**1. Introduction**

Furan is a five-membered heterocyclic organic compound containing one oxygen and four carbon atoms. Its derivatives are a wide group of heterocyclic molecules owing to a vast array of biological activities. Organic compounds in which the furan structure is a building block have been described in the literature as possessing antibacterial, antiviral, pesticidal, cytotoxic, antitumorigenic, psychotropic, and anti-inflammatory properties. They also have an effect on the cardiovascular system, as well as hypoglycemic, antifertility, and ulcer-healing properties [1].

There are many different kinds of bacteria that are susceptible to Nitrofurantoin **1**. It is used for treating urinary tract infections that are caused by Escherichia coli, enterococci, Staphylococcus aureus, and certain strains of Klebsiella and Enterobacter species that are susceptible to Nitrofurantoin **1 [2]** (Figure 1).

Some well-known furan derivatives are ranbezolid **2** [3], nifurzide **3** [4], and ranitidine **4** [5] widely used as anti-bacterial, anti-infective, and H2 receptor antagonists, respectively (Figure 2).

On other hand, the N-containing heterocycles are of great importance, not only because of their affluence, but above all because of their chemical, biological, and technical significance. Together, they create a large group of compounds that play a powerful role in biological investigations such as antibacterial, anticancer, anti-inflammatory, antiviral, anti-tumor, and anti-diabetic applications [6].

In the search for new biofunctional compounds, we were interested in obtaining new hybrid molecules containing both a furan fragment and a nitrogen-containing core in their structure.

**Citation:** Manolov, S.; Ivanov, I.; Bojilov, D.; Nedialkov, P. Synthesis, In Silico, and In Vitro Biological Evaluation of New Furan Hybrid Molecules. *Processes* **2022**, *10*, 1997. https://doi.org/10.3390/pr10101997

Academic Editors: Elzbieta Klewicka and Davide Dionisi

Received: 24 August 2022 Accepted: 29 September 2022 Published: 2 October 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 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/).

**Figure 1.** Structural formula of nitrofurantoin **1**.

**Figure 2.** Structural formulas of ranbezolid, nifurzide, and ranitidine.

In a recent study, Li and co-workers synthesized new tetrahydroquinoline and tetrahydroisoquinolines containing 2-phenyl-5-furan moiety as PDE4 inhibitors [7].

Using Pd-catalyzed coupling reactions of 2-(alkyltelluro)furan with terminal alkynes, Zeni et al. managed to synthesize a series of acetylenic furan hybrids [8]. The obtained compounds were tested for anti-inflammatory activity and showed very promising results.

The significance of furan-containing amides continues to fascinate scientists. Publications in recent years have focused on the discovery and application of new synthetic methods, as well as the preparation of their biologically active analogs [9–11].

#### **2. Materials and Methods**

#### *2.1. Synthesis*

The reagents were purchased from commercial suppliers (Sigma-Aldrich S.A. and Riedel-de Haën, Sofia, Bulgaria) and used as received. A Bruker Advance II+600 spectrometer was used for the recording of the NMR spectral data (BAS-IOCCP—Sofia, Bruker, Billerica, MA, USA). All compounds were analyzed in CDCl3 at 600 MHz and 150.9 MHz for 1H-NMR and 13C-NMR, respectively. Chemical shifts were determined to tetramethylsilane (TMS) (δ = 0.00 ppm) as an internal standard; the coupling constants are given in Hz. Recorded NMR spectra were taken at room temperature (approx. 295 K). The MS analysis was carried out on a Q Exactive Plus high-resolution mass spectrometer (HRMS) with a heated electrospray ionization source (HESI-II) (Thermo Fisher Scientific, Inc., Bremen, Germany) equipped with a Dionex Ultimate 3000RSLC ultrahigh-performance liquid

chromatography (UHPLC) system (Thermo Fisher Scientific, Inc.). For the TLC analysis, precoated 0.2 mm Fluka silica gel 60 plates (Merck KGaA, Darmstadt, Germany) were used. *Synthesis of hybrid compounds 7*.

Furan-2-carbonyl chloride **6** (1 mmol) was added to a solution of the corresponding amine **5a–d** (1 mmol) in dichloromethane (15 mL). Triethylamine (1.2 mmol) was added after 10 min. After 30 min, the reaction mixture was washed with diluted hydrochloric acid (H2O:HCl = 4:1 *v*/*v*), a saturated solution of Na2CO3, and water. The organic layer was dried using anhydrous Na2SO4, concentrated, and filtered on a short column with neutral Al2O3.

