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...
The main objective of this work was to synthesize novel compounds with a benzo[de][1,2,4]triazolo... more The main objective of this work was to synthesize novel compounds with a benzo[de][1,2,4]triazolo[5,1-a]isoquinoline scaffold by employing (dioxo-benzo[de]isoquinolin-2-yl) thiourea as a building block. Molecular docking was conducted in the COX-2 active site to predict the plausible binding mode and rationalize the structure-activity relationship of the synthesized compounds. The structures of the synthesized compounds were confirmed by HREI-MS, and NMR spectra along with X-ray diffraction were collected for products 1 and 5. Thereafter, anti-inflammatory effect of molecules 1-20 was evaluated in vivo using carrageenan-induced paw edema method, revealing significant inhibition potency in albino rats with an activity comparable to that of the standard drugs indomethacin. Compounds 8, 9, 15 and 16 showed the highest anti-inflammatory activity. However, thermal sensitivity-hot plat test, a radiological examination and motor coordination assessment were performed to test the activity a...
Fungal infections threaten human health, particularly in immune-compromised patients worldwide. A... more Fungal infections threaten human health, particularly in immune-compromised patients worldwide. Although there are a large number of antifungal agents available, the desired clinical attributes for the treatment of fungal infections have not yet been achieved. Azoles are the mainstay class of the clinically used antifungal agents. In the current study, the synthesis, spectroscopic characterization, and antifungal activity of certain new oximino ethers Va-n bearing imidazole nuclei are reported. The (E)-configuration of the imine double bond of the synthesized compounds Va-n has been confirmed via single crystal X-ray analysis of compound Vi as a representative example of this class of compounds. The molecular structure of compound Vi was crystallized in the monoclinic, P2₁/c, a = 18.7879(14) Å, b = 5.8944(4) Å, c = 16.7621(12) Å, β = 93.063(3)°, V = 1855.5(2) ų, Z = 4. The in vitro antifungal activity of the synthesized compounds Va-n were evaluated using diameter of the inhibition...
Acta Crystallographica Section E Crystallographic Communications
In the title N-Mannich bases, 3-(adamantan-1-yl)-4-(4-fluorophenyl)-1-[(4-phenylpiperazin-1-yl)me... more In the title N-Mannich bases, 3-(adamantan-1-yl)-4-(4-fluorophenyl)-1-[(4-phenylpiperazin-1-yl)methyl]-4,5-dihydro-1H-1,2,4-triazole-5-thione (C29H34FN5S) (I), and 3-(adamantan-1-yl)-4-(4-fluorophenyl)-1-{[4-(2-methoxyphenyl)piperazin-1-yl]-methyl}-4,5-dihydro-1H-1,2,4-triazole-5-thione (C30H36FN5OS) (II), fluorophenyl, adamantane and piperazine moieties are linked to a planar triazole ring. There is an additional phenyl ring on the piperazine ring in (I) and a methoxyphenyl ring in (II). In compound (I), the fluorophenyl and phenyl rings are inclined to the triazole ring by 86.55 (13) and 60.52 (12)°, respectively, and the two aryl rings are inclined to one another by 66.37 (13)°. In compound (II), the corresponding dihedral angles are 83.35 (13), 71.38 (15) and 11.97 (16)°, respectively. The crystal structure of (I) shows pairs of C—H...F hydrogen bonds forming inversion dimers, while in the crystal of compound (II), in addition to the C—H...F hydrogen bonds that generate chains p...
Zeitschrift für Kristallographie - New Crystal Structures
C 27 H 19 N5O5S, monoclinic, P21/c (no. 14), a = 14.2789(4) Å, b = 27.3722(9) Å, c = 13.0126(4) Å... more C 27 H 19 N5O5S, monoclinic, P21/c (no. 14), a = 14.2789(4) Å, b = 27.3722(9) Å, c = 13.0126(4) Å, β = 101.805
Background: Due to their interesting and versatile biological activity, thiophene-containing comp... more Background: Due to their interesting and versatile biological activity, thiophene-containing compounds have attracted the attention of both chemists and medicinal chemists. Some of these compounds have anticancer, antibacterial, antiviral, and antioxidant activity. In addition, the thiophene nucleus has been used in the synthesis of a variety of heterocyclic compounds.
