Search results for: nucleophilic%20substitution
Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 27

Search results for: nucleophilic%20substitution

27 Theoretical Evaluation of the Effect of Solvent on the Feasibility of the Reaction of 2-Chlorobenzimidazole With Four N,N′-Cyclic Azomethine Imines to Construct Polycyclic Benzimidazoles

Authors: Mohamed Abdoul-Hakim, A. Zeroual, H. Garmes

Abstract:

In this work, we theoretically evaluated the reactivity of four 4-methyl-3-oxo-1,2-pyrazolidinium ylides with 2-Chlorobenzimidazole in MeOH in basic medium using DFT at the B3LYP/6-311+G(d,p) level. The analysis of the results shows that apart from its ability to retain its electrons, the deprotonated 2-Chlorobenzimidazole has a higher nucleophilic character. The reaction requires energy input to initiate the nucleophilic attack of the 2-Chlorobenzimidazole anion, and the inclusion of the solvent effect facilitates the formation of two regioisomers via an intramolecular vinyl nucleophilic substitution (SNVi). The transition states of this latter step are stabilized by charge transfer interactions σ(N-C) →σ*(C-Cl) for the more favorable regioisomer and n(N)→σ*(C-Cl) for the other regioisomer.

Keywords: benzonitrile N-oxide, DFT, intramolecular vinyl nucleophilic substitution (SNVi), 4-methyl-3-OXO-1, 2-pyrazolidinium ylides

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26 Theoretical Evaluation of Oxirane and Aziridine Opening Regioselectivity, Solvent Effect, and Strength of Nucleophilic and Nucleofugal Groups for the Preparation of Benzimidazole-Fused 1,4-Benzoxazepine

Authors: M. Abdoul-Hakim, a. Zeroual, H. Garmes

Abstract:

In a route for the preparation of 1,4-benzoxazepine fused to benzimidazole, the use of 2-(2-methoxyphenyl)-benzimidazole or styrene-derived N-tosylaziridine does not give the desired products. On this basis, we theoretically studied this reaction using DFT at the B3LYP/6-31+G(d) level. The analysis of the results shows a preferential nucleophilic attack of 2-(2-fluorophenyl)-benzimidazole on the terminal carbon atom of the Alkylepoxides and on the substituted carbon of N-tosylaziridine. Taking into account the solvent effect (DMF) makes the reactions spontaneous for the opening of epoxides and N-tosylaziridine and disfavors the intramolecularnucleophilic aromatic substitution reaction step of the products of the attack of 2-(2-methoxyphenyl)benzimidazole on an epoxide and those of the opening of N-tosylaziridine, which is consistent with the experiment.

Keywords: alkylepoxides, 4-benzoxazepine fused to benzimidazole imine, benzonitrile N-oxide, DFT, intramolecular nucleophilic aromatic substitution, N-tosyl aziridine

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25 Theoretical Evaluation of the Preparation of Polycyclic Benzimidazole Derivatives

Authors: M. Abdoul-Hakim, A. Zeroual, H. Garmes

Abstract:

In this work, the reaction of 2-chlorobenzimidazole with two distinct 1,3-dipoles such as benzonitrile N-oxide and an azomethine imine was carried out by DFT at the B3LYP/6-311+G(d, p) level to understand the effect of solvent (MeOH). The results show that MeOH has a significant effect on the evolution of the reaction. The charge transfer interactions n(O) → σ*(C-Cl), n(N)→σ*(C-Cl) and σ(N-C) →σ*(C-Cl) stabilize the transition states in an intramolecular nucleophilic substitution (SNi) step of the imidoyl group. Finally, this study provides a theoretical basis for the design of different polycyclic benzimidazole.

Keywords: azomethine imine, benzonitrile N-oxide, DFT, intramolecular nucleophilic substitution (SNi), polycyclic benzimidazole

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24 Prediction of the Regioselectivity of 1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides with 2(5H)-Furanones Using Recent Theoretical Reactivity Indices

Authors: Imad Eddine Charif, Wafaa Benchouk, Sidi Mohamed Mekelleche

Abstract:

The regioselectivity of a series of 16 1,3-dipolar cycloaddition reactions of nitrile oxides with 2(5H)-furanones has been analysed by means of global and local electrophilic and nucleophilic reactivity indices using density functional theory at the B3LYP level together with the 6-31G(d) basis set. The local electrophilicity and nucleophilicity indices, based on Fukui and Parr functions, have been calculated for the terminal sites, namely the C1 and O3 atoms of the 1,3-dipole and the C4 and C5 atoms of the dipolarophile. These local indices were calculated using both Mulliken and natural charges and spin densities. The results obtained show that the C5 atom of the 2(5H)-furanones is the most electrophilic site whereas the O3 atom of the nitrile oxides is the most nucleophilic centre. It turns out that the experimental regioselectivity is correctly reproduced, indicating that both Fukui- and Parr-based indices are efficient tools for the prediction of the regiochemistry of the studied reactions and could be used for the prediction of newly designed reactions of the same kind.

Keywords: 1, 3-dipolar cycloaddition, density functional theory, nitrile oxides, regioselectivity, reactivity indices

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23 Regioselective Nucleophilic Substitution of the Baylis-Hillman Adducts with Iodine

Authors: Zahid Shafiq, Li Liu, Dong Wang, Yong-Jun Chen

Abstract:

As synthetic organic methods are increasingly concerned with the growing importance of sustainable chemistry, iodine recently has emerged as an inexpensive, non-toxic, readily available and environmentally benign catalyst for various organic transformations to afford the corresponding products in high yields with high regio- and chemoselectivity. Iodine has found widespread applications in various organic synthesis such as Michael addition, coupling reaction and also in the multicomponent synthesis where it can efficiently activate C=C, C=O, C=N, and so forth. Iodine not only has been shown to be an efficient mild Lewis acid in various processes, but also due to its moderate nature, and water tolerance, reactions catalyzed by iodine can be effectively carried out in neutral media under very mild conditions. We have successfully described an efficient procedure for the nucleophilic substitution of the Baylis-Hillman (BH) adducts and their corresponding acetates with indoles to get α-substitution product using catalytic Silver Triflate (AgOTf) as Lewis acid. At this point, we were interested to develop an environmentally benign catalytic system to effect this substitution reaction and to avoid the use of metal Lewis acid as a catalyst. Since, we observed the formation of -product during the course of the reaction, we also became interested to explore the reaction conditions in order to control regioselectivity and to obtain both regioisomers. The developed methodology resulted in regioselective substitution products with controlled selectivity. Further, the substitution products were used to synthesize various Tri- and Tetracyclo Azepino indole derivatives via reductive amination.

