-1H-benzo[f]-chromene-2-carbonitrile (4) was synthesized via a reaction of 6-methoxynaphthalen-2-ol (1), 2,5-dichlorobenzaldehyde (2), and malononitrile (3) in ethanolic piperidine solution under microwave irradiation. The newly synthesized β-enaminonitrile was characterized by FT-IR, 1H NMR, 13C NMR, mass spectroscopy, elemental analysis and X-ray diffraction data. Its cytotoxic activity was evaluated against three different human cancer cell lines MDA-MB-231, A549, and MIA PaCa-2 in comparison to the positive controls etoposide and camptothecin employing the XTT cell viability assay. The analysis of the Hirshfeld surface was utilized to visualize the reliability of the crystal package. The obtained results confirmed that the tested molecule revealed promising cytotoxic activities against the three cancer cell lines. Furthermore, theoretical calculations (DFT) were carried out with the Becke3-Lee-Yang-parr (B3LYP) level u...
N-(Anthracen-9-ylmethyl)-N-methyl-2-(phenylsulfonyl)ethanamine 3 has been synthesized via the aza... more N-(Anthracen-9-ylmethyl)-N-methyl-2-(phenylsulfonyl)ethanamine 3 has been synthesized via the aza-Michael addition approach by reaction of the corresponding amine with the vinyl sulfone derivative under microwave conditions. The structure of the aza-Michael product 3 is elucidated by X-ray crystallography. The study of molecular packing by employing the Hirshfeld analysis indicates that the percentages of O…H, C…H and H…H contacts are 16.8%, 34.1% and 48.6%, respectively, where the O...H hydrogen bonds have the characteristics of short and strong contacts while the C...H contacts are considered weak. Density functional theory (DFT) investigations show that the aza-Michael product 3 is polar with a net dipole moment of 5.2315 debye.
A series of triazolo-thiadiazepines 4a–k were synthesized with excellent yields using dehydrated ... more A series of triazolo-thiadiazepines 4a–k were synthesized with excellent yields using dehydrated PTSA as a catalyst in toluene. Two triazolo-thiadiazines were obtained; 8a was formed directly by reflux in ethanol, whereas, PTSA promoted the formation of 8b. The molecular structure of the formed triazolo-thiadiazepines is identical to the imine-form 4a–k and not the enamine-tautomer 6a–k. The structures of the newly synthesized triazolo-thiadiazepines 4a–k and triazolo-thiadiazines 8a–b were elucidated using NMR (1H, and 13C), 2D NMR, HRMS, and X-ray single crystal. Furthermore, 4a was deduced using X-ray single crystal diffraction analysis. These new thiadiazepine hits represent an optimized series of previously synthesized indole-triazole derivatives for the inhibition of EGFR. The cytotoxicity activity against two cancer cell lines including human liver cancer (HEPG-2) and breast cancer (MCF-7) was promising, with IC50 between 12.9 to 44.6 µg/mL and 14.7 to 48.7 µg/mL for the test...
A simple, cost-effective method under environmentally benign conditions is a very important conce... more A simple, cost-effective method under environmentally benign conditions is a very important concept for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. The present work describes an efficient and eco-friendly protocol for the synthesis of 2-amino-N-(2-substituted-ethyl)benzamide and 3-substituted-2,3-dihydroquinazolin-4(1H)-one derivatives. The novel feature of this protocol is the use of 2-methyl tetrahydrofuran (2-MeTHF) as an eco-friendly alternative solvent to tetrahydrofuran (THF) in the first step. In the second step, methanol in the presence of potassium carbonate as a catalyst was used under conventional heating or microwave irradiation, which provided an eco-friendly method to afford the target products in excellent yields and purities. NMR (1H and 13C), elemental analysis, and LC-MS confirmed the structures of all compounds. X-ray crystallography further confirmed the structure of the intermediate 2-amino-N-(2-substituted-ethyl)benzamide 3a. The molecular s...
Certain Biginelli pyrimidines with ester substitution in C5 were subjected to unexpected ring ope... more Certain Biginelli pyrimidines with ester substitution in C5 were subjected to unexpected ring opening upon solvent-free reaction with hydrazine hydrate to give three products: pyrazole, arylidenehydrazines, and urea/thiourea, respectively. The nonisolable carbohydrazide intermediates are formed firstly followed by the intermolecular nucleophilic attack of terminal amino group of hydrazide function on sp2 C6 rather than the sp3 C4 to give the ring adduct which was produced as a final product.