Zeitschrift für Kristallographie - New Crystal Structures
C 16 H 13 NO 2 S, P¯ (no. 2), a = 8.0873(4) Å, b = 12.7820(7) Å, c = 13.5574 Å, α = 74.880(2)°, β... more C 16 H 13 NO 2 S, P¯ (no. 2), a = 8.0873(4) Å, b = 12.7820(7) Å, c = 13.5574 Å, α = 74.880(2)°, β = 75.421(2)°, γ = 76.391(2)°, V = 1287.61(12) Å 3 , Z = 4, Rgt(F) = 0.0413, wR ref (F 2 ) = 0.1075, T = 100 K.
Zeitschrift für Kristallographie - New Crystal Structures
Crystal structure of (16S)-12,16-epoxy-11, 14-dihydroxy-17(15/16)-abeo-3a,18-cyclo-8,11,13abietat... more Crystal structure of (16S)-12,16-epoxy-11, 14-dihydroxy-17(15/16)-abeo-3a,18-cyclo-8,11,13abietatrien-7-one, C 20 H 24 O 4 Abstract C 20 H 24 O4, orthorhombic, P212121, a = 8.3007(4) Å, b = 12.0111 Å, c = 17.0604(9) Å, V = 1700.93(15) Å 3 , Z = 4, Rgt(F) = 0.0621, wR ref (F 2 ) = 0.1413, T = 296(2) K.
Zeitschrift für Kristallographie - New Crystal Structures
C 19 H 18 O4, orthorhombic, Pbcn, a = 21.1472(8) Å, b = 9.7978(4) Å, c = 14.5181(6) Å, V = 3008.1... more C 19 H 18 O4, orthorhombic, Pbcn, a = 21.1472(8) Å, b = 9.7978(4) Å, c = 14.5181(6) Å, V = 3008.1(2) Å 3 , Z = 8, Rgt(F) = 0.0520, wR ref (F 2 ) = 0.1194, T = 100(2).
Journal of Enzyme Inhibition and Medicinal Chemistry
2017) Synthesis, in vitro antitumour activity, and molecular docking study of novel 2-substituted... more 2017) Synthesis, in vitro antitumour activity, and molecular docking study of novel 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinone analogues, ABSTRACT A novel series of 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinones 1-20 was synthesised and evaluated for in vitro antitumour activity. N-(4-Chlorophenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio)acetamide (7) and N-(3,4,5 trimethoxybenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide (19) exhibited excellent antitumour properties, with mean growth inhibitory concentration (GI 50 ) of 17.90 and 6.33 mM, respectively, compared with those of 5-fluorouracil 5-FU, gefitinib, and erlotinib (mean GI 50 : 18.60, 3.24, and 7.29 mM, respectively). Comparison of the GI 50 (mM) values of compounds 7 and 19 versus those of 5-FU, gefitinib, and erlotinib against an in vitro subpanel of tumour cells lines showed that compounds 7 and 19 have activities almost equal to or higher than that of those standard drugs, especially against lung, CNS, and breast cancer cells. However, compounds 5, , and 20 exhibited effective antitumour activity against the different cell lines tested, with growth inhibition percentage (MGI%) of 19, 24, 19, 17, 16, 15, and 16, respectively. A modelling study was performed for compounds 7 and 19 by docking them into the EGFR kinase enzyme to study their mode of binding with the putative binding site.
The chlorinated ethanoanthracenes: 4,5,12-and 1,8,12-(trichloro-9,10-dihydro-9,10ethanoanthracene... more The chlorinated ethanoanthracenes: 4,5,12-and 1,8,12-(trichloro-9,10-dihydro-9,10ethanoanthracene-12-carbonitriles) (1 and 2), which are regioisomers, were synthesized and characterized using nuclear magnetic resonance ( 1 H-and 13 C-NMR) and infrared (IR) spectroscopic techniques. The structure of isomer 1 was further confirmed using a single-crystal X-ray technique. The relative stabilities of the title compounds were calculated using the density functional theory (DFT) method on the basis of their total energies and thermodynamic parameters. Isomer 1 is thermodynamically more stable than isomer 2 in the gas phase and in solution. The calculated molecular geometry of isomer 1 agreed well with the experimental X-ray structure. The atomic charge distribution at the different atomic sites was calculated using natural bond orbital analysis. Isomer 2 was predicted to be more polar than isomer 1.