Keywords: indole, regioselective, Baylis-Hillman, substitution

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22 Reactions of 4-Aryl-1H-1,2,3-Triazoles with Cycloalkenones and Epoxides: Synthesis of 2,4- and 1,4-Disubstituted 1,2,3-Triazoles

Authors: Ujjawal Kumar Bhagat, Kamaluddin, Rama Krishna Peddinti

Abstract:

The Huisgen’s 1,3-dipolar [3+2] cycloaddition of organic azides and alkynes often give the mixtures of both the regioisomers 1,4- and 1,5- disubstituted 1,2,3-triazoles. Later, in presence of metal salts (click chemistry) such as copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was used for the synthesis of 1,4-disubstituted 1,2,3-triazoles as a sole products regioselectively. Also, the ‘click reactions’ of Ruthenium-catalyzed azides-alkynes cycloaddition (RuAAC) is used for the synthesis of 1,5-disubstituted 1,2,3-triazoles as a single isomer. The synthesis of 1,4- and 1.5-disubstituted 1,2,3-triazoles has become the gold standard of ‘click chemistry’ due to its reliability, specificity, and biocompatibility. The 1,4- and 1,5-disubstituted 1,2,3-triazoles have emerged as one of the most powerful entities in the varieties of biological properties like antibacterial, antitubercular, antitumor, antifungal and antiprotozoal activities. Some of the 1,4,5-trisubstituted 1,2,3-triazoles exhibit Hsp90 inhibiting properties. The 1,4-disubstituted 1,2,3-triazoles also play a big role in the area of material sciences. The triazole-derived oligomeric, polymeric structures are the potential materials for the preparation of organic optoelectronics, silicon elastomers and unimolecular block copolymers. By the virtue of hydrogen bonding and dipole interactions, the 1,2,3-triazole moiety readily associates with the biological targets. Since, the 4-aryl-1H-1,2,3-triazoles are stable entities, they are chemically robust and very less reactive. In this regard, the addition of 4-aryl-1H-1,2,3-triazoles as nucleophiles to α,β-unsaturated carbonyls and nucleophilic substitution with the epoxides constitutes a powerful and challenging synthetic approach for the generation of disubstituted 1,2,3-triazoles. Herein, we have developed aza-Michael addition of 4-aryl-1H-1,2,3-triazoles to 2-cycloalken-1-ones in the presence of an organic base (DABCO) in acetonotrile solvent leading to the formation of disubstituted 1,2,3-triazoles. The reaction provides 1,4-disubstituted triazoles, 3-(4-aryl-1H-1,2,3-triazol-1-yl)cycloalkanones in major amount along with 1,5-disubstituted 1,2,3-triazoles, minor regioisomers with excellent combined chemical yields (upto99%). The nucleophilic behavior of 4-aryl-1H-1,2,3-triazoles was also tested in the ring opening of meso-epoxides in the presence of organic bases (DABCO/Et3N) in acetonotrile solvent furnishing the two regioisomers1,4- and 1,5-disubstituted 1,2,3-triazoles. Thus, the novelty of this methodology is synthesis of diversified disubstituted 1,2,3-triazoles under metal free condition.The results will be presented in detail.

Keywords: aza-Michael addition, cycloalkenones, epoxides, triazoles

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21 New Derivatives 7-(diethylamino)quinolin-2-(1H)-one Based Chalcone Colorimetric Probes for Detection of Bisulfite Anion in Cationic Micellar Media

Authors: Guillermo E. Quintero, Edwin G. Perez, Oriel Sanchez, Christian Espinosa-Bustos, Denis Fuentealba, Margarita E. Aliaga

Abstract:

Bisulfite ion (HSO3-) has been used as a preservative in food, drinks, and medication. However, it is well-known that HSO3- can cause health problems like asthma and allergic reactions in people. Due to the above, the development of analytical methods for detecting this ion has gained great interest. In line with the above, the current use of colorimetric and/or fluorescent probes as a detection technique has acquired great relevance due to their high sensitivity and accuracy. In this context, 2-quinolinone derivatives have been found to possess promising activity as antiviral agents, sensitizers in solar cells, antifungals, antioxidants, and sensors. In particular, 7-(diethylamino)-2-quinolinone derivatives have attracted attention in recent years since their suitable photophysical properties become promising fluorescent probes. In Addition, there is evidence that photophysical properties and reactivity can be affected by the study medium, such as micellar media. Based on the above background, 7-(diethylamino)-2-quinolinone derivatives based chalcone will be able to be incorporated into a cationic micellar environment (Cetyltrimethylammonium bromide, CTAB). Furthermore, the supramolecular control induced by the micellar environment will increase the reactivity of these derivatives towards nucleophilic analytes such as HSO3- (Michael-type addition reaction), leading to the generation of new colorimetric and/or fluorescent probes. In the present study, two derivatives of 7-(diethylamino)-2-quinolinone based chalcone DQD1-2 were synthesized according to the method reported by the literature. These derivatives were structurally characterized by 1H, 13C NMR, and HRMS-ESI. In addition, UV-VIS and fluorescence studies determined absorption bands near 450 nm, emission bands near 600 nm, fluorescence quantum yields near 0.01, and fluorescence lifetimes of 5 ps. In line with the foregoing, these photophysical properties aforementioned were improved in the presence of a cationic micellar medium using CTAB thanks to the formation of adducts presenting association constants of the order of 2,5x105 M-1, increasing the quantum yields to 0.12 and the fluorescence lifetimes corresponding to two lifetimes near to 120 and 400 ps for DQD1 and DQD2. Besides, thanks to the presence of the micellar medium, the reactivity of these derivatives with nucleophilic analytes, such as HSO3-, was increased. This was achieved through kinetic studies, which demonstrated an increase in the bimolecular rate constants in the presence of a micellar medium. Finally, probe DQD1 was chosen as the best sensor since it was assessed to detect HSO3- with excellent results.

Keywords: bisulfite detection, cationic micelle, colorimetric probes, quinolinone derivatives

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20 Chemical Modification of PVC and Its Surface Analysis by Means of XPS and Contact Angle Measurements

Authors: Ali Akrmi, Mohamed Beji, Ahmed Baklouti, Fatma Djouani, Philippe Lang, Mohamed M. Chehimi

Abstract:

Poly(vinyl chloride) (PVC) is a highly versatile polymer with excellent balance of properties and numerous applications such as water pipes, packaging and polymer materials of importance in the biomedical sector. However, depending on the applications, it is necessary to modify PVC by mixing with a plasticizer; surface modification using plasma, surface grafting or flame treatment; or bulk chemical modification which affects the entire PVC chains at an extent that can be tuned by the polymer chemist. The targeted applications are improvement of chemical resistance, avoiding or limitation of migration of toxic plasticizers, improvement of antibacterial properties, or control of blood compatibility.

