Pyrrolidine-based hybrid compounds: design, synthesis, in vitro and in vivo pharmacological properties and molecular docking studies
Senanur Taş, H. Ali Döndaş, Naciye Yaktubay Döndaş, Samet Poyraz, Tuğba Taşkın‐Tok, Gülüzar Atli, Samet Belveren, Tuncay İnce, Yeliz Demir, Mehmet Bertan Yılmaz, Mahmut Ülger, Mehmet Ali Tamer, José M. Sansano, Christopher M. Pask
Abstract
Aims To design, synthesize, and evaluate pyrrolidine-based hybrids bearing indole, thiourea, and vinyl sulfone pharmacophores as dual inhibitors of human carbonic anhydrase I/II (hCAI/II) and acetylcholinesterase (AChE), with secondary profiling of complementary bioactivities.Materials & methods Three hybrids (6a, 6b, 8) were obtained via imine azomethine ylide 1,3-dipolar cycloaddition and derivatization. Structures were confirmed spectroscopically and assayed in vitro for hCAI/II and AChE inhibition. Additional evaluations included antioxidant (DPPH), antibacterial, antifungal, antituberculosis (M. tuberculosis H37Rv), cytotoxicity (HCT116, DPSCs), anti-inflammatory (COX-2, SOD1 ELISA, mouse xylene-induced), antidepressant (forced swim test), molecular docking, and in silico ADMET.Results Compound 6b was the most potent inhibitor (hCAII Ki 75.79 ± 2.83 nM, AChE Ki 43.17 ± 10.44 nM), outperforming acetazolamide (Ki 299.33 ± 45.44 nM) and tacrine (Ki 103.47 ± 11.54 nM). Compound 6a showed the strongest antioxidant effect (72.30% DPPH), antibacterial activity against A. baumannii (MIC 125 µg/ml, comparable to ampicillin), and superior anti-TB potency (MIC 31.25 µg/ml). Compound 6b exhibited stronger antibacterial activity (MIC 62.5 µg/ml). Both reduced COX-2 levels, and 6a increased SOD1. The hybrids were selectively cytotoxic to HCT116, sparing DPSCs. Docking studies confirmed key binding interactions, while ADMET predicted favorable profiles. Conclusions The hybrids validate a focused dual-target strategy. Compound 6b is the most potent hCAII and AChE inhibitor, while 6a emerges as a broader multi-target lead with antioxidant, antimicrobial, anti-inflammatory, and antidepressant potential.