Studies on the Chemical Reactivity of 6,8-dibromo-7-hydroxychromone-3-carboxaldehyde Towards Some Nitrogen Nucleophilic Reagents

A. Ibrahim M., M. El-Gohary N.

E. Ali T., A. Abdel-Aziz S., M. El-Edfawy S., A. Mohamed E., M. Abdel-Kariem S.

Ibrahim M.A.

A simple and convenient synthesis of a novel series of pyrido[1,2- a ]benzimidazoles was efficiently achieved from the condensation reactions of 1 H -benzimidazol-2-ylacetonitrile ( 1 ) with some 3-substituted chromones, chromone-3-carboxylic acids, chromone-3-carboxamides, ethyl chromone-3-carboxylates and chromone-3-carbonitriles. Reaction of compound 1 with 2-aminochromone-3-carboxaldehydes produced 2-amino-3-(1 H -benzimidazol-2-yl)chromeno[2,3- b ]pyridines. The reaction mechanisms and spectral data were also discussed.

A. Ibrahim M., E. Ali T., M. El-Kazak A., M. Mohamed A.

Goel R., Sharma V., Budhiraja A., Ishar M.P.

An efficient synthesis of novel antifungal 3a,9a-dihydro-1-ethoxycarbonyl-1-cyclopenteno[5,4-b]benzopyran-4-ones (10a-j) through 1,3-dipolar cycloaddition of all carbon 1,3-dipole (7) with substituted 3-formylchromones (8a-j) has been developed. The synthesized compounds were characterized spectroscopically and evaluated in vitro for antifungal activity against various strains. Some of the compounds 10b, 10d and 10i exhibit significant inhibitory potential against Aspergillus niger, Saccahromyces cerevisiae and Candida albicans.

Al-Shaalan N.H.

The Schiff base hydrazone ligand HL was prepared by the condensation reaction of 7-chloro-4-quinoline with o-hydroxyacetophenone. The ligand behaves either as monobasic bidentate or dibasic tridentate and contain ONN coordination sites. This was accounted for be the presence in the ligand of a phenolic azomethine and imine groups. It reacts with Cu(II), Ni(II), Co(II), Mn(II), UO2 (VI) and Fe(II) to form either mono- or binuclear complexes. The ligand and its metal complexes were characterized by elemental analyses, IR, NMR, Mass, and UV-Visible spectra. The magnetic moments and electrical conductance of the complexes were also determined. The Co(II), Ni(II) and UO2 (VI) complexes are mononuclear and coordinated to NO sites of two ligand molecules. The Cu(II) complex has a square-planar geometry distorted towards tetrahedral, the Ni(II) complex is octahedral while the UO2 (VI) complex has its favoured heptacoordination. The Co(II), Mn(II) complexes and also other Ni(II) and Fe(III) complexes, which were obtained in the presence of Li(OH) as deprotonating agent, are binuclear and coordinated via the NNNO sites of two ligand molecules. All the binuclear complexes have octahedral geometries and their magnetic moments are quite low compared to the calculated value for two metal ions complexes and thus antiferromagnetic interactions between the two adjacent metal ions. The ligand HL and metal complexes were tested against a strain of Gram +ve bacteria (Staphylococcus aureus), Gram −ve bacteria (Escherichia coli), and fungi (Candida albicans). The tested compounds exhibited high antibacterial activities.

Isaad J., Achari A.E.

A simple water-soluble aldehyde functionalized chromone 5 was utilized as a doubly activated Michael acceptor type of chemodosimeter for cyanide in water. The water solubility of the probe 5 is due to the incorporation of two glycerol units on the starting prepared chemodosimeter. This sensory system is able to selectively distinguish cyanide among fluoride and many other anions at micromolar concentrations and instantly detect cyanide in water at ambient temperatures with a detection limit down to 1.0 mM. Thus, the chemodosimeter 5 was applied to the quantitative determination of cyanide anion in drinking water sample (drinking water from commence).

Grolik J., Zwoliński K., Sieroń L., Eilmes J.