The crystal structures of five new chalcones derived from N-ethyl-3-acetylindole with different s... more The crystal structures of five new chalcones derived from N-ethyl-3-acetylindole with different substituents were investigated: (E)-3-(4-bromophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one (3a); (E)-3-(3-bromophenyl)-1-(1-ethyl-1H-indol-3-yl)prop-2-en-1-one (3b); (E)-1-(1-ethyl-1H-indol-3-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (3c); (E)-1-(1-ethyl-1H-indol-3-yl)-3-mesitylprop-2-en-1-one (3d); and (E)-1-(1-ethyl-1H-indol-3-yl)-3-(furan-2-yl)prop-2-en-1-one (3e). The molecular packing of the studied compounds is controlled mainly by C–H⋅⋅⋅O hydrogen bonds, C–H⋅⋅⋅π interactions, and π···π stacking interactions, which were quantitatively analyzed using Hirshfeld topology analysis. Using density functional theory (DFT) calculations, the order of polarity (3b ˂ 3d ˂ 3e ˂ 3a ˂ 3c) was determined. Several chemical reactivity indices such as the ionization potential (I), electron affinity (A), chemical potential (μ), hardness (η), electrophilicity (ω) and nucleophilicity (N) indices were c...
1056 Most sickle cell anemia patients (HBB glu6val homozygotes) indigenous to the Eastern Provinc... more 1056 Most sickle cell anemia patients (HBB glu6val homozygotes) indigenous to the Eastern Province of Saudi Arabia have a fetal hemoglobin (HbF) level of about 20% that is associated with a mild clinical phenotype. Their HbS gene is on the Saudi-Indian (SI) haplotype characterized by an Xmn1 restriction site at position −158 5' to HBG2 (rs7482144), a Hinc2 site 5' to HBE (rs3834466) and other polymorphisms in the HBB gene-like cluster. However, the functional elements within the HBB gene-like cluster and elsewhere in the genome causing high HbF are yet to be determined. In a previous study we found that Saudi HbS homozygotes with the SI haplotype had a common region of autozygosity that spanned about 126 kb and included the complete HBB cluster. We have sequenced 13.6 kb in the HBD-HBG1 intergenic region (chr11:5255683-5269326, HG19), the region of the Corfu deletion. We found a SNP at position −68 bp 5' to HBD (c.-118 C>T) only in individuals with a SI haplotype. Thi...
Life-threatening fungal infections accounts for a major global health burden especially for indiv... more Life-threatening fungal infections accounts for a major global health burden especially for individuals suffering from cancer, acquired immune deficiency syndrome (AIDS), or autoimmune diseases. (2E)-2-[1-(1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-N-(2-chlorophenyl)hydrazinecarboxamide has been synthesized and characterized using various spectroscopic tools to be evaluated as a new antifungal agent. The (E)-configuration of the imine moiety of the title molecule has been unequivocally identified with the aid of single crystal X-ray analysis. The molecular structure of compound 4 was crystallized in the monoclinic, P21/c, a = 8.7780 (6) Å, b = 20.5417 (15) Å, c = 11.0793 (9) Å, β = 100.774 (2)°, V = 1962.5 (3) Å3, and Z = 4. Density functional theory computations have thoroughly explored the electronic characteristics of the title molecule. Moreover, molecular docking studies and Hirshfeld surface analysis were also executed on the title compound 4. The in vitro antifung...
The search for a simple and efficient method for the synthesis of sulfonamide and sulfonate deriv... more The search for a simple and efficient method for the synthesis of sulfonamide and sulfonate derivatives under mild and eco-friendly conditions is of continuing interest. Sulfonyl chlorides are still the best choice as starting materials for the preparation of target products. Here, we report a simple, efficient and eco-friendly method for the synthesis of sulfonamide and sulfonate carboxylic acid derivatives under green conditions using water and sodium carbonate as HCl scavengers to produce the products with high yields and purities. Two derivatives, 4-(tosyloxy)benzoic acid (5a) and 4-((4-methylphenyl)sulfonamido)benzoic acid (5b), were reacted with 2-morpholinoethan-1-amine under green conditions, where OxymaPure/diisopropylcarbodiimide (DIC) was used as a coupling reagent and 2-MeTHF as a solvent to give the target product with high yield and purity. nuclear magnetic resonance (NMR) and elemental analysis confirmed the structures of all obtained products. X-ray crystallography c...
The development of drug-resistance and high morbidity rates due to life-threatening fungal infect... more The development of drug-resistance and high morbidity rates due to life-threatening fungal infections account for a major global health problem. A new antifungal imidazole-based oximino ester 5 has been prepared and characterized with the aid of different spectroscopic tools. Single crystal X-ray analysis doubtlessly identified the (E)-configuration of the imine fragment of the title compound. Compound 5, C18H15N3O5, was crystallized in the monoclinic, P21/c, a = 10.4067 (5) Å, b = 6.8534 (3) Å, c = 23.2437 (12) Å, β = 94.627 (2)°, V = 1652.37 (14) Å3, Z = 4. Spectral and electronic features of compound 5 have been thoroughly explored with the aid of density function theory (DFT) simulations and the data were compared with the experimental results. In addition, Hirshfeld surface analysis and molecular docking simulations were executed on the target compound. Molecular docking results are fairly consistent with the experimental in vitro antifungal potential of the oximino ester 5.
