Synthesis, spectroscopic characterization, DFT analysis, and in silico evaluation of novel spirothiophene-containing methoxybenzamide derivatives
JOURNAL OF MOLECULAR STRUCTURE, cilt.1379, 2027 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1379
- Basım Tarihi: 2027
- Doi Numarası: 10.1016/j.molstruc.2026.147352
- Dergi Adı: JOURNAL OF MOLECULAR STRUCTURE
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Gazi Üniversitesi Adresli: Evet
Özet
This study describes the synthesis, spectroscopic characterization, and computational evaluation of three positional methoxybenzamide-substituted spirothiophene derivatives (2-4). The target compounds were obtained by reacting the corresponding aminothiophene precursor with 2-, 3-, or 4-methoxybenzoyl chloride, affording yields of 70-81%. Their structures were confirmed by FT-IR, "1H NMR, and "13C NMR-APT spectroscopy. Characteristic NH, C---N, and amide C--O stretching bands, together with the expected proton and carbon resonances, supported the proposed structures. DFT calculations were performed to examine the optimized geometries, frontier molecular orbital distributions, and molecular electrostatic potential characteristics of the compounds. The MEP maps identified the principal electron-rich and electron-deficient regions, while NCI-RDG analysis revealed that weak van der Waals interactions were dominant in all three isomers, with substitution-dependent differences in attractive and sterically repulsive regions. These differences may influence the conformational preferences and accessibility of polar interaction sites. In silico ADMET analysis indicated favorable rule-based physicochemical and drug-likeness metrics; however, high predicted alerts for DILI, mutagenicity, genotoxicity, and related toxicity endpoints, together with low predicted solubility and high plasma protein binding, indicate substantial safety and developability concerns. PASS analysis generated preliminary hypotheses regarding possible antineoplastic, apoptosis-related, antimitotic, MAP kinase-, FYN-, and FAK-associated activities. Molecular docking against JNK3/MAPK10, JNK2/MAPK9, FYN, and FAK/PTK2 indicated possible binding modes and predicted affinity trends, particularly for the meta- and para-methoxy derivatives toward FYN and FAK/PTK2. These computational findings should be regarded as hypothesis-generating predictions rather than evidence of biological activity and require validation through experimental cytotoxicity and kinase-inhibition studies.