Journal of Asian natural products research, Jan 31, 2017
Two new sesquiterpene lactones 3R, 8R-dihydroxygermacr-4(15),9(10)-dien-6S,7S,11RH,12,6-olide (1)... more Two new sesquiterpene lactones 3R, 8R-dihydroxygermacr-4(15),9(10)-dien-6S,7S,11RH,12,6-olide (1) and 1R, 8S-dihydroxy-11R,13-dihydrobalchanin(2), together with two known compounds 11-epiartapshin (3) and 3'-hydroxygenkwanin (4), were isolated from Artemisia sieberi. Their structures were elucidated by 1D, 2D NMR, MS, and X-ray diffraction. Compound 4 inhibited Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus with Minimal inhibitory concentration values of 50 and 25 μg/disk, respectively. All the isolated compounds exhibited moderate antifungal activities.
Journal of enzyme inhibition and medicinal chemistry, 2017
Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994.... more Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994. Adopting a structural rigidification approach, a novel series of 3-phenylthiazolo[3,2-a]benzimidazoles 4a-d was designed and synthesised, in an attempt to develop potent anticancer agent that can target the bulk of tumour cells and CSCs. The anti-proliferative activity of the synthesised compounds was evaluated against two cell lines, namely; colon cancer HT-29 and triple negative breast cancer MDA-MB-468 cell lines. Also, their inhibitory activity against the cell surface expression of CD133 was examined. In particular, compound 4b emerged as a promising hit molecule as it manifested good antineoplastic potency against both tested cell lines (IC50 = 9 and 12 μM, respectively), beside its ability to inhibit the cell surface expression of CD133 by 50% suggesting a promising potential of effectively controlling the tumour by eradicating the tumour bulk and inhibiting the proliferation of ...
Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiaz... more Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino)benzenesulfonamides (4a-m and 7a-g). All the newly prepared sulfonamides were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. In particular, hCA isoforms II and IX (tumor-associated) were more susceptible to inhibition by the synthesized derivatives, with KIs in the range of 2.6-598.2 nM for hCA II, and of 16.1-321 nM for hCA IX. All compounds (4a-m and 7a-g) were evaluated for their anti-proliferative activity against breast cancer MCF-7 and colorectal cancer Caco-2 cell lines. Compound 4c was found to be the most potent derivative against MCF-7 (IC50 = 3.96 ± 0.21 μM), while 4j was the most active member against Caco-2 cells (IC50 = 5.87 ± 0.37 μM). Compound 4c induced the intrinsic apoptotic mitochondrial pathway in MCF-7 cells; evidenced by the en...
European journal of medicinal chemistry, Jan 18, 2017
A small library of benzimidazole-fused pyrrolo[3,4-b]quinoline has been synthesized from readily ... more A small library of benzimidazole-fused pyrrolo[3,4-b]quinoline has been synthesized from readily available benzimidazole 2-carbaldehyde and various substituted arylamines in good to excellent yields utilizing an intramolecular Povarov reaction catalyzed by boron trifluoride diethyl etharate as the key final step. The compounds thus synthesized can be considered as decarbonyl analogues of the anticancer alkaloid luotonin A and were evaluated in a DNA relaxation assay for their ability to inhibit human topoisomerase I. Interestingly, two of the compounds showed a remarkable activity that is comparable to that of the standard drug camptothecin. The compounds were also evaluated for their cytotoxic effect in four highly aggressive human cancer cell lines, namely KB, MDA-MB231 (breast), LNCap (prostate), and HT1080 (fibrosarcoma). Some of the compounds obtained showed promising cytotoxicities for these four cell lines.
A new series of adamantane-isothiourea hybrid derivatives, namely 4-arylmethyl (Z)-N'-(adaman... more A new series of adamantane-isothiourea hybrid derivatives, namely 4-arylmethyl (Z)-N'-(adamantan-1-yl)-morpholine-4-carbothioimidates 7a-e and 4-arylmethyl (Z)-N'-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioimidates 8a-e were prepared via the reaction of N-(adamantan-1-yl)morpholine-4-carbothioamide 5 and N-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioamide 6 with benzyl or substituted benzyl bromides, in acetone, in the presence of anhydrous potassium carbonate. The structures of the synthesized compounds were confirmed by ¹H-NMR, (13)C-NMR, electrospray ionization mass spectral (ESI-MS) data, and X-ray crystallographic data. The in vitro antimicrobial activity of the new compounds was determined against certain standard strains of pathogenic bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 7b, 7d and 7e displayed potent broad-spectrum antibacterial activity, while compounds 7a, 7c, 8b, 8d and 8e were active against the tested Gram-positive bac...