Keywords: poly(vinyl chloride), nucleophilic substitution, sulfonylcarbamates, XPS

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19 A Density Functional Theory Study of Metal-Porphyrin Graphene for CO2 Hydration

Authors: Manju Verma, Parag A. Deshpande

Abstract:

Electronic structure calculations of hydrogen terminated metal-porphyrin graphene were carried out to explore the catalytic activity for CO2 hydration reaction. A ruthenium atom was substituted in place of carbon atom of graphene and ruthenium chelated carbon atoms were replaced by four nitrogen atoms in metal-porphyrin graphene system. Ruthenium atom created the active site for CO2 hydration reaction. Ruthenium-porphyrin graphene followed the mechanism of carbonic anhydrase enzyme for CO2 conversion to HCO3- ion. CO2 hydration reaction over ruthenium-porphyrin graphene proceeded via the elementary steps: OH- formation from H2O dissociation, CO2 bending in presence of nucleophilic attack of OH- ion, HCO3- ion formation from proton migration, HCO3- ion desorption by H2O addition. Proton transfer to yield HCO3- ion was observed as a rate limiting step from free energy landscape.

Keywords: ruthenium-porphyrin graphene, CO2 hydration, carbonic anhydrase, heterogeneous catalyst, density functional theory

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18 Molecular Electrostatic Potential in Z-3N(2-Ethoxyphenyl), 2-N'(2-Ethoxyphenyl) Imino Thiazolidin-4-one Molecule by Ab Initio and DFT Methods

Authors: Manel Boulakoud, Abdelkader Chouaih, Fodil Hamzaoui

Abstract:

In the present work we are interested in the determination of the Molecular electrostatic potential (MEP) in Z-3N(2-Ethoxyphenyl), 2-N’(2-Ethoxyphenyl) imino thiazolidin-4-one molecule by ab initio and Density Functional Theory (DFT) in the ground state. The MEP is related to the electronic density and is a very useful descriptor in understanding sites for electrophilic attack and nucleophilic reactions as well as hydrogen bonding interactions. First, geometry optimization was carried out using Hartree–Fock (HF) and DFT methods with 6-311G(d,p) basis set. In order to get more information on the molecule, its stability has been analyzed by natural bond orbital (NBO) analysis. Mulliken population analyses have been calculated. Finally, the molecular electrostatic potential (MEP) and HOMO-LUMO energy levels have been performed. The calculated HOMO and LUMO energies show also the charge transfer within the molecule. The energy gap obtained is about 4 eV which explain the stability of the studied compound. The obtained molecular electrostatic potential from the two methods confirms the nature of the electron charge transfer at the molecular shell and locate the electropositive part and the electronegative part in molecular scale of the title compound.

Keywords: DFT, ab initio, HOMO-LUMO, organic compounds

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17 Chiral Diphosphine Ligands and Their Transition Metal Diphosphine Complexes in Asymmetric Catalysis

Authors: Shannen Lorraine, Paul Maragh, Tara Dasgupta, Kamaluddin Abdur-Rashid

Abstract:

(R)-(4,4',6,6'-tetramethoxybiphenyl-2,2'-diyl)bis(diphenylphosphine) (R-Ph-Garphos), and (S)-(4,4',6,6'-tetramethoxybiphenyl-2,2'-diyl)bis(diphenylphosphine) (S-Ph-Garphos) are novel, nucleophilic, chiral atropisomeric ligands. The research explored the synthesis of chiral transition metal complexes containing these ligands and their applications in various asymmetric catalytic transformations. Herein, the transition metal complexes having ruthenium(II), rhodium(I) and iridium(I) metal centres will be discussed. These are air stable complexes and were characterized by CHN analysis, 1H, 13C, and 31P NMR spectroscopy, and polarimetry. Currently, there is an emphasis on 'greener' catalysts and the need for 'green' solvents in asymmetric catalysis. As such, the Ph-Garphos ligands were demethylated thereby introducing hydroxyl moieties unto the ligand scaffold. The facile tunability of the biaryl diphosphines led to the preparation of the (R)-(4,4',6,6'-tetrahydroxybiphenyl-2,2'-diyl)bis(diphenylphosphine) (R-Ph-Garphos-OH), and (S)-(4,4',6,6'-tetrahydroxybiphenyl-2,2'-diyl)bis(diphenylphosphine) (S-Ph-Garphos-OH) ligands. These were successfully characterized by CHN analysis, 1H, 13C, and 31P NMR spectroscopy, and polarimetry. The use of the Ph-Garphos and Ph-Garphos-OH ligands and their transition metal complexes in asymmetric hydrogenations will be reported. Additionally, the scope of the research will highlight the applicability of the Ph-Garphos-OH ligand and its transitional metal complexes as 'green' catalysts.

Keywords: catalysis, asymmetric hydrogenation, diphosphine transition metal complexes, Ph-Garphos ligands

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16 Theoretical Study of Acetylation of P-Methylaniline Catalyzed by Cu²⁺ Ions

Authors: Silvana Caglieri

Abstract:

Theoretical study of acetylation of p-methylaniline catalyzed by Cu2+ ions from the analysis of intermediate of the reaction was carried out. The study of acetylation of amines is of great interest by the utility of its products of reaction and is one of the most frequently used transformations in organic synthesis as it provides an efficient and inexpensive means for protecting amino groups in a multistep synthetic process. Acetylation of amine is a nucleophilic substitution reaction. This reaction can be catalyzed by Lewis acid, metallic ion. In reaction mechanism, the metallic ion formed a complex with the oxygen of the acetic anhydride carbonyl, facilitating the polarization of the same and the successive addition of amine at the position to form a tetrahedral intermediate, determining step of the rate of the reaction. Experimental work agreed that this reaction takes place with the formation of a tetrahedral intermediate. In the present theoretical work were investigated the structure and energy of the tetrahedral intermediate of the reaction catalyzed by Cu2+ ions. Geometries of all species involved in the acetylation were made and identified. All of the geometry optimizations were performed by the method at the DFT/B3LYP level of theory and the method MP2. Were adopted the 6-31+G* basis sets. Energies were calculated using the Mechanics-UFF method. Following the same procedure it was identified the geometric parameters and energy of reaction intermediate. The calculations show 61.35 kcal/mol of energy for the tetrahedral intermediate and the energy of activation for the reaction was 15.55 kcal/mol.