The bis(2-hydroxybenzoyl) derivative of dibenzotetraaza[14]annulene was employed as a substrate for producing new lacunar-type receptors. Alkylation of both phenolic OH groups using aliphatic dibromides and ditosylates efficiently leads to the expected bridged products without recourse to a high dilution procedure. Four new dibenzotetraaza[14]annulene-based lacunar receptors, and one unbridged open-chain bis-octoxy analogue have been synthesized. Synthetic procedures, analytical and spectroscopic characterization are reported. Conformations of the macrocyclic rings in the products as well as non-covalent interactions are discussed on the basis of their crystal structures.

Oh K., Jeon H.B., Han Y., Lee Y., Park J., Lee S., Yang D., Kwon M., Shin J., Lee H.

The synthesis and bioactivity of bromophenols are described. A new series of bromophenols was synthesized by reactions of corresponding phenol analogs with bromine. The synthesized compounds were tested for inhibitory activity against isocitrate lyase (ICL) of Candida albicans and antimicrobial activity against Gram-positive and, Gram-negative bacteria and fungi. Among the synthesized bromophenols, bis(3-bromo-4,5-dihydroxyphenyl)methanone ( 11 ) and (3-bromo-4,5-dihydroxyphenyl)(2,3-dibromo-4,5-dihydroxyphenyl)methanone ( 12 ) displayed potent inhibitory activities against ICL, showing a stronger inhibitory effects than were found with natural bromophenol 1 . The preliminary structure–activity relationships were investigated in order to determine the essential structural requirements for the inhibitory activities of these compounds against ICL of C. albicans .

Mohammed Musthafa T.N., Siddiqui Z.N., Husain F.M., Ahmad I.

A series of novel chromone derivatives have been synthesized employing 3-formylchromones and 5-acetyl-1,3-dimethylbarbituric acid as starting materials both under conventional heating method and microwave irradiation technique in good yields. The synthesized compounds were screened in vitro antibacterial activity against the representative panel of two Gram-positive bacteria and two Gram-negative bacteria. The synthesized compounds were also tested for their inhibitory action against three strains of fungus. The various compounds show potent inhibitory action against test organisms.

Steenackers H.P., Levin J., Janssens J.C., Weerdt A.D., Balzarini J., Vanderleyden J., De Vos D.E., De Keersmaecker S.C.

A library of 25 3-alkyl-5-methylene-2(5 H )-furanones and two 3-alkylmaleic anhydrides was synthesized and tested for the antagonistic effect against the biofilm formation by Salmonella Typhimurium and the quorum sensing regulated bioluminescence of Vibrio harveyi . A library of 25 1′-unsubstituted and 1′-bromo or 1′-acetoxy 3-alkyl-5-methylene-2( 5H )-furanones and two 3-alkylmaleic anhydrides was synthesized using existing and new methods. This library was tested for the antagonistic effect against the biofilm formation by Salmonella Typhimurium and the quorum sensing regulated bioluminescence of Vibrio harveyi . The length of the 3-alkyl chain and the bromination pattern of the ring structure were found to have a major effect on the biological activity of the 1′-unsubstituted furanones. Remarkably, the introduction of a bromine atom on the 1′ position of the 3-alkyl chain did drastically enhance the activity of the furanones in both biological test systems. The introduction of an acetoxy function in this position did in general not improve the activity. Finally, the potential of the (bromo)alkylmaleic anhydrides as a new and chemically easily accessible class of biofilm and quorum sensing inhibitors was demonstrated.

Sosnovskikh V.Y., Moshkin V.S.

3-(Diaminomethylidene)chromane-2,4-diones were synthesized from 4-oxo-4H-chromene-3-carbaldehyde and hydroxylamine in the presence of sodium hydroxide without isolation of intermediate products. Reflux of 3-(diaminomethylidene)chromane-2,4-dione in acetic anhydride gives rise to their monoacetyl derivatives at one of the amino groups.

Ali T.E., Ibrahim M.A.