In this study, a new series of quinazoline derivatives (3-26) was synthesized and characterized v... more In this study, a new series of quinazoline derivatives (3-26) was synthesized and characterized via physicochemical and spectral means. Treatment of 2-amino-5-methylbenzoic acid with butyl isothiocyanate resulted in the new 2-thioxoquinazolin-4-one (3). Alkylation and hydrazinolysis of the inherent thioxo group in (1-3) afforded the corresponding thioethers (4-23) and hydrazine derivatives (24 and 25), then 24 was further transformed into tricyclic derivative 26 via cyclocondensation reaction. Compounds 1 and 2, which were previously synthesized, were found to exhibit anticancer activity. The cytotoxicity of all compounds was evaluated in vitro against the HeLa and MDA-MB231 cancer cell lines, including 1 and 2 for comparison, using MTT assay. The treatment of the cells was performed with the synthesized compounds and gefitinib at 0, 1, 5, 10, 25, and 50 μM and incubated for 24 h in 50% DMSO. The IC50 values of the target compounds were reported in μM, using gefitinib as a standard. Our results indicated that all compounds exhibited significant in vitro cytotoxicity against both cell lines. While compounds 1-3 showed good activity, compounds 21-23 were found to be more potent than gefitinib. Thus, compounds 21-23 may be potential anticancer agents, with IC50 values ranging from 1.85 to 2.81 μM in relation to gefitinib (IC50 = 4.3 and 28.3 μM against HeLa and MDA-MB231 cells, respectively).
Journal of enzyme inhibition and medicinal chemistry, 2017
Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence... more Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a-h, 10a-h and 13a-c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC50 = 12.35 ± 0.12 and 12.00 ± 0.13 μM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC50 = 29.38 ± 1.24 μM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 1...
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...
The main objective of this work was to synthesize novel compounds with a benzo[de][1,2,4]triazolo... more The main objective of this work was to synthesize novel compounds with a benzo[de][1,2,4]triazolo[5,1-a]isoquinoline scaffold by employing (dioxo-benzo[de]isoquinolin-2-yl) thiourea as a building block. Molecular docking was conducted in the COX-2 active site to predict the plausible binding mode and rationalize the structure-activity relationship of the synthesized compounds. The structures of the synthesized compounds were confirmed by HREI-MS, and NMR spectra along with X-ray diffraction were collected for products 1 and 5. Thereafter, anti-inflammatory effect of molecules 1-20 was evaluated in vivo using carrageenan-induced paw edema method, revealing significant inhibition potency in albino rats with an activity comparable to that of the standard drugs indomethacin. Compounds 8, 9, 15 and 16 showed the highest anti-inflammatory activity. However, thermal sensitivity-hot plat test, a radiological examination and motor coordination assessment were performed to test the activity a...
Fungal infections threaten human health, particularly in immune-compromised patients worldwide. A... more Fungal infections threaten human health, particularly in immune-compromised patients worldwide. Although there are a large number of antifungal agents available, the desired clinical attributes for the treatment of fungal infections have not yet been achieved. Azoles are the mainstay class of the clinically used antifungal agents. In the current study, the synthesis, spectroscopic characterization, and antifungal activity of certain new oximino ethers Va-n bearing imidazole nuclei are reported. The (E)-configuration of the imine double bond of the synthesized compounds Va-n has been confirmed via single crystal X-ray analysis of compound Vi as a representative example of this class of compounds. The molecular structure of compound Vi was crystallized in the monoclinic, P2₁/c, a = 18.7879(14) Å, b = 5.8944(4) Å, c = 16.7621(12) Å, β = 93.063(3)°, V = 1855.5(2) ų, Z = 4. The in vitro antifungal activity of the synthesized compounds Va-n were evaluated using diameter of the inhibition...