Keywords: amides, amines, DFT, MP2

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15 Synthesis and Characterization of Some New Diamines and Their Thermally Stable Polyimides

Authors: Zill-E-Huma, Humaira Siddiqi

Abstract:

This paper comprises of synthesis of thermally stable, mechanically strong polyimides. The polyimides were considered as most diverse class of polymers having unlimited applications. They were widely used as optical wave guides, in aerospace, for gas separation, as biomaterials and in electronics. Here the focus was to increase thermal stability and mechanical strength of polyimides. For this purpose two monomers were synthesized and were further polymerized via anhydrides to polyimides. The monomer diamines were synthesized by nucleophilic attack of aniline/2-fluoro aniline on hydroxy benzaldehydes. The two diamines synthesized were 3-(bis(4-aminophenyl) methyl) phenol (3OHDA) and 4-(bis(4-amino-3-fluorophenyl) methyl) phenol (2F4OHDA). These diamines were then reacted with dianhydrides to get polyimides. Two neat polyimides of both diamines with pyromellitic dianhydride (PMDA) and one neat polyimide of 4'-(Hexafluoroisopropylidene) diphthalic dianhydride (6FDA) with 3OHDA were synthesized. To compare the properties of synthesized polyimides like thermal stability, rigidity, flexibility, toughness etc. a commercial diamine oxydianiline (ODA) was used. Polyimides from oxydianiline were basically rigid. Nine different polyimide blends were synthesized from 3OHDA and commercial diamines ODA to have a better comparison of properties. TGA and mechanical testing results showed that with the increase in the percentage of 3OHDA in comparison to ODA the flexibility, toughness, strength of polyimide, thermal stability goes on increasing. So, synthesized diamines were responsible for improvement of properties of polyimides.

Keywords: diamines, dianhydrides, oxydianiline, polyimides

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14 Electrochemical Sensing of L-Histidine Based on Fullerene-C60 Mediated Gold Nanocomposite

Authors: Sanjeeb Sutradhar, Archita Patnaik

Abstract:

Histidine is one of the twenty-two naturally occurring essential amino acids exhibiting two conformations, L-histidine and D-histidine. D-Histidine is biologically inert, while L-histidine is bioactive because of its conversion to neurotransmitter or neuromodulator histamine in both brain as well as central nervous system. The deficiency of L-histidine causes serious diseases like Parkinson’s disease, epilepsy and the failure of normal erythropoiesis development. Gold nanocomposites are attractive materials due to their excellent biocompatibility and are easy to adsorb on the electrode surface. In the present investigation, hydrophobic fullerene-C60 was functionalized with homocysteine via nucleophilic addition reaction to make it hydrophilic and to successively make the nanocomposite with in-situ prepared gold nanoparticles with ascorbic acid as reducing agent. The electronic structure calculations of the AuNPs@Hcys-C60 nanocomposite showed a drastic reduction of HOMO-LUMO gap compared to the corresponding molecules of interest, indicating enhanced electron transportability to the electrode surface. In addition, the electrostatic potential map of the nanocomposite showed the charge was distributed over either end of the nanocomposite, evidencing faster direct electron transfer from nanocomposite to the electrode surface. This nanocomposite showed catalytic activity; the nanocomposite modified glassy carbon electrode showed a tenfold higher kₑt, the electron transfer rate constant than the bare glassy carbon electrode. Significant improvement in its sensing behavior by square wave voltammetry was noted.

Keywords: fullerene-C60, gold nanocomposites, L-Histidine, square wave voltammetry

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13 Synthesis, Structural, Spectroscopic and Nonlinear Optical Properties of New Picolinate Complex of Manganese (II) Ion

Authors: Ömer Tamer, Davut Avcı, Yusuf Atalay

Abstract:

Novel picolinate complex of manganese(II) ion, [Mn(pic)2] [pic: picolinate or 2-pyridinecarboxylate], was prepared and fully characterized by single crystal X-ray structure determination. The manganese(II) complex was characterized by FT-IR, FT-Raman and UV–Vis spectroscopic techniques. The C=O, C=N and C=C stretching vibrations were found to be strong and simultaneously active in IR and spectra. In order to support these experimental techniques, density functional theory (DFT) calculations were performed at Gaussian 09W. Although the supramolecular interactions have some influences on the molecular geometry in solid state phase, the calculated data show that the predicted geometries can reproduce the structural parameters. The molecular modeling and calculations of IR, Raman and UV-vis spectra were performed by using DFT levels. Nonlinear optical (NLO) properties of synthesized complex were evaluated by the determining of dipole moment (µ), polarizability (α) and hyperpolarizability (β). Obtained results demonstrated that the manganese(II) complex is a good candidate for NLO material. Stability of the molecule arising from hyperconjugative interactions and charge delocalization was analyzed using natural bond orbital (NBO) analysis. The highest occupied and the lowest unoccupied molecular orbitals (HOMO and LUMO) which is also known the frontier molecular orbitals were simulated, and obtained energy gap confirmed that charge transfer occurs within manganese(II) complex. Molecular electrostatic potential (MEP) for synthesized manganese(II) complex displays the electrophilic and nucleophilic regions. From MEP, the the most negative region is located over carboxyl O atoms while positive region is located over H atoms.

Keywords: DFT, picolinate, IR, Raman, nonlinear optic

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12 Benzene Sulfonamide Derivatives: Synthesis, Absorption, Distribution, Metabolism, and Excretion (ADME) Studies, Anti-proliferative Activity, and Docking Simulation with Theoretical Investigation

Authors: Asmaa M. Fahim

Abstract:

In this elucidation, we synthesized different heterocyclic compounds attached to Benzene sulfonamide moiety via (E)-N-(4-(3-(4-bromophenyl)acryloyl)phenyl)-4-methyl benzene sulfonamide which is obtained from Nucleophilic substitution reaction between 4-methylbenzene sulfonyl chloride and 1-(4-aminophenyl)ethan-1-one in pyridine to get N-(4-acetyl phenyl)-4-methyl benzenesulfonamide which reacted 4-bromobenzal dehyde undergoes aldol condensation in NaOH to afford the corresponding chalchone 4. Moreover, the reactivity of chalchone 4 showed several active methylene derivatives utilized the pressurized microwave irradiation as a green energy resource. Chalcone 4 was allowed to react with ethyl cyanoacetate and acetylacetone, respectively, at 70 °C with pressure under microwave reaction condition to afford the 5-cyano-6-oxo-1,2,5,6-tetrahydropyridin-2-yl)-4-methylbenzenesulfonamide 6 and N-(4'-acetyl-4''-bromo-5'-oxo-2',3',4',5'-tetrahydro-[1,1':3',1''-terphenyl]-4-yl)-4-methylbenzenesulfonamide 8 derivatives. Moreover, the reactivity of this sulphonamide chalchone with NH2NH2 in EtOH and acetic acid, which gave 2,5-dihydro-1H-imidazol-4-yl)-4-methyl benzenesulfonamide, 1H-pyrazol-3-yl)-4-methyl and reactivity with NH2OH.HCl gave isoxazol-3-yl)-4-methylbenzenesulfonamide derivatives. The synthesized compounds were screened for their ADME properties and directed to antitumor activity on HepG2 hepatocellular carcinoma and MCF-7 breast cancer and exhibited excellent behavior against standard drugs; these results were confirmed through molecular simulations with different proteins. Additionally, the Density Functional Theory analysis of optimized structures investigated their physical descriptors, FMO, ESP and MEP, which correlated with biological evaluation.