Three series of novel fused nitrogen heterocyclic systems such as 1,2,4-triazolo[1,5-α ] pyridines (5-7 and 9), pyrido[1,2-b][1,2,4]triazines (10, 11, 13 and 15), and pyrido[1,2-b][1,2,4]triazepines (17, 18, 20 and 22) linked with a chromone moiety were synthesized from the key intermediate 1,6-diamino-(6-chloro-4-oxo-4H-chromen-3-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile (4) with some electrophilic reagents. The structures of the novel compounds were established by elemental analyses and spectral data. All the products were also screened invitro for their antimicrobial activity. Compounds 7, 9 and 15 showed the highest activities when compared with the reference drugs.

Ibrahim M.A., El-Mahdy K.M.

Some new hydrazone derivatives 3a–e have been obtained from 2-amino-3-formylchromone (1). Heterocyclization of thiocarbohydrazone derivative 3e via reaction with some electrophilic reagents afforded 1,2,4-triazoles 6–8 and 1,2,4-triazines 9–13. Condensation reactions of aldehyde 1 with o-aminoaldehydes and/or ketones afforded some new isolated and condensed heterocyclic systems 17, 19, and 20. The newly synthesized compounds were screened for their antimicrobial activity.

Ibrahim M.A.

A new series of 2,3-disubstituted-5-oxochromeno[2,3-b]pyridine derivatives has been obtained throughout a 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed reaction of 4-oxo-4H-chromene-3-carbonitrile with various active methyl and methylene compounds. The Friedlander reaction of 2-amino-4-oxo-4H-chromene-3-carboxaldehyde with the same active methyl and methylene compounds led to the identical products, suggesting that basic catalyzed ring rearrangement took place during the course of reaction.

Ibrahim M.A., Badran A., Attai M.M., El-Gohary N.M., Hussain Z., Farouk O.

The electron deficient centers in α,β-unsaturated ketone 3 are C-2 and C=O of chromone moieties as well as C=O and H-β of α,β-unsaturated ketone segment. To investigate the reactivity of various electron deficient centers and to synthesize some heterocyclic systems, compound 3 was allowed to react with some binucleophilic reagents. The antimicrobial activity of some compounds showed a notable inhibitory effect on the microorganisms that were being studied. The synthesized compounds were verified by spectral and analytical data. The structure of the prepared compounds were optimized at the DFT/B3LYP level of theory employing 6-311G(d,p). Density Functional Theory (DFT) was used to compute the chemical reactivity descriptors. Compound 9 is more stable and less reactive than other compounds. MEP mapping was applied at the same computational level to identify the favored locations for electrophilic and nucleophilic assault, providing additional insight into the regioselectivity in the desired reaction. Moreover, the most reactive sites of compound 3 were investigated by Fukui function descriptor using Mulliken charges. The 13C and 1H-NMR spectra of the prepared compound were measured experimentally in DMSO, and correlated with the theoretical calculations that performed by 6-311G(d,p) of DFT-B3LYP method. All compounds met Veber's and Lipinski's requirements according to in silico predictions made with the SwissADME online server, suggesting the possibility for usage as oral active drugs. The synthesized compounds were also subjected to molecular docking studies to investigate their binding pattern and affinity for the CDKs active site and correlated with antimicrobial data.

Ibrahim M.A., Abdel-Megid M., Farouk O., El-Gohary N.M., Nabeel A.I., Attai M.M., Badran A.

Halim S.A., Badran A., Roushdy N., Ahmed E.M., Ibrahim M.A., Farag A.A.