Acta Crystallographica Section E Crystallographic Communications
In the title N-Mannich bases, 3-(adamantan-1-yl)-4-(4-fluorophenyl)-1-[(4-phenylpiperazin-1-yl)me... more In the title N-Mannich bases, 3-(adamantan-1-yl)-4-(4-fluorophenyl)-1-[(4-phenylpiperazin-1-yl)methyl]-4,5-dihydro-1H-1,2,4-triazole-5-thione (C29H34FN5S) (I), and 3-(adamantan-1-yl)-4-(4-fluorophenyl)-1-{[4-(2-methoxyphenyl)piperazin-1-yl]-methyl}-4,5-dihydro-1H-1,2,4-triazole-5-thione (C30H36FN5OS) (II), fluorophenyl, adamantane and piperazine moieties are linked to a planar triazole ring. There is an additional phenyl ring on the piperazine ring in (I) and a methoxyphenyl ring in (II). In compound (I), the fluorophenyl and phenyl rings are inclined to the triazole ring by 86.55 (13) and 60.52 (12)°, respectively, and the two aryl rings are inclined to one another by 66.37 (13)°. In compound (II), the corresponding dihedral angles are 83.35 (13), 71.38 (15) and 11.97 (16)°, respectively. The crystal structure of (I) shows pairs of C—H...F hydrogen bonds forming inversion dimers, while in the crystal of compound (II), in addition to the C—H...F hydrogen bonds that generate chains p...
Zeitschrift für Kristallographie - New Crystal Structures
C 27 H 19 N5O5S, monoclinic, P21/c (no. 14), a = 14.2789(4) Å, b = 27.3722(9) Å, c = 13.0126(4) Å... more C 27 H 19 N5O5S, monoclinic, P21/c (no. 14), a = 14.2789(4) Å, b = 27.3722(9) Å, c = 13.0126(4) Å, β = 101.805
Background: Due to their interesting and versatile biological activity, thiophene-containing comp... more Background: Due to their interesting and versatile biological activity, thiophene-containing compounds have attracted the attention of both chemists and medicinal chemists. Some of these compounds have anticancer, antibacterial, antiviral, and antioxidant activity. In addition, the thiophene nucleus has been used in the synthesis of a variety of heterocyclic compounds.
Zeitschrift für Kristallographie - New Crystal Structures
C 16 H 13 NO 2 S, P¯ (no. 2), a = 8.0873(4) Å, b = 12.7820(7) Å, c = 13.5574 Å, α = 74.880(2)°, β... more C 16 H 13 NO 2 S, P¯ (no. 2), a = 8.0873(4) Å, b = 12.7820(7) Å, c = 13.5574 Å, α = 74.880(2)°, β = 75.421(2)°, γ = 76.391(2)°, V = 1287.61(12) Å 3 , Z = 4, Rgt(F) = 0.0413, wR ref (F 2 ) = 0.1075, T = 100 K.
Zeitschrift für Kristallographie - New Crystal Structures
Crystal structure of (16S)-12,16-epoxy-11, 14-dihydroxy-17(15/16)-abeo-3a,18-cyclo-8,11,13abietat... more Crystal structure of (16S)-12,16-epoxy-11, 14-dihydroxy-17(15/16)-abeo-3a,18-cyclo-8,11,13abietatrien-7-one, C 20 H 24 O 4 Abstract C 20 H 24 O4, orthorhombic, P212121, a = 8.3007(4) Å, b = 12.0111 Å, c = 17.0604(9) Å, V = 1700.93(15) Å 3 , Z = 4, Rgt(F) = 0.0621, wR ref (F 2 ) = 0.1413, T = 296(2) K.
Zeitschrift für Kristallographie - New Crystal Structures
C 19 H 18 O4, orthorhombic, Pbcn, a = 21.1472(8) Å, b = 9.7978(4) Å, c = 14.5181(6) Å, V = 3008.1... more C 19 H 18 O4, orthorhombic, Pbcn, a = 21.1472(8) Å, b = 9.7978(4) Å, c = 14.5181(6) Å, V = 3008.1(2) Å 3 , Z = 8, Rgt(F) = 0.0520, wR ref (F 2 ) = 0.1194, T = 100(2).