Keywords: synthesis, green chemistry, antitumor activity, DFT study

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11 A Rationale to Describe Ambident Reactivity

Authors: David Ryan, Martin Breugst, Turlough Downes, Peter A. Byrne, Gerard P. McGlacken

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An ambident nucleophile is a nucleophile that possesses two or more distinct nucleophilic sites that are linked through resonance and are effectively “in competition” for reaction with an electrophile. Examples include enolates, pyridone anions, and nitrite anions, among many others. Reactions of ambident nucleophiles and electrophiles are extremely prevalent at all levels of organic synthesis. The principle of hard and soft acids and bases (the “HSAB principle”) is most commonly cited in the explanation of selectivities in such reactions. Although this rationale is pervasive in any discussion on ambident reactivity, the HSAB principle has received considerable criticism. As a result, the principle’s supplantation has become an area of active interest in recent years. This project focuses on developing a model for rationalizing ambident reactivity. Presented here is an approach that incorporates computational calculations and experimental kinetic data to construct Gibbs energy profile diagrams. The preferred site of alkylation of nitrite anion with a range of ‘hard’ and ‘soft’ alkylating agents was established by ¹H NMR spectroscopy. Pseudo-first-order rate constants were measured directly by ¹H NMR reaction monitoring, and the corresponding second-order constants and Gibbs energies of activation were derived. These, in combination with computationally derived standard Gibbs energies of reaction, were sufficient to construct Gibbs energy wells. By representing the ambident system as a series of overlapping Gibbs energy wells, a more intuitive picture of ambident reactivity emerges. Here, previously unexplained switches in reactivity in reactions involving closely related electrophiles are elucidated.

Keywords: ambident, Gibbs, nucleophile, rates

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10 Rapid Formation of Ortho-Boronoimines and Derivatives for Reversible and Dynamic Bioconjugation Under Physiological Conditions

Authors: Nicholas C. Rose, Christopher D. Spicer

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The regeneration of damaged or diseased tissues would provide an invaluable therapeutic tool in biological research and medicine. Cells must be provided with a number of different biochemical signals in order to form mature tissue through complex signaling networks that are difficult to recreate in synthetic materials. The ability to attach and detach bioactive proteins from material in an iterative and dynamic manner would therefore present a powerful way to mimic natural biochemical signaling cascades for tissue growth. We propose to reversibly attach these bioactive proteins using ortho-boronoimine (oBI) linkages and related derivatives formed by the reaction of an ortho-boronobenzaldehyde with a nucleophilic amine derivative. To enable the use of oBIs for biomaterial modification, we have studied binding and cleavage processes with precise detail in the context of small molecule models. A panel of oBI complexes has been synthesized and screened using a novel Förster resonance energy transfer (FRET) assay, using a cyanine dye FRET pair (Cy3 and Cy5), to identify the most reactive boron-aldehyde/amine nucleophile pairs. Upon conjugation of the dyes, FRET occurs under Cy3 excitation and the resultant ratio of Cy3:Cy5 emission directly correlates to conversion. Reaction kinetics and equilibria can be accurately quantified for reactive pairs, with dissociation constants of oBI derivatives in water (KD) found to span 9-orders of magnitude (10⁻²-10⁻¹¹ M). These studies have provided us with a better understanding of oBI linkages that we hope to exploit to reversibly attach bioconjugates to materials. The long-term aim of the project is to develop a modular biomaterial platform that can be used to help combat chronic diseases such as osteoarthritis, heart disease, and chronic wounds by providing cells with potent biological stimuli for tissue engineering.

Keywords: dynamic, bioconjugation, bornoimine, rapid, physiological

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9 The Growth Reaction, Membrane Potential and Oxidative Stress of Maize Coleoptile Cells Incubated in the Presence of the Naphthoquinones

Authors: Malgorzata Rudnicka, Waldemar Karcz

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Introduction: Naphthoquinones are widely occurring organic compounds produced by bacteria, fungi, and plants. They can act as the functional components of biochemical systems (plastoquinone) as well as biologically active substances, which have a negative impact on environmental processes. Naphthoquinones seem to act through two mechanisms: a covalent modification of biological molecules at their nucleophilic sites or by generation of reactive oxygen species (ROS) connected with redox cycling. Investigating the effect of naphthoquinones (1,4-naphthoquinone, lawsone and naphthazarin) on the elongation growth, membrane potential and the level of oxidative stress of maize cells seems to be important due to the possibility of using these substances as herbicides. Methods: All experiments were performed on etiolated maize coleoptile segments. Simultaneous measurements of elongation growth and pH of the incubation medium were carried out using an angular position transducer, allowing a precise record of the growth kinetics. To compare the oxidative stress level induced by all tested naphthoquinones, the changes in malondialdehyde content, as well as superoxide dismutase and catalase activities were measured. In order to measure the membrane potential of parenchymal cells the standard electrophysiology technique was used. Results: Naphthoquinones such as: 1,4-naphthoquinone, lawsone and naphthazarin were studied. It was found that all of the naphthoquinones diminished the growth of the maize coleoptile cells depending on the type of naphthoquinones and their concentration. Interestingly, naphthazarin at the intermediate concentration was less toxic compared to the others. In addition, the effect of naphthoquinones on the oxidative stress was dependent on their concentration as well. Superoxide dismutase and catalase activities were changed in the presence of higher concentrations of naphthoquinones. Similar interrelations were observed for membrane potential changes. Conclusion: It can be concluded that naphthoquinones tested differ in their toxic effect on the growth of maize coleoptile cells. Furthermore, naphthoquinones can be distinguish considering the oxidative stress level and membrane potential changes. The results presented here give new insight into the possible opportunities of practical usage of naphthoquinones for herbicides improvement.

