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.

Thiophene is a five-membered sulfur containing a heteroaromatic ring. Its presence in compounds of therapeutic interest is remarkable, leading to various studies to develop strategies to synthesize new biologically active thiophene analogues. Due to the presence of a ketone function, 2-acetylthiophenes derivatives are good intermediates to prepare such important compounds. Since its discovery, the Vilsmeier–Haack reaction has always been a subject of great interest to organic chemists and continues to attract considerable attention. It is a powerful tool in organic chemistry. This reagent is widely used for the chloroformylation of ketones leading to 3-chloroacroleins, which are scaffolds to prepare 5-aryl-2-acetylthiophenes derivatives. Our team aimed to develop and functionalize heterocyclic compounds with promising biological and pharmacological activities, including some new concepts of green chemistry; as a part of our research, different derivatives of 5-aryl-2-acetylthiophenes were achieved in good yields and then used to prepare the new compounds.

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.

The present work focuses on establishing a green protocol that reduces long‐term energy consumption and enables solvent‐free conditions for the preparation of 2‐aminothiophene‐3‐carbonitrile derivatives and to assess their antimicrobial properties. The strategy is based on an optimized Gewald reaction under microwave irradiation, affording the desired compounds in good yields. The structure of all the synthesized derivatives was confirmed by spectroscopic analyses. Their antimicrobial potential was evaluated using both in vitro and in silico studies against ten different bacterial strains and three fungal species. Remarkably, compounds 1 and 8 exhibited the strongest antibacterial activity with a minimum inhibitory concentration (MIC) of 0.156 mg/mL. Meanwhile, in the antifungal activity, compounds 4 and 6 demonstrated the most significant inhibition zones, with MICs of 0.625 and 0.312 mg/mL, respectively. Molecular docking analyses indicated strong binding affinities for compounds 1 , 3 , 6 , 7 , and 8 with key microbial targets. Furthermore, ADME‐Tox predictions revealed a promising safety profile with no signs of hepatotoxicity. These findings highlight the potential of the synthesized 2‐aminothiophene‐3‐carbonitrile derivatives as effective antimicrobial agents and encourage their further exploration in drug development.