**Synthesis, Molecular Docking, Molecular Dynamics Studies, and In Vitro Biological Evaluation of New Biofunctional Ketoprofen Derivatives with Different** *N***-Containing Heterocycles**

**Stanimir Manolov <sup>1</sup> , Dimitar Bojilov <sup>1</sup> , Iliyan Ivanov 1,\* , Gabriel Marc <sup>2</sup> , Nadezhda Bataklieva 1, Smaranda Oniga <sup>3</sup> , Ovidiu Oniga <sup>2</sup> and Paraskev Nedialkov <sup>4</sup>**


**Abstract:** Herein, we report the synthesis of four new hybrid molecules between ketoprofen or 2-(3-benzoylphenyl)propanoic acid and *N*-containing heterocyclic compounds, such as piperidine, pyrrolidine, 1,2,3,4-tetrahydroquinoline, and 1,2,3,4-tetrahydroisoquinoline. The obtained hybrid compounds were fully characterized using 1H- and 13C-NMR, UV-Vis, and HRMS spectra. Detailed HRMS analysis is provided for all novel hybrid molecules. The compounds were assessed for their *in vitro* anti-inflammatory and antioxidant activity. The lipophilicity of the hybrids was determined, both theoretically (*cLogP*) and experimentally (RM). The affinity of the compounds to the human serum albumin was assessed *in silico* by molecular docking study using two software, and the stability of the predicted complexes was evaluated by molecular dynamics study. All novel hybrids have shown very good *HPSA* activity, statistically close when compared to the reference—quercetin. The molecular docking confirmed the obtained *in vitro* results. Tetrahydroquinoline derivative **3c** and tetrahydroisoquinoline derivative **3d** have the highest affinity for albumin. They show stronger anti-inflammatory action than their predecessor, ketoprofen and the regularly used ibuprofen.

**Keywords:** ketoprofen; pyrrolidine; piperidine; 1,2,3,4-tetrahydroquinoline; 1,2,3,4-tetrahydroisoquinoline; hybrid molecules; *in vitro* biological activity; molecular docking; molecular dynamics
