Development of Benzo[b]thiophene Linked-Oxadiazole Derivatives for Potential Antimicrobial and Anti-TB Targets: Evaluation of ADME-Tox and In-silico Docking

Novel thiazolo[5,4-b]pyridine–sulfonamide conjugates: Synthesis, structure–activity relationship, and molecular docking studies

A series of thiazolo[5,4-b]pyridine–based sulfonamide derivatives was designed and synthesized using a cyanoacetyl sulfonamide intermediate to access various heterocyclic frameworks. Their antimicrobial activity was evaluated in vitro against Staphylococcus aureus , Escherichia coli , and Candida albicans using agar diffusion and minimum inhibitory concentration (MIC) determination. Several compounds exhibited potent antibacterial activity with MIC values ranging from 3.125 to 12.5 μg/mL, where compounds 10 , 16 , and 21 showed broad-spectrum activity comparable to or superior to reference drugs. Structure–activity relationship (SAR) analysis indicated that electron-withdrawing and aromatic substituents enhanced antimicrobial potency. Molecular docking studies against dihydrofolate reductase (DHFR, PDB ID: 2W9S) supported the experimental results, revealing favorable binding interactions and high affinity of the most active compounds. These findings suggest that thiazolo[5,4-b]pyridine–sulfonamide hybrids represent promising scaffolds for the development of new antimicrobial agents.

Green synthesis of tetrahydropyridine-3-carboxylate derivatives and evaluation of antimicrobial and antimalarial activities supported by molecular docking, POM studies, and drug-likeness analysis

A series of novel haloarene-decorated tetrahydropyridine derivatives B(1a–1f) were synthesized via a simple, environmentally benign one-pot multicomponent reaction employing ethanol as a green solvent and [Et₃NH][HSO₄] as a Brønsted acid ionic liquid catalyst. The reaction utilized methyl acetoacetate (1 mmol), substituted aromatic aldehydes (2 mmol), and substituted anilines (2 mmol) at 60 °C to afford the desired compounds. All compounds were evaluated for their in vitro antimicrobial activity against three fungal strains (Candida albicans, Aspergillus niger, and Aspergillus clavatus), two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and two Gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes), using the serial broth dilution method. Additionally, their antimalarial potential was assessed against chloroquine- and quinine-sensitive 3D7 and multidrug-resistant Dd2 strains of Plasmodium falciparum. Among the synthesized derivatives, compounds B1a, B1b, and B1b exhibited the most potent antimicrobial and antimalarial activities. Molecular docking studies revealed that compound B1f showed the highest binding affinity toward S. aureus nucleoside diphosphate kinase, with a predicted free binding energy of − 913 kcal/mol. Pharmacological profiling suggested favorable drug-like properties and non-toxic behavior. These findings highlight haloarene-decorated tetrahydropyridine derivatives as promising dual-action candidates with potential to combat both bacterial and malarial infections.

Water-Mediated Synthesis, Antimicrobial Evaluation, Molecular Docking, and ADMET Profiling of Novel 2-Amino-3,5-dicarbonitrile-6-sulfanylpyridines

Design, Synthesis, and Antibacterial Evaluation of Novel Non‐Oxazolidinone Analogues of Linezolid to Investigate the Role of the Oxazolidinone Ring

A new series of non‐oxazolidinone derivatives 5a–d and 6 was designed and synthesized as potential analogues of Linezolid. The aim of this work was to develop compounds with improved antibacterial activity, the ability to overcome bacterial resistance, and reduced toxicity. The synthesized compounds were evaluated for their in vitro antimicrobial activity against several pathogenic Gram‐positive and Gram‐negative bacterial strains, including multidrug‐resistant isolates (MRSA). In addition, a probability of resistance development assay was performed to assess their potential to induce bacterial resistance. The biological evaluation revealed that all synthesized derivatives exhibited lower antibacterial activity compared to Linezolid and gentamycin, highlighting the crucial role of the oxazolidinone ring in its antibacterial activity. Molecular docking studies were conducted to investigate the binding mode of the new compounds within the active site of the 50S ribosomal subunit. The docking results showed lacking structural superimposition with Linezolid within the binding pocket, and lacking several key interactions required for strong binding, which may explain their reduced antibacterial potency relative to the reference drug.

DEVELOPMENT AND SYNTHESIS OF NEW TINIDAZOLE-BASED NITRONE DERIVATIVES: STRUCTURAL CHARACTERIZATION AND IN VITRO BIOLOGICAL EVALUATION

Objective: The rapid emergence of multi-drug resistant (MDR) bacterial pathogens has intensified the search for novel antimicrobial scaffolds. This study reports the design, synthesis, and biological evaluation of a new series of nitrone derivatives based on the Tinidazole scaffold. Methods: A library of compounds (M1–M3) was synthesized via the condensation of various aryl-substituted benzaldehydes with tinidazole-derived hydroxylamine intermediates. The molecular structures and stereochemical configurations of the synthesized hybrids were rigorously confirmed using spectral characterization techniques, including FT-IR, 1H NMR, 13C NMR, and Mass Spectrometry, which consistently indicated the formation of the stable (Z)-isomeric form. Results: The in vitro biological evaluation revealed that these nitrone derivatives possess potent broad-spectrum antibacterial activity against Gram-positive (Staphylococcus aureus) and Gram-negative (Klebsiella pneumoniae) clinical isolates. Notably, compounds M1 (4-F), M2 (H), and M3 (4-Br) exhibited exceptional zones of inhibition (ZOI) ranging from 41 to 46 mm at the highest concentrations, significantly outperforming the standard drug (ST), which reached a maximum ZOI of 22 mm. Furthermore, the compounds demonstrated significant antioxidant potential in the DPPH radical scavenging assay. Novelty: The Structure-Activity Relationship (SAR) analysis suggests that the electronic and lipophilic modulation of the aryl-substituted nitrone framework, particularly with halogenated substituents, plays a pivotal role in enhancing membrane permeability and bactericidal efficacy. These findings position tinidazole-based nitrones as highly promising candidates for the development of next-generation antimicrobial agents to combat resistant pathogens.

Design, synthesis, biological assessment, and integrated computational analysis of new pyrazole-based antimicrobial candidates

The emergence of antimicrobial resistance needs the development of new chemotherapeutic scaffolds. Pyrazole derivatives are recognized for their broad biological activity; however, further structural innovation is required to enhance antimicrobial efficacy and safety. Thus, new pyrazole-based candidates were designed and synthesized using 3-(4-chlorophenyl)-1-phenylpyrazol-4-yl-2-cyanoacryloyl chloride as a versatile precursor. A series of mono- and bidentate nucleophile-derived compounds was prepared and evaluated for antimicrobial activity against Gram-positive and Gram-negative bacteria and Candida albicans. Several derivatives exhibited potent antibacterial and antifungal activity, particularly against Gram-positive strains, with minimum inhibitory concentrations comparable to standard drugs. Most compounds showed low cytotoxicity toward HepG2 cells, which was further reduced upon antioxidant co-treatment. Notably, vitamin C and N-acetylcysteine showed synergistic enhancement of antimicrobial and antibiofilm effects. Molecular docking studies against dihydropteroate synthase (DHPS, PDB: 5U0V) revealed favorable binding interactions, with the thiophene-based derivative 10 displaying ligand efficiency comparable to the co-crystallized ligand 7VJ. Overall, these findings highlight pyrazole-based scaffolds as promising antimicrobial candidates with favorable biological profiles, providing a strong basis for further structural optimization.