Keywords: growth rate, membrane potential, naphthoquinones, oxidative stress

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8 Glycerol-Based Bio-Solvents for Organic Synthesis

Authors: Dorith Tavor, Adi Wolfson

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In the past two decades a variety of green solvents have been proposed, including water, ionic liquids, fluorous solvents, and supercritical fluids. However, their implementation in industrial processes is still limited due to their tedious and non-sustainable synthesis, lack of experimental data and familiarity, as well as operational restrictions and high cost. Several years ago we presented, for the first time, the use of glycerol-based solvents as alternative sustainable reaction mediums in both catalytic and non-catalytic organic synthesis. Glycerol is the main by-product from the conversion of oils and fats in oleochemical production. Moreover, in the past decade, its price has substantially decreased due to an increase in supply from the production and use of fatty acid derivatives in the food, cosmetics, and drugs industries and in biofuel synthesis, i.e., biodiesel. The renewable origin, beneficial physicochemical properties and reusability of glycerol-based solvents, enabled improved product yield and selectivity as well as easy product separation and catalyst recycling. Furthermore, their high boiling point and polarity make them perfect candidates for non-conventional heating and mixing techniques such as ultrasound- and microwave-assisted reactions. Finally, in some reactions, such as catalytic transfer-hydrogenation or transesterification, they can also be used simultaneously as both solvent and reactant. In our ongoing efforts to design a viable protocol that will facilitate the acceptance of glycerol and its derivatives as sustainable solvents, pure glycerol and glycerol triacetate (triacetin) as well as various glycerol-triacetin mixtures were tested as sustainable solvents in several representative organic reactions, such as nucleophilic substitution of benzyl chloride to benzyl acetate, Suzuki-Miyaura cross-coupling of iodobenzene and phenylboronic acid, baker’s yeast reduction of ketones, and transfer hydrogenation of olefins. It was found that reaction performance was affected by the glycerol to triacetin ratio, as the solubility of the substrates in the solvent determined product yield. Thereby, employing optimal glycerol to triacetin ratio resulted in maximum product yield. In addition, using glycerol-based solvents enabled easy and successful separation of the products and recycling of the catalysts.

Keywords: glycerol, green chemistry, sustainability, catalysis

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7 Identification and Characterization of in Vivo, in Vitro and Reactive Metabolites of Zorifertinib Using Liquid Chromatography Lon Trap Mass Spectrometry

Authors: Adnan A. Kadi, Nasser S. Al-Shakliah, Haitham Al-Rabiah

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Zorifertinib is a novel, potent, oral, a small molecule used to treat non-small cell lung cancer (NSCLC). zorifertinib is an Epidermal Growth Factor Receptor (EGFR) inhibitor and has good blood–brain barrier permeability for (NSCLC) patients with EGFR mutations. zorifertinibis currently at phase II/III clinical trials. The current research reports the characterization and identification of in vitro, in vivo and reactive intermediates of zorifertinib. Prediction of susceptible sites of metabolism and reactivity pathways (cyanide and GSH) of zorifertinib were performed by the Xenosite web predictor tool. In-vitro metabolites of zorifertinib were performed by incubation with rat liver microsomes (RLMs) and isolated perfused rat liver hepatocytes. Extraction of zorifertinib and it's in vitro metabolites from the incubation mixtures were done by protein precipitation. In vivo metabolism was done by giving a single oral dose of zorifertinib(10 mg/Kg) to Sprague Dawely rats in metabolic cages by using oral gavage. Urine was gathered and filtered at specific time intervals (0, 6, 12, 18, 24, 48, 72,96and 120 hr) from zorifertinib dosing. A similar volume of ACN was added to each collected urine sample. Both layers (organic and aqueous) were injected into liquid chromatography ion trap mass spectrometry(LC-IT-MS) to detect vivozorifertinib metabolites. N-methyl piperizine ring and quinazoline group of zorifertinib undergoe metabolism forming iminium and electro deficient conjugated system respectively, which are very reactive toward nucleophilic macromolecules. Incubation of zorifertinib with RLMs in the presence of 1.0 mM KCN and 1.0 Mm glutathione were made to check reactive metabolites as it is often responsible for toxicities associated with this drug. For in vitro metabolites there were nine in vitro phase I metabolites, four in vitro phase II metabolites, eleven reactive metabolites(three cyano adducts, five GSH conjugates metabolites, and three methoxy metabolites of zorifertinib were detected by LC-IT-MS. For in vivo metabolites, there were eight in vivo phase I, tenin vivo phase II metabolitesofzorifertinib were detected by LC-IT-MS. In vitro and in vivo phase I metabolic pathways wereN- demthylation, O-demethylation, hydroxylation, reduction, defluorination, and dechlorination. In vivo phase II metabolic reaction was direct conjugation of zorifertinib with glucuronic acid and sulphate.

Keywords: in vivo metabolites, in vitro metabolites, cyano adducts, GSH conjugate

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6 Immiscible Polymer Blends with Controlled Nanoparticle Location for Excellent Microwave Absorption: A Compartmentalized Approach

Authors: Sourav Biswas, Goutam Prasanna Kar, Suryasarathi Bose

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In order to obtain better materials, control in the precise location of nanoparticles is indispensable. It was shown here that ordered arrangement of nanoparticles, possessing different characteristics (electrical/magnetic dipoles), in the blend structure can result in excellent microwave absorption. This is manifested from a high reflection loss of ca. -67 dB for the best blend structure designed here. To attenuate electromagnetic radiations, the key parameters i.e. high electrical conductivity and large dielectric/magnetic loss are targeted here using a conducting inclusion [multiwall carbon nanotubes, MWNTs]; ferroelectric nanostructured material with associated relaxations in the GHz frequency [barium titanate, BT]; and a loss ferromagnetic nanoparticles [nickel ferrite, NF]. In this study, bi-continuous structures were designed using 50/50 (by wt) blends of polycarbonate (PC) and polyvinylidene fluoride (PVDF). The MWNTs was modified using an electron acceptor molecule; a derivative of perylenediimide, which facilitates π-π stacking with the nanotubes and stimulates efficient charge transport in the blends. The nanoscopic materials have specific affinity towards the PVDF phase. Hence, by introducing surface-active groups, ordered arrangement can be tailored. To accomplish this, both BT and NF was first hydroxylated followed by introducing amine-terminal groups on the surface. The latter facilitated in nucleophilic substitution reaction with PC and resulted in their precise location. In this study, we have shown for the first time that by compartmentalized approach, superior EM attenuation can be achieved. For instance, when the nanoparticles were localized exclusively in the PVDF phase or in both the phases, the minimum reflection loss was ca. -18 dB (for MWNT/BT mixture) and -29 dB (for MWNT/NF mixture), and the shielding was primarily through reflection. Interestingly, by adopting the compartmentalized approach where in, the lossy materials were in the PC phase and the conducting inclusion (MWNT) in PVDF, an outstanding reflection loss of ca. -57 dB (for BT and MWNT combination) and -67 dB (for NF and MWNT combination) was noted and the shielding was primarily through absorption. Thus, the approach demonstrates that nanoscopic structuring in the blends can be achieved under macroscopic processing conditions and this strategy can further be explored to design microwave absorbers.

