Design, synthesis, biological evaluation, and in silico studies of novel pyrrolidine based hybrids bearing indole, chromone, and benzoylthiourea pharmacophores as multitarget hCA and AChE inhibitors
Computational Biology and Chemistry, cilt.125, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 125
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.compbiolchem.2026.109337
- Dergi Adı: Computational Biology and Chemistry
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Applied Science & Technology Source, BIOSIS, Chemical Abstracts Core, Chimica, Compendex, EMBASE, MEDLINE, zbMATH, Academic Search Ultimate (EBSCO)
- Anahtar Kelimeler: Carbonic anhydrase, Cholinesterase, Chromone, In silico, Indole, Pyrrolidine, Thiourea
- Çukurova Üniversitesi Adresli: Evet
Özet
In this study, novel pyrrolidine-based compounds bearing indole, chromone, and benzoylthiourea pharmacophores were rationally designed, synthesized, and evaluated as dual inhibitors of carbonic anhydrase I/II (hCA I, hCA II) and acetylcholinesterase (AChE). The target compounds were synthesized via imine azomethine ylide 1,3-dipolar cycloaddition and in selected cases, benzoyl isothiocyanate condensation reactions. Their structures were fully characterized using FTIR, NMR, microanalysis, and single-crystal X-ray diffraction (for 1ba). Compound 2ad (hCA I, Ki = 35.56 ± 5.10 nM, hCA II, Ki = 31.10 ± 4.84 nM) exhibited remarkable inhibitory activity against both hCA I and hCA II, outperforming the reference acetazolamide (AZA) (hCA I, Ki = 303.45 ± 10.21 nM, hCA II, Ki = 240.15 ± 8.65 nM). Compounds 1aa and 2bd demonstrated potent AChE inhibitory activity, displaying approximately 3-fold and 4-fold higher potency than tacrine (TAC), with Ki values of 47.92 ± 8.25 nM, and 35.04 ± 7.69 nM, respectively. An in silico approach, including molecular docking and ADMET analyses, was employed to elucidate the binding interactions and pharmacokinetic profiles of the synthesized compounds. Docking simulations revealed that compound 2ad showed favorable binding affinities toward hCA I and hCA II (−8.24 and −10.09 kcal/mol, respectively), while compounds 2bd and 1aa showed highly favorable binding energies toward AChE (−12.48 and −11.56 kcal/mol, respectively), forming stable interactions comparable to reference inhibitors. Furthermore, ADMET predictions indicated good oral absorption and favorable drug-likeness properties, although optimization may be required to enhance blood–brain barrier (BBB) permeability. The experimental and computational findings support the strong interaction potential of compound 2ad toward hCA II, whereas compounds 2bd and 1aa exhibit high binding affinity toward AChE, in agreement with the experimental inhibition data.