The novel 6-ethyl-3-{[(3-cyano-4,6-dimethyl-2-oxo-1,2-dihydropyridin-1-yl)imino] methyl}-4H-pyrano[3,2-c]quinoline-4,5(6H)-dione (EPIMPQ) was obtained by reacting pyrano[3,2-c]quinoline-3-carboxaldehyde (1) with 1-amino-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (2). For the first time, the EPIMPQ thin films were produced using simple, easy, and efficient thermal evaporation under a vacuum. Based on its correct elemental analysis and spectrum data, the structure of EPIMPQ was inferred using FTIR, 1H NMR, 13C NMR, and mass spectra. Density Functional Theory (DFT/B3LYP) methods using the 6–311++G(d,p) basis set were used to achieve the optimized molecular structure and the related geometrical parameters. The molecular electrostatic potential (MEP), chemical activity characteristics, and non-linear optical (NLO) properties have also been investigated. Optical spectroscopy was used to determine the optical band gap and other dispersion parameters of the films, which was vital in the development of photodiode devices. The optical band transitions of EPIMPQ were investigated, and the direct optical gap was determined to be 2.75 eV and 3.06 eV. Furthermore, the current-voltage (J-V) characteristics of EPIMPQ film-based devices under the illumination of 80 mW/cm2 show that as the reverse bias is increased, the photoresponsivity of EPIMPQ film-based devices increases. The attractive phototransient features of the produced devices show that they can be employed as photodiode devices.

Ahmed A., Ibrahim M.A., Badran A.

Condensation reaction of 3-formylchromone (1) with 1-ethyl-4-hydroxyquinolin-2(1H)-one (2) in glacial acetic acid afforded the condensation product 4; in 1:2 molar ratio. Compound 4 was used as precursor for construction of some propenones linked pentacyclic quinolinopyranoquinoline. Ring opening of chromone moiety in compound 4 was achieved via reactions with a diversity of primary amines leading to propenone derivatives 5-7 and 11-13 in good yields (62-73%). All propanone derivatives exist in the E-configuration as deduced from their 1H NMR spectra. DFT/B3LYP functional was used with 6-311+G(d,p) basis sets for all theoretical calculations. Based on optimized geometry, the chemical potential (Pi), electronegativity (χ), hardness (η) and electrophilicity index (ω) are some of the global reactivity descriptors that were computed to predict the chemical reactivity of the studied compounds; where compound 13 has the highest softness and electrophilicity index (ω). Moreover, to determine the relative stability of compounds 1-4, the thermodynamic parameters such as enthalpy and free energies of the reactions were computed; where compound 4 has the lowest free energy of reaction (-439.61 kcal/mol), so its formation is spontaneous. By utilizing molecular electrostatic potential (MEP) and local-based descriptors in the form of condensed Fukui functions of the starting compound 4, the susceptible sites for electrophilic and nucleophilic attack were investigated. For compound 4, fk+ and Δfk values are more positive at C9 and C7 than other sites and these sites have more electrophilic characters. Therefore, nucleophilic attacks began at C9. On the other hand, the GIAO approximation was used to compute the 1H and 13C-NMR chemical shift values in the ground state, of the present compounds, where a good agreement was observed between experimental and theoretical chemical shift results. Further, the calculated first hyperpolarizability of prepared compounds are found to be greater than that of urea. So, these compounds are ideal candidates for non-linear optical applications. The synthesized compounds were screened for their antimicrobial and anticancer activities showing variable inhibitory action. Compounds 5, 7 and 13 were more effective antimicrobial candidates against all tested microorganisms, while compound 13 was the most active against HepG-2 cell lines. Furthermore, a quantitative structure–activity relationship (QSAR) (relationship between DFT calculated descriptors and biological activities pIC50) model was built by applying multiple linear regression (MLR) on the synthesized compounds as anticancer agents. Moreover, Lipinski's rule of five indicates no problems with oral bioavailability of the prepared compounds.

Alshaye N.A., Ibrahim M.A.

Kustin R.P., Chernov N.M., Shutov R.V., Yakovlev I.P.

Reactions of ethyl 3-(4-oxo-4H-chromen-3-yl)prop-2-enoates with 1,2-binucleophilic agents (hydrazine, phenylhydrazine, hydroxylamine) leads to the formation of some new pyrazole and isoxazole derivatives. The reactions proceed under mild conditions (ethanol, room temperature) to form the title products with high yields (71–99%).

Gorbulenko N., Shokol T., Khilya V.

Heterocycle modified chromones are attracting increasing attention as novel potential therapeutic agents due to their effective bioactivities and low toxicity. This review describes all strategies and versatile synthons that have been developed for the synthesis of isoflavone heterocyclic analogs containing isolated 5-member heterocyclic rings with three identical or different heteroatoms. Their biological activity is also presented.

