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Papers by Haitham Elleuch

Anti-melanogenesis potential of a new series of Morita-Baylis-Hillman adducts in B16F10 melanoma cell line, 2019

Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radi... more Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radiation. An excessive synthesis of melanin leads to hyperpigmentation disorders. Tyrosinase catalyzes the rate limiting steps on melanogenesis. Therefore, tyrosinase inhibitors have potential applications in medicine and cosmetic felds.
We carried out herein the screening of a family of cyclic Morita-Baylis-Hillman adducts (MBH) to fnd out their effects on tyrosinase activity and on melanogenesis in murine melanoma B16F10 cell line. Kinetic analysis of tyrosinase inhibition showed that compounds 1a (2-hydroxymethyl) cyclohex-2-enone) and 3f (diethyl (1-(6-
oxocyclohex-1-en-1-yl) ethyl-phosphonate) were competitive inhibitors, whereas the compound 2b (6-oxocyclohex-1-en-1-yl) ethyl acetate) was a non-competitive one. Additionally we have found that (1a, 2b and 3f) compounds had a strong melanogenesis inhibition effect in isobutylmethylxanthine (IBMX)-treated murine melanoma B16F10 cells when tested at low and non cytotoxic dose (10–50 µM), by attenuating the melanin production, intracellular tyrosinase activity and tyrosinase expression. Thus, we suggest that these compounds could be used as effective skin-whitening agents.

Transition-metal-free nucleophilic allylic substitutions of Morita–Baylis–Hillman bromides with aliphatic and aromatic amines, 2016

A simple protocol for the preparation of functionalized allylic amines under mild, transition-met... more A simple protocol for the preparation of functionalized allylic amines under mild, transition-metal-free conditions from the reaction of Morita–Baylis–Hillman (MBH) bromides with amines is described herein. The treatment of the MBH bromides with various amines in the presence of NaI and Et3N in aqueous acetone solution and at room temperature affords the corresponding functionalized allyl amines in moderate to good yields (45–87%). The reaction is rapid and carried out at room temperature.

First DMAP mediated direct conversion of Morita–Baylis–Hillman alcohols into γ ketoallylphosphonates, 2016

An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both... more An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both primary and secondary Morita–Baylis–Hillman (MBH) alcohols by trialkyl phosphites with or without DMAP, used as additive, and under solvent-free conditions, is described herein for the first time. Subsequently, a highly regioselective Luche reduction of the primary phosphonate 2a (R = H) gave the corresponding γ-hydroxyallylphosphonate 5 that further reacted with tosylamines in the presence of diiodine (15 mol %) as a catalyst, affording the corresponding SN2-type products 6a–d in 63 to 70% isolated yields. Alternatively, the alcohol 5 produced the corresponding acetate 7 which, mediated by Ce(III), was successfully converted into the corresponding γ-aminoallylphosphonates 8a–d.
Beilstein J. Org. Chem. 2016, 12, 2906–2915.

Potential antioxidant activity of Morita-Baylis-Hillman adducts, 2018

The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encourage... more The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encouraged us to synthesize new series of products belonging to this class of compounds, possessing different functionalities and exhibiting potential antioxidant activity.
As part of our on-going program on targeting molecules with antioxidant activity, we describe herein different DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activities of MBH alcohols and their derivatives including acetates, phosphonates and hydrazonophosphonates. The obtained results showed that the strongest DPPH radical scavenging activity was observed in the case of hydrazonophosphonates in comparison to the other MBH derivatives.

Synthesis, spectroscopic characterization and solution behavior of new tin tetrachloride adducts with g-keto allyl phosphonates, 2017

Four new octahedral complexes of the type [SnCl4L2] (L ¼ g-keto allyl phosphonate) (1e4) were pre... more Four new octahedral complexes of the type [SnCl4L2] (L ¼ g-keto allyl phosphonate) (1e4) were prepared and characterized by multinuclear (1H, 13C, 31P and 119Sn) NMR, IR spectroscopy and elemental analysis.
The NMR data show, as expected, that these complexes exist in solution as mixtures of cis and trans isomers. More importantly, the solution structure was confirmed by 119Sn NMR spectra which show two triplets corresponding to the two isomers. In addition, the solution behavior of these complexes in the presence of excess ligand was studied by variable temperature NMR using the coalescence temperature method. The metal-ligand exchange activation energies were therefore determined and found to be in the range 57e60 kJ/mol. The effect of remote substituents on the metal-ligand interaction was studied and compared with closely related tin-phosphoryl complexes.
1127 (2017) 169-174

Chemoselective reaction of ethane-1,2-dithiol, hydrazines, and hydroxylamine onto γ-keto allyl phosphonates and phosphine oxides, 2017

An efficient protocol involving highly chemoselective reaction of ethane-1,2-dithiol, hydroxylami... more An efficient protocol involving highly chemoselective reaction of ethane-1,2-dithiol, hydroxylamine, and hydrazine derivatives with a series of γ-keto allyl phosphonates in the presence of p-toluene sulfonic acid (PTSA), is described herein. All the synthesized compounds are obtained in 76-98% yields and fully characterized.

Synthesis of a Series of γ‑Keto Allyl Phosphonates, 2016

Under solvent-free conditions and at 80 °C, a DMAP- or imidazole-mediated clean and rapid convers... more Under solvent-free conditions and at 80 °C, a DMAP- or imidazole-mediated clean and rapid conversion of cyclic Morita−Baylis−Hillman (MBH) acetates into the corresponding γ-keto allyl phosphonates in 70−93% yields is described herein. This allylic nucleophilic substitution works well with primary and secondary acetates bearing, at the β′-position, linear or branched alkyl groups and aryl groups.