Keywords: barium titanate, EMI shielding, MWNTs, nickel ferrite

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5 Novel Adomet Analogs as Tools for Nucleic Acids Labeling

Authors: Milda Nainyte, Viktoras Masevicius

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Biological methylation is a methyl group transfer from S-adenosyl-L-methionine (AdoMet) onto N-, C-, O- or S-nucleophiles in DNA, RNA, proteins or small biomolecules. The reaction is catalyzed by enzymes called AdoMet-dependent methyltransferases (MTases), which represent more than 3 % of the proteins in the cell. As a general mechanism, the methyl group from AdoMet replaces a hydrogen atom of nucleophilic center producing methylated DNA and S-adenosyl-L-homocysteine (AdoHcy). Recently, DNA methyltransferases have been used for the sequence-specific, covalent labeling of biopolymers. Two types of MTase catalyzed labeling of biopolymers are known, referred as two-step and one-step. During two-step labeling, an alkylating fragment is transferred onto DNA in a sequence-specific manner and then the reporter group, such as biotin, is attached for selective visualization using suitable chemistries of coupling. This approach of labeling is quite difficult and the chemical hitching does not always proceed at 100 %, but in the second step the variety of reporter groups can be selected and that gives the flexibility for this labeling method. In the one-step labeling, AdoMet analog is designed with the reporter group already attached to the functional group. Thus, the one-step labeling method would be more comfortable tool for labeling of biopolymers in order to prevent additional chemical reactions and selection of reaction conditions. Also, time costs would be reduced. However, effective AdoMet analog appropriate for one-step labeling of biopolymers and containing cleavable bond, required for reduction of PCR interferation, is still not known. To expand the practical utility of this important enzymatic reaction, cofactors with activated sulfonium-bound side-chains have been produced and can serve as surrogate cofactors for a variety of wild-type and mutant DNA and RNA MTases enabling covalent attachment of these chains to their target sites in DNA, RNA or proteins (the approach named methyltransferase-directed Transfer of Activated Groups, mTAG). Compounds containing hex-2-yn-1-yl moiety has proved to be efficient alkylating agents for labeling of DNA. Herein we describe synthetic procedures for the preparation of N-biotinoyl-N’-(pent-4-ynoyl)cystamine starting from the coupling of cystamine with pentynoic acid and finally attaching the biotin as a reporter group. The synthesis of the first AdoMet based cofactor containing a cleavable reporter group and appropriate for one-step labeling was developed.

Keywords: adoMet analogs, DNA alkylation, cofactor, methyltransferases

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4 Synthesis, Physicochemical Characterization and Study of the Antimicrobial Activity of Chlorobutanol

Authors: N. Hadhoum, B. Guerfi, T. M. Sider, Z. Yassa, T. Djerboua, M. Boursouti, M. Mamou, F. Z. Hadjadj Aoul, L. R. Mekacher

Abstract:

Introduction and objectives: Chlorobutanol is a raw material, mainly used as an antiseptic and antimicrobial preservative in injectable and ophthalmic preparations. The main objective of our study was the synthesis and evaluation of the antimicrobial activity of chlorobutanol hemihydrates. Material and methods: Chlorobutanol was synthesized according to the nucleophilic addition reaction of chloroform to acetone, identified by an infrared absorption using Spectrum One FTIR spectrometer, melting point, Scanning electron microscopy and colorimetric reactions. The dosage of carvedilol active substance was carried out by assaying the degradation products of chlorobutanol in a basic solution. The chlorobutanol obtained was subjected to bacteriological tests in order to study its antimicrobial activity. The antibacterial activity was evaluated against strains such as Escherichia coli (ATCC 25 922), Staphylococcus aureus (ATCC 25 923) and Pseudomonas aeroginosa (ATCC = American type culture collection). The antifungal activity was evaluated against human pathogenic fungal strains, such as Candida albicans and Aspergillus niger provided by the parasitology laboratory of the Hospital of Tizi-Ouzou, Algeria. Results and discussion: Chlorobutanol was obtained in an acceptable yield. The characterization tests of the product obtained showed a white and crystalline appearance (confirmed by scanning electron microscopy), solubilities (in water, ethanol and glycerol), and a melting temperature in accordance with the requirements of the European pharmacopoeia. The colorimetric reactions were directed towards the presence of a trihalogenated carbon and an alcohol function. The spectral identification (IR) showed the presence of characteristic chlorobutanol peaks and confirmed the structure of the latter. The microbiological study revealed an antimicrobial effect on all strains tested (Sataphylococcus aureus (MIC = 1250 µg/ml), E. coli (MIC = 1250 µg/ml), Pseudomonas aeroginosa (MIC = 1250 µg/ml), Candida albicans (MIC =2500 µg/ml), Aspergillus niger (MIC =2500 µg/ml)) with MIC values close to literature data. Conclusion: Thus, on the whole, the synthesized chlorobutanol satisfied the requirements of the European Pharmacopoeia, and possesses antibacterial and antifungal activity; nevertheless, it is necessary to insist on the purification step of the product in order to eliminate the maximum impurities.

Keywords: antimicrobial agent, bacterial and fungal strains, chlorobutanol, MIC, minimum inhibitory concentration

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3 Bis-Azlactone Based Biodegradable Poly(Ester Amide)s: Design, Synthesis and Study

Authors: Kobauri Sophio, Kantaria Tengiz, Tugushi David, Puiggali Jordi, Katsarava Ramaz