Ibrahim M.A.

A. Ibrahim M., Badran A.

Shatokhin S.S., Tuskaev V.A., Gagieva S.C., Markova A.A., Pozdnyakov D.I., Melnikova E.K., Bulychev B.M., Oganesyan E.T.

• One-pot metal free synthesis of new hybride molecules. • 9 new compounds have been synthesized and characterized. • Cytotoxicity against human colon cancer cells HCT116 and breast cancer cells MCF7. • Antioxidant activity comparable to the reference drug Trolox. The reaction of 3-formylchromones and 4-((2-aminophenyl)imino)-2,6-di‑tert-butylcyclohexa-2,5-dienone gave a series of N-substituted benzimidazole derivatives, characterized by 1 H and 13 C NMR spectroscopy, mass spectrometry and elemental analysis. The molecular structures of compounds 1 and 4 were determined by single crystal X-ray diffraction studies. Compounds 1–8 exhibit cytotoxic activity against human colon cancer cells HCT116 and breast cancer cells MCF7 at submicromolar concentrations. Compound 6 is more active against tumor cells than non-malignant fibroblasts. Compounds 1, 3, 5 and 7 exhibit antioxidant activity comparable to the reference drug Trolox.

Badran A., El‐Gohary N.M., Ibrahim M.A., Hashiem S.H.

The reactivity of 3-substituted-6,8-dimethylchromone derivatives 1-5 was investigated toward selected nucleophilic reagents namely; 3-amino-1,2,4-triazole, 2-aminobenzimidazole, 7-chloro-4-hydrazinoquinoline, and 5,6-diphenyl-3-hydrazino-1,2,4-triazine. These nucleophiles were allowed to react with 6,8-dimethylchromone-3-carboxaldehyde (1) through condensation with the aldehyde group with opening of γ-pyrone ring giving compounds 6, 7, 10, and 11. Reactions with 6,8-dimethylchromone-3-carbonitrile (2), and 6,8-dimethylchromone-3-carboxylic acid (3) occur via attack at position 2 in both compounds followed by cycloaddition onto the nitrile function (in case of carbonitrile 2) or decarboxylation and cyclocondensation with the carbonyl group (in case of carboxylic acid 3). The current nucleophilic reagents reacted with simple condensation products 4 and 5, in boiling dioxane, through nucleophilic addition at the exocyclic vinyl bond followed by addition at the CN group giving 6,8-dimethylchromone linked various heterocyclic systems 20-27.

Ibrahim M.A., El‐Kazak A.M.

Ibrahim M.A., Hassanin H.M., Gabr Y., Alnamer Y.A.

Ibrahim M.A., Badran A., El-Gohary N.M., Hashiem S.H.

Ibrahim M.A., Halim S.A., Roushdy N., Farag A.A., El-Gohary N.M.

Condensation reaction of 6-formylvisnagin (1) with o-phenylenediamine afforded the novel 4-methoxyfuro[3`,2`:6,7]chromeno[2,3-e]benzo[b][1,4]diazepin-5(12H)-one (MFCBD). Hypothetical examination for the harmony geometries of the recently synthesized MFCBD has been done by Density Functional Theory (DFT) at the B3LYP/6-311G (d,p). The TD-DFT computations were explored for the electronic absorption spectra which the measured in polar and nonpolar solvents. The spectrophotometer measurements of both transmittance and reflectance in the range of 200–2500 nm were used for obtaining the significant optical constants. The optical absorption coefficient was analyzed to obtain the type of transition and found to be directly allowed with energy gaps of 1.1 and 2.93 eV. The dispersion parameters were extracted on the basis of the single oscillator mode using Wemple-DiDomenico and Selemier relationships. The dark and illuminated current density-voltage characteristics of the MFCBD-based heterojunction showed rectifying property which may be due to the formation of the organic/inorganic interface. The obtained phototransient current confirms the sensibility of the prepared heterojunction to the light illumination of 100 mW/cm2. The results support the applicability for the heterojunction in the field photodiode application.