Multitarget Bicyclic Pyrrolidines: Synthesis, Biological Evaluation, Ionization Constants, and Molecular Docking
Journal of Molecular Structure, cilt.1380, 2027 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1380
- Basım Tarihi: 2027
- Doi Numarası: 10.1016/j.molstruc.2026.147416
- 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)
- Anahtar Kelimeler: antimicrobial, enzyme inhibition, ionization constants, molecular docking, potentiometry, Pyrrolidine
- Çukurova Üniversitesi Adresli: Evet
Özet
In this study, a new series of indole-containing bicyclic pyrrolidine derivatives (2a–f) was synthesized and evaluated for their multifunctional biological activities and physicochemical properties. Structural characterization by FT-IR confirmed the characteristic functional groups, while 1H and 13C NMR spectra supported the expected proton and carbon environments of the bicyclic pyrrolidine framework, and HRMS measurements were consistent with the calculated molecular masses of the synthesized compounds. All compounds exhibited stronger inhibition than the reference inhibitors against acetylcholinesterase (AChE) and carbonic anhydrase isoenzymes (hCA I and hCA II). Among them, 2c showed the highest activity against hCA I (IC50 = 56.38 nM), 2e against hCA II (IC50 = 84.23 nM), and 2d against AChE (IC50 = 23.45 nM). These values were lower than those of the reference inhibitors acetazolamide (hCA I: 217.43 nM; hCA II: 198.66 nM) and tacrine (AChE: 112.58 nM). The antibacterial results indicated moderate activity overall; however, some derivatives exhibited enhanced potency against A. baumannii (MIC = 62.50 µg/mL), corresponding to approximately two-fold higher activity than reference antibiotic ampicillin. In antituberculosis (anti-TB) assays, 2a was identified as the most active compound (MIC = 15.62 µg/mL), whereas antifungal activity remained limited. Ionization constants were determined by potentiometric titration in 25% (v/v) DMSO–water at 298 K and I = 0.1 mol dm-3 (NaCl). The pKa values were found in the ranges of 2.78–3.36, 5.35–6.50, and 11.11–12.37. Molecular docking studies supported the experimental enzyme inhibition results and revealed favorable interactions of the most active compounds with key amino acid residues located in the active sites of AChE, hCA I, and hCA II. These findings demonstrate distinct activity profiles within the investigated bicyclic pyrrolidine series and provide a basis for further exploration of this scaffold for multitarget enzyme inhibition and anti-TB activity.