European journal of medicinal chemistry, Jan 15, 2018
Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for it... more Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for its significant role in the progression of different types of malignant tumors, where development of small molecules targeting EGFR is well known strategy for design of antitumor agents. Herein, we report the design and synthesis of two series of 6-(2-substitutedacetamido)-4-anilinoquinazolines (6a-x and 13a-d) as EGFR inhibitors. All the newly synthesized quinazoline derivatives were in vitro evaluated for their anti-proliferative activity towards MCF-7 (Breast Cancer) and HepG2 (Hepatocellular carcinoma) cell lines. In particular, compound 6n showed significant inhibitory activity against MCF-7 and HepG2 cell lines (IC = 3 and 16 μM, respectively), compared to that of Erlotinib (IC = 20 and 25 μM, respectively). Western blotting of 6n at MCF-7 cell line revealed the dual inhibitory activity of 6n towards diminishing the phosphorylated levels for EGFR and ERK. Also, ELISA assay confirmed ...
Enaminones, 4-methyl-1-[4-(piperazin/morpholin-1-yl) phenyl] pent-2-en-1-one (⁻) were synthesized... more Enaminones, 4-methyl-1-[4-(piperazin/morpholin-1-yl) phenyl] pent-2-en-1-one (⁻) were synthesized by refluxing 1-[4-(piperazin/morpholin-1-yl) phenyl] ethan-1-one (⁻) with dimethylformamide dimethylacetal (DMF⁻DMA) without any solvent. The three dimensional structure of enaminone () containing morpholine moiety was confirmed by single crystal X-ray crystallography. Finally, the dihydropyrimidinone derivatives (⁻) were obtained by reacting enaminones (⁻) with urea and different substituted benzaldehydes in the presence of glacial acetic acid. Dihydropyrimidinone derivatives containing piperazine/morpholine moiety were synthesized in a good yield by means of simple and efficient method.
Journal of enzyme inhibition and medicinal chemistry, 2018
On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindo... more On account of their significance as apoptosis inducing agents, merging indole and 3-hydrazinoindolin-2-one scaffolds is a logic tactic for designing pro-apoptotic agents. Consequently, 27 hybrids (6a-r, 9a-f and 11a-c) were synthesised and evaluated for their cytotoxicity against MCF-7, HepG-2 and HCT-116 cancer cell lines. SAR studies unravelled that N-propylindole derivatives were the most active compounds such as 6n (MCF-7; IC=1.04 µM), which displayed a significant decrease of cell population in the G2/M phase and significant increase in the early and late apoptosis by 19-folds in Annexin-V-FTIC assay. Also, 6n increased the expression of caspase-3, caspase-9, cytochrome C and Bax and decreased the expression of Bcl-2. Moreover, compounds 6i, 6j, 6n and 6q generated ROS by significant increase in the level of SOD and depletion of the levels of CAT and GSH-Px in MCF-7.
International journal of molecular sciences, Jan 25, 2017
The development of low-cost catalytic systems that mimic the activity of tyrosinase enzymes (Cate... more The development of low-cost catalytic systems that mimic the activity of tyrosinase enzymes (Catechol oxidase) is of great promise for future biochemistry technologic demands. Herein, we report the synthesis of new biomolecules systems based on hydrazone derivatives containing a pyrazole moiety (L1-L6) with superior catecholase activity. Crystal structures of L1 and L2 biomolecules were determined by X-ray single crystal diffraction (XRD). Optimized geometrical parameters were calculated by density functional theory (DFT) at B3LYP/6-31G (d, p) level and were found to be in good agreement with single crystal XRD data. Copper (II) complexes of the compounds (L1-L6), generated in-situ, were investigated for their catalytic activities towards the oxidation reaction of catechol to ortho-quinone with the atmospheric dioxygen, in an attempt to model the activity of the copper containing enzyme tyrosinase. The studies showed that the activities depend on four parameters: the nature of the l...
In our ongoing efforts to develop potent antitubercular agents based on the 6-phenylnicotinohydra... more In our ongoing efforts to develop potent antitubercular agents based on the 6-phenylnicotinohydrazide, herein we report the design, synthesis and biological evaluation of three sets of 6-phenylnicotinohydrazide derivatives 8a-g, 12 and 16a, b. The designed compounds were synthesized and in vitro evaluated for their antitubercular activity. In addition, their antifungal and antibacterial activities were evaluated as well. The nicotinohydrazide class displayed different levels of antimicrobial activity and possessed a distinctive pattern of selectivity against the tested microorganisms. However, the 2,6-dichlorobenzylidene counterpart 8b emerged as the most active one in this study, with superior antimycobacterial activity (minimum inhibitory concentration (MIC)=3.90 µg/mL) and potent broad-spectrum antimicrobial activities with MIC range of 0.24-1.95 µg/mL. The structure-activity relationship for such nicotinohydrazides has been established. Further, the cytotoxicity of the most acti...
Journal of enzyme inhibition and medicinal chemistry, 2018
Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment opt... more Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a-p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated th...
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Papers by Hazem Ghabbour