Boulanouar Messaoudi

A theoretical DFT investigation of the reaction of 3,4-dihydro-2H-pyrrole-1-oxide (nitrone) with two alkenes cis- and trans-2-butene has been thoroughly probed at B3LYP/6-31G(d) level of theory. The regioselectivity as well as the detailed mechanism of reaction has been studied and analyzed. The reaction is characterized by a concerted asynchronous mechanism and the products P2 and P4 are the most favorable products kinetically and thermodynamically. A good agreement with the experimental data has been found.

Introduction: The global rise in antimicrobial resistance demands innovative therapeutic approaches. This study investigates novel 2-Aryl-9-chloro-5,6,7,8-tetrahydrothieno[3,2-b]quinoline derivatives (2a-e) as potential dual-action agents, targeting both pathogenic microorganisms and the phospholipase C-γ (PLC-γ) signaling pathway implicated in inflammatory responses. Method: Five derivatives were synthesized through a single-step POCl3-catalyzed cyclocondensation of thiophene carboxylic acids with cyclohexanone, yielding 55-71% of purified products. Antimicrobial efficacy was evaluated against Gram-positive (Staphylococcus aureus ATCC 25923, Bacillus cereus ATCC 10876), Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa clinical isolate), and Candida albicans ATCC 10231 strains using standardized CLSI protocols. Computational studies employed molecular docking (MolDock) and binding free energy calculations against PLC-γ (PDB ID:5EG3). Results: Among the tested compounds, compounds 2-c and 2-e showed strong antibacterial activity against Staphylococcus aureus, even surpassing gentamicin. Compounds 2-b and 2-d, on the other hand, showed significant antifungal activity against Candida albicans, equivalent to that of DEPTIL BFC. Molecular docking revealed compound 2d (L4) as the most potent PLC-γ inhibitor (ΔG=- 116.127 kcal/mol), forming π-alkyl interactions with Ala 567 in the catalytic pocket. discussion: Among the five Aryl-CTTQ compounds tested, all samples demonstrated strong antibacterial activity, with MICs ranging from 6.25 to 25 µg/mL in DMSO. Additionally, only compounds 2-b and 2-d demonstrated moderate antifungal activity against Candida albicans. The in silico analysis identified compound L4 as the most promising, displaying the highest binding affinity and a stable interaction with the target phospholipase C-γ. This systematic, computer-aided design approach not only pinpointed potential biological targets but also provided valuable insights into the structural features driving the compounds' activity. Discussion: The structure-activity relationship demonstrates that chloro-substitution at position 9 enhances antimicrobial potency, while aryl modifications at position 2 influence PLC-γ binding affinity. These findings suggest a unique dual mechanism of action distinct from conventional antimicrobials. Conclusion: his study highlights the biological potential of [Aryl-CTTQ] derivatives (2a-e), in particular their marked antibacterial activity and, for some, moderate antifungal activity. Compound 2d (L4) is distinguished by its high affinity for phospholipase C-γ, identified through in vitro and in silico analyses. These results validate the effectiveness of a computer-aided design approach to develop new therapeutic agents.

Biopolymers have become more and more attractive nowadays for both experimental and theoretical studies because of their importance in our daily life. In this contribution, the electronic properties and reactivity behavior of some biomonomers; chitin and chitosan have been thoroughly investigated theoretically using density functional theory (DFT) B3LYP/6-31G(d) level of theory. The regioselectivity of these molecules has been rationalized by using both Fukui and Parr indices in order to explain and show the most probable sites to be attacked towards nucleophiles and electrophiles. For the three studied monomers, the oxygen and nitrogen atoms were found to be the most reactive sites. Parr functions and Fukui functions found to be complementary while explaining the possible regioselectivity.

A theoretical study of the inhibition efficiency of three organic heterocyclic molecules has been thoroughly probed using density functional theory B3LYP/6-31G(d) level. The calculated global quantities such as electrophilicity and nucleophilicity show that the three organic inhibitors are nucleophiles. The obtained values of charge transfer and energy of back-donation show that the 2-amino-4-(4-bromophenyl)thiophene-3-carbonitrile is the best inhibitor. Parr function indices have been calculated to determine the most preferred sites for the nucleophilic attacks towards the electrophilic transition metal surface of copper. The electrostatic surface potential has been mapped in order to explore the major regions of the molecules responsible of the inhibition. It is found that the zone surrounding the nitrogen atom and the -aromatic system of benzene are the one forming the protection layer. The theoretical results are in good commitment with the experimental results.

The experimentally observed regioselectivity of a series of alkenes reactions with some nitrones has been thoroughly investigated theoretically using density functional theory (DFT) B3lyp/6-31G(d) level of theory. Both Fukui and Parr indices have been calculated to explain and show the most reactive sites. The electrostatic surface potential has also been studied and analyzed in order to show the positive and negative regions responsible of the possible interaction between the two studied reactants. The theoretical results are in good agreement with the experimental findings.

Several levels of theory such as Møller-Plesset MP2, G3, and CBS-QB3, have been used in order to investigate the complex and multichannel potential energy surface of the reaction of but-3-enal with the triplet oxygen atom. The results show that the O-addition channel is dominant. The different possible pathways of oxygen atom attack are thoroughly studied to better understand and explain the reaction mechanism. Regarding the oxidation of but-3-enal by triplet oxygen O(3P), it is shown that the major thermodynamic product is H3CC(O)CH2C(O)H (P3) being the most stable for the whole reaction. However, the most favored product kinetically is H2CC(OH)CH2C(O)H (P2). For the H-abstraction second possible pathway, the most favored product both kinetically and thermodynamically is found to be P8. The activation energy and calculated rate constants are consistent with the proposed addition mechanism.

The concept of detection limit was combined with quantum chemical calculations for trace analysis of cadmium and lead in aqueous solution using deprotonated 8-hydroxyquinoline (oxine) as ligand. The DFT study was performed using 6-31G(d), cc-pVTZ and SDD basis sets in combination with different theoretical methods such as; B3LYP, MP2 and M06L implemented in Gaussian 09 program package. The obtained results of the study in the gas and aqueous phases show that the chemical stability of the complex was found in the order Pb-oxine > Cd-oxine. Based on the calculations done, the stability order was relative to the detection limit (LOD) for the two metals Cd and Pb. Thus, a reverse relationship between LOD and binding energy has been found.