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Biodegradable biomaterials (BB) are of high interest for numerous applications in modern medicine as resorbable surgical materials and drug delivery systems. This kind of materials can be cleared from the body after the fulfillment of their function that excludes a surgical intervention for their removal. One of the most promising BBare amino acids based biodegradable poly(ester amide)s (PEAs) which are composed of naturally occurring (α-amino acids) and non-toxic building blocks such as fatty diols and dicarboxylic acids. Key bis-nucleophilic monomers for synthesizing the PEAs are diamine-diesters-di-p-toluenesulfonic acid salts of bis-(α-amino acid)-alkylenediesters (TAADs) which form the PEAs after step-growth polymerization (polycondensation) with bis-electrophilic counter-partners - activated diesters of dicarboxylic acids. The PEAs combine all advantages of the 'parent polymers' – polyesters (PEs) and polyamides (PAs): Ability of biodegradation (PEs), a high affinity with tissues and a wide range of desired mechanical properties (PAs). The scopes of applications of thePEAs can substantially be expanded by their functionalization, e.g. through the incorporation of hydrophobic fragments into the polymeric backbones. Hydrophobically modified PEAs can form non-covalent adducts with various compounds that make them attractive as drug carriers. For hydrophobic modification of the PEAs, we selected so-called 'Azlactone Method' based on the application of p-phenylene-bis-oxazolinons (bis-azlactones, BALs) as active bis-electrophilic monomers in step-growth polymerization with TAADs. Interaction of BALs with TAADs resulted in the PEAs with low MWs (Mw2,800-19,600 Da) and poor material properties. The high-molecular-weight PEAs (Mw up to 100,000) with desirable material properties were synthesized after replacement of a part of BALs with activated diester - di-p-nitrophenylsebacate, or a part of TAAD with alkylenediamine – 1,6-hexamethylenediamine. The new hydrophobically modified PEAs were characterized by FTIR, NMR, GPC, and DSC. It was shown that after the hydrophobic modification the PEAs retain the biodegradability (in vitro study catalyzed by α-chymptrypsin and lipase), and are of interest for constructing resorbable surgical and pharmaceutical devices including drug delivering containers such as microspheres. The new PEAs are insoluble in hydrophobic organic solvents such as chloroform or dichloromethane (swell only) that allowed elaborating a new technology of fabricating microspheres.

Keywords: amino acids, biodegradable polymers, bis-azlactones, microspheres

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2 The Role of Piceatannol in Counteracting Glyceraldehyde-3-Phosphate Dehydrogenase Aggregation and Nuclear Translocation

Authors: Joanna Gerszon, Aleksandra Rodacka

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In the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, protein and peptide aggregation processes play a vital role in contributing to the formation of intracellular and extracellular protein deposits. One of the major components of these deposits is the oxidatively modified glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Therefore, the purpose of this research was to answer the question whether piceatannol, a stilbene derivative, counteracts and/or slows down oxidative stress-induced GAPDH aggregation. The study also aimed to determine if this natural occurring compound prevents unfavorable nuclear translocation of GAPDH in hippocampal cells. The isothermal titration calorimetry (ITC) analysis indicated that one molecule of GAPDH can bind up to 8 molecules of piceatannol (7.3 ± 0.9). As a consequence of piceatannol binding to the enzyme, the loss of activity was observed. Parallel with GAPDH inactivation the changes in zeta potential, and loss of free thiol groups were noted. Nevertheless, the ligand-protein binding does not influence the secondary structure of the GAPDH. Precise molecular docking analysis of the interactions inside the active center allowed to presume that these effects are due to piceatannol ability to assemble a covalent binding with nucleophilic cysteine residue (Cys149) which is directly involved in the catalytic reaction. Molecular docking also showed that simultaneously 11 molecules of ligand can be bound to dehydrogenase. Taking into consideration obtained data, the influence of piceatannol on level of GAPDH aggregation induced by excessive oxidative stress was examined. The applied methods (thioflavin-T binding-dependent fluorescence as well as microscopy methods - transmission electron microscopy, Congo Red staining) revealed that piceatannol significantly diminishes level of GAPDH aggregation. Finally, studies involving cellular model (Western blot analyses of nuclear and cytosolic fractions and confocal microscopy) indicated that piceatannol-GAPDH binding prevents GAPDH from nuclear translocation induced by excessive oxidative stress in hippocampal cells. In consequence, it counteracts cell apoptosis. These studies demonstrate that by binding with GAPDH, piceatannol blocks cysteine residue and counteracts its oxidative modifications, that induce oligomerization and GAPDH aggregation as well as it prevents hippocampal cells from apoptosis by retaining GAPDH in the cytoplasm. All these findings provide a new insight into the role of piceatannol interaction with GAPDH and present a potential therapeutic strategy for some neurological disorders related to GAPDH aggregation. This work was supported by the by National Science Centre, Poland (grant number 2017/25/N/NZ1/02849).

Keywords: glyceraldehyde-3-phosphate dehydrogenase, neurodegenerative disease, neuroprotection, piceatannol, protein aggregation

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1 Exploring Bio-Inspired Catecholamine Chemistry to Design Durable Anti-Fungal Wound Dressings

Authors: Chetna Dhand, Venkatesh Mayandi, Silvia Marrero Diaz, Roger W. Beuerman, Seeram Ramakrishna, Rajamani Lakshminarayanan

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Sturdy Insect Cuticle Sclerotization, Incredible Substrate independent Mussel’s bioadhesion, Tanning of Leather are some of catechol(amine)s mediated natural processes. Chemical contemplation spots toward a mechanism instigated with the formation of the quinone moieties from the respective catechol(amine)s, via oxidation, followed by the nucleophilic addition of the amino acids/proteins/peptides to this quinone leads to the development of highly strong, cross-linked and water-resistant proteinacious structures. Inspired with this remarkable catechol(amine)s chemistry towards amino acids/proteins/peptides, we attempted to design highly stable and water-resistant antifungal wound dressing mats with exceptional durability using collagen (protein), dopamine (catecholamine) and antifungal drugs (Amphotericin B and Caspofungin) as the key materials. Electrospinning technique has been used to fabricate desired nanofibrous mat including Collagen (COLL), COLL/Dopamine (COLL/DP) and calcium incorporated COLL/DP (COLL-DP-Ca2+). The prepared protein-based scaffolds have been studied for their microscopic investigations (SEM, TEM, and AFM), structural analysis (FT-IR), mechanical properties, water wettability characteristics and aqueous stability. Biocompatibility of these scaffolds has been analyzed for dermal fibroblast cells using MTS assay, Cell TrackerTM Green CMFDA and confocal imaging. Being the winner sample, COLL-DP-Ca2+ scaffold has been selected for incorporating two antifungal drugs namely Caspofungin (Peptide based) and Amphotericin B (Non-Peptide based). Antifungal efficiency of the designed mats has been evaluated for eight diverse fungal strains employing different microbial assays including disc diffusion, cell-viability assay, time kill kinetics etc. To confirm the durability of these mats, in term of their antifungal activity, drug leaching studies has been performed and monitored using disc diffusion assay each day. Ex-vivo fungal infection model has also been developed and utilized to validate the antifungal efficacy of the designed wound dressings. Results clearly reveal dopamine mediated crosslinking within COLL-antifungal scaffolds that leads to the generation of highly stable, mechanical tough, biocompatible wound dressings having the zone of inhabitation of ≥ 2 cm for almost all the investigated fungal strains. Leaching studies and Ex-vivo model has confirmed the durability of these wound dressing for more than 3 weeks and certified their suitability for commercialization. A model has also been proposed to enlighten the chemical mechanism involved for the development of these antifungal wound dressings with exceptional robustness.

Keywords: catecholamine chemistry, electrospinning technique, antifungals, wound dressings, collagen

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