Anti-melanogenesis potential of a new series of Morita-Baylis-Hillman adducts in B16F10 melanoma cell line, 2019

Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radi... more Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radiation. An excessive synthesis of melanin leads to hyperpigmentation disorders. Tyrosinase catalyzes the rate limiting steps on melanogenesis. Therefore, tyrosinase inhibitors have potential applications in medicine and cosmetic felds.
We carried out herein the screening of a family of cyclic Morita-Baylis-Hillman adducts (MBH) to fnd out their effects on tyrosinase activity and on melanogenesis in murine melanoma B16F10 cell line. Kinetic analysis of tyrosinase inhibition showed that compounds 1a (2-hydroxymethyl) cyclohex-2-enone) and 3f (diethyl (1-(6-
oxocyclohex-1-en-1-yl) ethyl-phosphonate) were competitive inhibitors, whereas the compound 2b (6-oxocyclohex-1-en-1-yl) ethyl acetate) was a non-competitive one. Additionally we have found that (1a, 2b and 3f) compounds had a strong melanogenesis inhibition effect in isobutylmethylxanthine (IBMX)-treated murine melanoma B16F10 cells when tested at low and non cytotoxic dose (10–50 µM), by attenuating the melanin production, intracellular tyrosinase activity and tyrosinase expression. Thus, we suggest that these compounds could be used as effective skin-whitening agents.

Transition-metal-free nucleophilic allylic substitutions of Morita–Baylis–Hillman bromides with aliphatic and aromatic amines, 2016

A simple protocol for the preparation of functionalized allylic amines under mild, transition-met... more A simple protocol for the preparation of functionalized allylic amines under mild, transition-metal-free conditions from the reaction of Morita–Baylis–Hillman (MBH) bromides with amines is described herein. The treatment of the MBH bromides with various amines in the presence of NaI and Et3N in aqueous acetone solution and at room temperature affords the corresponding functionalized allyl amines in moderate to good yields (45–87%). The reaction is rapid and carried out at room temperature.

First DMAP mediated direct conversion of Morita–Baylis–Hillman alcohols into γ ketoallylphosphonates, 2016

An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both... more An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both primary and secondary Morita–Baylis–Hillman (MBH) alcohols by trialkyl phosphites with or without DMAP, used as additive, and under solvent-free conditions, is described herein for the first time. Subsequently, a highly regioselective Luche reduction of the primary phosphonate 2a (R = H) gave the corresponding γ-hydroxyallylphosphonate 5 that further reacted with tosylamines in the presence of diiodine (15 mol %) as a catalyst, affording the corresponding SN2-type products 6a–d in 63 to 70% isolated yields. Alternatively, the alcohol 5 produced the corresponding acetate 7 which, mediated by Ce(III), was successfully converted into the corresponding γ-aminoallylphosphonates 8a–d.
Beilstein J. Org. Chem. 2016, 12, 2906–2915.

Potential antioxidant activity of Morita-Baylis-Hillman adducts, 2018

The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encourage... more The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encouraged us to synthesize new series of products belonging to this class of compounds, possessing different functionalities and exhibiting potential antioxidant activity.
As part of our on-going program on targeting molecules with antioxidant activity, we describe herein different DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activities of MBH alcohols and their derivatives including acetates, phosphonates and hydrazonophosphonates. The obtained results showed that the strongest DPPH radical scavenging activity was observed in the case of hydrazonophosphonates in comparison to the other MBH derivatives.

Synthesis, spectroscopic characterization and solution behavior of new tin tetrachloride adducts with g-keto allyl phosphonates, 2017

Four new octahedral complexes of the type [SnCl4L2] (L ¼ g-keto allyl phosphonate) (1e4) were pre... more Four new octahedral complexes of the type [SnCl4L2] (L ¼ g-keto allyl phosphonate) (1e4) were prepared and characterized by multinuclear (1H, 13C, 31P and 119Sn) NMR, IR spectroscopy and elemental analysis.
The NMR data show, as expected, that these complexes exist in solution as mixtures of cis and trans isomers. More importantly, the solution structure was confirmed by 119Sn NMR spectra which show two triplets corresponding to the two isomers. In addition, the solution behavior of these complexes in the presence of excess ligand was studied by variable temperature NMR using the coalescence temperature method. The metal-ligand exchange activation energies were therefore determined and found to be in the range 57e60 kJ/mol. The effect of remote substituents on the metal-ligand interaction was studied and compared with closely related tin-phosphoryl complexes.
1127 (2017) 169-174

Chemoselective reaction of ethane-1,2-dithiol, hydrazines, and hydroxylamine onto γ-keto allyl phosphonates and phosphine oxides, 2017

An efficient protocol involving highly chemoselective reaction of ethane-1,2-dithiol, hydroxylami... more An efficient protocol involving highly chemoselective reaction of ethane-1,2-dithiol, hydroxylamine, and hydrazine derivatives with a series of γ-keto allyl phosphonates in the presence of p-toluene sulfonic acid (PTSA), is described herein. All the synthesized compounds are obtained in 76-98% yields and fully characterized.

Synthesis of a Series of γ‑Keto Allyl Phosphonates, 2016

Under solvent-free conditions and at 80 °C, a DMAP- or imidazole-mediated clean and rapid convers... more Under solvent-free conditions and at 80 °C, a DMAP- or imidazole-mediated clean and rapid conversion of cyclic Morita−Baylis−Hillman (MBH) acetates into the corresponding γ-keto allyl phosphonates in 70−93% yields is described herein. This allylic nucleophilic substitution works well with primary and secondary acetates bearing, at the β′-position, linear or branched alkyl groups and aryl groups.