Discovery of new molecular hybrid derivatives with coumarin scaffold bearing pyrazole/oxadiazole moieties: Molecular docking, POM analyses, in silico pharmacokinetics and in vitro antimicrobial evaluation with identification of potent antitumor pharmacophore sites

• Published in: Bioorganic chemistry 2024-12, Vol.153, p.107761, Article 107761
• Main Authors: Tataringa, Gabriela, Tuchilus, Cristina, Ahmed, Mukhtar, Ahmed, Sumeer, Bhat, Ajmal R., Ben Hadda, Taibi, Zbancioc, Ana-Maria, Fahelelbom, Khairi M.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Candida albicans - drug effects; Coumarin; Coumarins - chemistry; Coumarins - pharmacology; Density Functional Theory; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Escherichia coli - drug effects; Humans; In vitro Antimicrobial; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Docking: POM analysis; Molecular Structure; Oxadiazole moieties; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Pharmacophore; Pseudomonas aeruginosa - drug effects; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Staphylococcus aureus - drug effects; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107761

[Display omitted] •Synthesis of coumarin-pyrazole and coumarin-oxadiazole hybrids.•Synthesized compounds exhibited notable in vitro antimicrobial evolution.•In vitro antimicrobial evolution, POM and molecular docking Analyses.•Identification of Potential Antitumor Pharmacophore Site.•In silico Pharmacokinetics and Structure-activity relationship studies. This synthetic organic methodology involves the creation of novel coumarin-based hybrids of series (1–4) with pyrazole ring and (5–8) with oxadiazole moiety. The targeted compounds were tested for In vitro Antimicrobial efficacy against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans pathogenic microbes using disc diffusion and broth microdilution with ciprofloxacin and fluconazole as reference standards. Density functional theory (DFT) studies were used to study atomic structure and reactivity, including absolute electronegativity (χ), electrophilicity (ω), electron acceptor (ω+), donor capabilities (ω–), electron affinity (EA), energy gap (ΔE), global hardness (η), global softness (S), and ionisation potential (IP) and FMOs, NBOs, MEP, and Mulliken Charge analysis. The POM tests found three integrated pharmacophore sites with antibacterial, antiviral, and anticancer activities. Molecular docking studies are also used to determine the S. aureus nucleoside diphosphate kinase receptor’s affinity and mode of action for the synthesized drugs. In silico analysis of thermodynamic and therapeutic effectiveness properties, including Lipinski’s ’rule of five’, Veber’s rule, and ADME properties, predicted toxicity-free, non-carcinogenic, and risk-free oral administration of the synthesized complexes.