Journal of Enzyme Inhibition and Medicinal Chemistry
2017) Synthesis, in vitro antitumour activity, and molecular docking study of novel 2-substituted... more 2017) Synthesis, in vitro antitumour activity, and molecular docking study of novel 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinone analogues, ABSTRACT A novel series of 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinones 1-20 was synthesised and evaluated for in vitro antitumour activity. N-(4-Chlorophenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio)acetamide (7) and N-(3,4,5 trimethoxybenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide (19) exhibited excellent antitumour properties, with mean growth inhibitory concentration (GI 50 ) of 17.90 and 6.33 mM, respectively, compared with those of 5-fluorouracil 5-FU, gefitinib, and erlotinib (mean GI 50 : 18.60, 3.24, and 7.29 mM, respectively). Comparison of the GI 50 (mM) values of compounds 7 and 19 versus those of 5-FU, gefitinib, and erlotinib against an in vitro subpanel of tumour cells lines showed that compounds 7 and 19 have activities almost equal to or higher than that of those standard drugs, especially against lung, CNS, and breast cancer cells. However, compounds 5, , and 20 exhibited effective antitumour activity against the different cell lines tested, with growth inhibition percentage (MGI%) of 19, 24, 19, 17, 16, 15, and 16, respectively. A modelling study was performed for compounds 7 and 19 by docking them into the EGFR kinase enzyme to study their mode of binding with the putative binding site.
The chlorinated ethanoanthracenes: 4,5,12-and 1,8,12-(trichloro-9,10-dihydro-9,10ethanoanthracene... more The chlorinated ethanoanthracenes: 4,5,12-and 1,8,12-(trichloro-9,10-dihydro-9,10ethanoanthracene-12-carbonitriles) (1 and 2), which are regioisomers, were synthesized and characterized using nuclear magnetic resonance ( 1 H-and 13 C-NMR) and infrared (IR) spectroscopic techniques. The structure of isomer 1 was further confirmed using a single-crystal X-ray technique. The relative stabilities of the title compounds were calculated using the density functional theory (DFT) method on the basis of their total energies and thermodynamic parameters. Isomer 1 is thermodynamically more stable than isomer 2 in the gas phase and in solution. The calculated molecular geometry of isomer 1 agreed well with the experimental X-ray structure. The atomic charge distribution at the different atomic sites was calculated using natural bond orbital analysis. Isomer 2 was predicted to be more polar than isomer 1.
Journal of Asian natural products research, Jan 31, 2017
Two new sesquiterpene lactones 3R, 8R-dihydroxygermacr-4(15),9(10)-dien-6S,7S,11RH,12,6-olide (1)... more Two new sesquiterpene lactones 3R, 8R-dihydroxygermacr-4(15),9(10)-dien-6S,7S,11RH,12,6-olide (1) and 1R, 8S-dihydroxy-11R,13-dihydrobalchanin(2), together with two known compounds 11-epiartapshin (3) and 3'-hydroxygenkwanin (4), were isolated from Artemisia sieberi. Their structures were elucidated by 1D, 2D NMR, MS, and X-ray diffraction. Compound 4 inhibited Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus with Minimal inhibitory concentration values of 50 and 25 μg/disk, respectively. All the isolated compounds exhibited moderate antifungal activities.
Journal of enzyme inhibition and medicinal chemistry, 2017
Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994.... more Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994. Adopting a structural rigidification approach, a novel series of 3-phenylthiazolo[3,2-a]benzimidazoles 4a-d was designed and synthesised, in an attempt to develop potent anticancer agent that can target the bulk of tumour cells and CSCs. The anti-proliferative activity of the synthesised compounds was evaluated against two cell lines, namely; colon cancer HT-29 and triple negative breast cancer MDA-MB-468 cell lines. Also, their inhibitory activity against the cell surface expression of CD133 was examined. In particular, compound 4b emerged as a promising hit molecule as it manifested good antineoplastic potency against both tested cell lines (IC50 = 9 and 12 μM, respectively), beside its ability to inhibit the cell surface expression of CD133 by 50% suggesting a promising potential of effectively controlling the tumour by eradicating the tumour bulk and inhibiting the proliferation of ...
Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiaz... more Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino)benzenesulfonamides (4a-m and 7a-g). All the newly prepared sulfonamides were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. In particular, hCA isoforms II and IX (tumor-associated) were more susceptible to inhibition by the synthesized derivatives, with KIs in the range of 2.6-598.2 nM for hCA II, and of 16.1-321 nM for hCA IX. All compounds (4a-m and 7a-g) were evaluated for their anti-proliferative activity against breast cancer MCF-7 and colorectal cancer Caco-2 cell lines. Compound 4c was found to be the most potent derivative against MCF-7 (IC50 = 3.96 ± 0.21 μM), while 4j was the most active member against Caco-2 cells (IC50 = 5.87 ± 0.37 μM). Compound 4c induced the intrinsic apoptotic mitochondrial pathway in MCF-7 cells; evidenced by the en...
European journal of medicinal chemistry, Jan 18, 2017
A small library of benzimidazole-fused pyrrolo[3,4-b]quinoline has been synthesized from readily ... more A small library of benzimidazole-fused pyrrolo[3,4-b]quinoline has been synthesized from readily available benzimidazole 2-carbaldehyde and various substituted arylamines in good to excellent yields utilizing an intramolecular Povarov reaction catalyzed by boron trifluoride diethyl etharate as the key final step. The compounds thus synthesized can be considered as decarbonyl analogues of the anticancer alkaloid luotonin A and were evaluated in a DNA relaxation assay for their ability to inhibit human topoisomerase I. Interestingly, two of the compounds showed a remarkable activity that is comparable to that of the standard drug camptothecin. The compounds were also evaluated for their cytotoxic effect in four highly aggressive human cancer cell lines, namely KB, MDA-MB231 (breast), LNCap (prostate), and HT1080 (fibrosarcoma). Some of the compounds obtained showed promising cytotoxicities for these four cell lines.
A new series of adamantane-isothiourea hybrid derivatives, namely 4-arylmethyl (Z)-N'-(adaman... more A new series of adamantane-isothiourea hybrid derivatives, namely 4-arylmethyl (Z)-N'-(adamantan-1-yl)-morpholine-4-carbothioimidates 7a-e and 4-arylmethyl (Z)-N'-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioimidates 8a-e were prepared via the reaction of N-(adamantan-1-yl)morpholine-4-carbothioamide 5 and N-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioamide 6 with benzyl or substituted benzyl bromides, in acetone, in the presence of anhydrous potassium carbonate. The structures of the synthesized compounds were confirmed by ¹H-NMR, (13)C-NMR, electrospray ionization mass spectral (ESI-MS) data, and X-ray crystallographic data. The in vitro antimicrobial activity of the new compounds was determined against certain standard strains of pathogenic bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 7b, 7d and 7e displayed potent broad-spectrum antibacterial activity, while compounds 7a, 7c, 8b, 8d and 8e were active against the tested Gram-positive bac...
In this study, a new series of quinazoline derivatives (3-26) was synthesized and characterized v... more In this study, a new series of quinazoline derivatives (3-26) was synthesized and characterized via physicochemical and spectral means. Treatment of 2-amino-5-methylbenzoic acid with butyl isothiocyanate resulted in the new 2-thioxoquinazolin-4-one (3). Alkylation and hydrazinolysis of the inherent thioxo group in (1-3) afforded the corresponding thioethers (4-23) and hydrazine derivatives (24 and 25), then 24 was further transformed into tricyclic derivative 26 via cyclocondensation reaction. Compounds 1 and 2, which were previously synthesized, were found to exhibit anticancer activity. The cytotoxicity of all compounds was evaluated in vitro against the HeLa and MDA-MB231 cancer cell lines, including 1 and 2 for comparison, using MTT assay. The treatment of the cells was performed with the synthesized compounds and gefitinib at 0, 1, 5, 10, 25, and 50 μM and incubated for 24 h in 50% DMSO. The IC50 values of the target compounds were reported in μM, using gefitinib as a standard. Our results indicated that all compounds exhibited significant in vitro cytotoxicity against both cell lines. While compounds 1-3 showed good activity, compounds 21-23 were found to be more potent than gefitinib. Thus, compounds 21-23 may be potential anticancer agents, with IC50 values ranging from 1.85 to 2.81 μM in relation to gefitinib (IC50 = 4.3 and 28.3 μM against HeLa and MDA-MB231 cells, respectively).
Journal of enzyme inhibition and medicinal chemistry, 2017
Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence... more Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a-h, 10a-h and 13a-c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC50 = 12.35 ± 0.12 and 12.00 ± 0.13 μM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC50 = 29.38 ± 1.24 μM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 1...
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Papers by Hazem Ghabbour