**1. Introduction**

*N*-heterocycles can be found in natural products and drug molecules and are indispensable components in the fields of organic synthesis, medicinal chemistry and materials science. The construction of these *N*-containing heterocycles by traditional methods usually requires the preparation of reactive intermediates. Through in recent decades, with the rapid advent of transition metal-catalyzed reactions, the synthesis of heterocycles from precursors with inert chemical bonds has become a challenge. Many have developed efficient methods for the preparation of *N*-heterocyclic compounds, such as aziridines, azetidines, indoles and quinolines and many others [1].

Pyrrolidine **1a** (Figure 1), also known as tetrahydropyrrole, is an organic compound with molecular formula (CH2)4NH. It is a cyclic secondary amine, also classified as a

**Citation:** Manolov, S.; Bojilov, D.; Ivanov, I.; Marc, G.; Bataklieva, N.; Oniga, S.; Oniga, O.; Nedialkov, P. Synthesis, Molecular Docking, Molecular Dynamics Studies, and In Vitro Biological Evaluation of New Biofunctional Ketoprofen Derivatives with Different *N*-Containing Heterocycles. *Processes* **2023**, *11*, 1837. https://doi.org/10.3390/ pr11061837

Academic Editors: Alexander Novikov and Andrea Temperini

Received: 25 May 2023 Revised: 15 June 2023 Accepted: 15 June 2023 Published: 17 June 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

saturated heterocycle. Many modifications of pyrrolidine are found in natural and synthetic drugs and drug candidates [2].

**Figure 1.** Structural formulas of pyrrolidine **1a**, piperidine **1b**, 1,2,3,4-tetrahydroquinoline **1c**, and 1,2,3,4-tetrahydroisoquinoline **1d**.

The pyrrolidine ring structure (Figure 1) is present in many natural alkaloids, such as nicotine and hygrin [3]. It is found in many medicines, such as procyclidine and bepridil. It also forms the basis for racetam compounds (e.g., piracetam and aniracetam). The amino acids proline and hydroxyproline are structurally derived from pyrrolidine [2]. Pyrrolidine is widely found in the literature as a fragment—part of a number of organic compounds possessing a number of biological activities, such as antiviral, anti-inflammatory, antibacterial, antidepressant, etc. [4].

Piperidine **1b** (Figure 1) is a key heterocyclic amine that is part of a number of pharmaceutical products and natural alkaloids, possessing a diverse range of biological activities [5]. Piperidine fragment **1b** is present in a vast array of natural alkaloids and approved pharmaceuticals [6]. For example, the alkaloid piperine gives a spicy taste in black paper [7]. This six-membered nitrogen-contained fully saturated ring is also found in stimulants (methylphenidate, pipradrol etc.), vasodilators (minoxidil), antipsychotics (droperidol, melperone, etc.), opioids (pethidine, fentanyl, etc.) and many others drugs.

The fully hydrogenated quinoline or 1,2,3,4-tetrahydroquinoline **1c** (Figure 1) is another example of a nitrogen-containing fragment that is widely distributed in nature and the same in pharmaceuticals. The structure of 1,2,3,4-tetrahydroquinoline **1c** is a very common structural motif and is found in numerous biologically active natural products and pharmacologically relevant therapeutic agents [8].

1,2,3,4-tetrahydroisoquinoline **1d** (Figure 1) is another cyclic secondary amine, widely distributed in nature, forming the isoquinoline alkaloids family. Many synthetic and natural molecules containing 1,2,3,4-tetrahydroisoquinoline skeleton have been reported to possess a wide range of pharmacological activities like antibacterial, anti-inflammatory, antifungal, antiviral, antimalarial, and anticancer, among others [9–14].

First synthesized back in 1967, ketoprofen continues to be widely used, and its interest continues to this day. It belongs to the group of nonsteroidal anti-inflammatory drugs (NSAIDs) belonging to the family of propionic derivatives of arylpropionic acid [15].

Ketoprofen (Figure 2) widespread use is mainly due to its antipyretic, analgesic and anti-inflammatory properties due to reversible inhibition of cyclooxygenase 1 and 2 (COX-1 and COX-2), which in turn reduces the production of pro-inflammatory prostaglandin precursors [16].

**Figure 2.** The structural formula of ketoprofen.

Because of the importance of these scaffolds in drug discovery and pharmaceutical chemistry, the development of new methodologies for the synthesis of new hybrids of *N*-containing heterocyclic derivatives remains to be a very active field of research, as evidenced by the publication of more than 500 articles in the field in recent years.

Obtaining new hybrid molecules constructed from ketoprofen fragments attached to an *N*-containing heterocycle is particularly fascinating in order to examine its bio functionality.