*Furan-2-yl(pyrrolidin-1-yl)methanone 7a*: light yellow oil, yield 94% (0.155 g), 1H NMR (600 MHz, CDCl3) δ 7.51 (dd, *J* = 1.7, 0.8 Hz, 1H), 7.06 (dd, *J* = 3.5, 0.8 Hz, 1H), 6.49 (dd, *J* = 3.5, 1.8 Hz, 1H), 3.84 (t, *J* = 6.8 Hz, 2H), 3.66 (t, *J* = 6.9 Hz, 2H), 2.00 (p, *J* = 6.7 Hz, 2H), 1.91 (p, *J* = 6.7 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 158.1 (C=O), 148.8 (O=C-C-O), 144.0 (O-CH=CH), 115.7 (C=CH-CH), 111.3 (C-CH=CH), 47.8 (CH2-CH2-N-), 47.0 (CH2-CH2- N-), 26.6 (CH2), 23.8 (CH2). UV λmax, MeOH: 272 (*ε* = 12,200) nm. HRMS Electrospray ionization (ESI) *m*/*z* calcd for [M+H]+ C9H12NO2 <sup>+</sup> = 166.0863, found 166.0860 (mass error Δ<sup>m</sup> = −1.82 ppm), calcd for [M+Na]<sup>+</sup> C9H11NO2Na+ = 188.0682, found 188.0679 (mass error Δ<sup>m</sup> = −1.60 ppm).

*Furan-2-yl(piperidin-1-yl)methanone 7b*: light yellow oil, yield 92% (0.165 g), 1H NMR (600 MHz, CDCl3) δ 7.40 (dd, *J* = 1.7, 0.8 Hz, 1H), 6.85 (dd, *J* = 3.4, 0.8 Hz, 1H), 6.39 (dd, *J* = 3.4, 1.8 Hz, 1H), 3.63 (s, 4H), 1.65–1.60 (m, 2H), 1.59–1.54 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 159.3 (C=O), 148.2 (O=C-C-O), 143.4 (O-CH=CH), 115.5 (C=CH-CH=CH-O), 111.1 (C=CH-CH=CH-O), 47.7 (N-CH2-CH2), 26.2 (N-CH2-CH2), 24.7 (CH2-CH2-CH2). UV λmax, MeOH: 272 (*ε* = 14,800) nm. HRMS Electrospray ionization (ESI) *m*/*z* calcd for [M+H]<sup>+</sup> C10H14NO2 <sup>+</sup> = 180.1019, found 180.1017 (mass error Δ<sup>m</sup> = −1.06 ppm), calcd for [M+Na]+ C10H13NO2Na+ = 202.0838, found 202.0836 (mass error Δ<sup>m</sup> = −0.99 ppm).

*(3,4-dihydroquinolin-1(2H)-yl)(furan-2-yl)methanone 7c*: light yellow oil, yield 95% (0.216 g), 1H NMR (600 MHz, CDCl3) δ 7.27 (dd, *J* = 1.7, 0.8 Hz, 1H), 7.11 (dd, *J* = 7.5, 0.8 Hz, 1H), 7.01 (td, *J* = 7.4, 1.2 Hz, 1H), 6.95 (ddd, *J* = 8.0, 4.5, 1.1 Hz, 1H), 6.84 (d, *J* = 8.0 Hz, 1H), 6.60 (d, *J* = 3.5 Hz, 1H), 6.30 (dd, *J* = 3.5, 1.7 Hz, 1H), 3.84 (t, *J* = 6.6 Hz, 2H), 2.73 (t, *J* = 6.6 Hz, 2H), 1.96 (p, *J* = 6.6 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 159.8, 147.9, 143.9, 138.9, 132.0, 128.4, 125.9, 124.9, 124.3, 116.4, 111.2, 44.2, 26.8, 24.0. UV λmax, MeOH: 291 (*ε* = 10,800) nm. HRMS Electrospray ionization (ESI) *m*/*z* calcd for [M+H]<sup>+</sup> C14H14NO2 <sup>+</sup> = 228.1019, found 228.1015 (mass error Δ<sup>m</sup> = −1.75 ppm), calcd for [M+Na]<sup>+</sup> C14H13NO2Na+ = 250.0838, found 250.0834 (mass error Δ<sup>m</sup> = 2.40 ppm).

*(3,4-dihydroisoquinolin-2(1H)-yl)(furan-2-yl)methanone 7d*: light yellow oil, yield 90% (0.205 g), 1H NMR (600 MHz, CDCl3) δ 7.55 (s, 1H), 7.24–7.17 (m, 4H), 7.07 (dd, J = 3.5, 0.7 Hz, 1H), 6.53 (dd, J = 3.5, 1.8 Hz, 1H), 4.88 (s, 2H), 4.01 (s, 2H), 3.00 (s, 2H). 13C NMR (151 MHz, CDCl3) δ 159.6 (C=O), 148.1 (O=C-C-O), 143.9 (O-CH=CH), 133.1 (C, Ar), 129.9 (C, Ar), 127.4 (C, Ar), 126.8(C, Ar), 126.5 (C, Ar), 125.3 (C, Ar), 116.3 (C=CH-CH), 111.3 (CH-CH=CH), 48.3 (Ar-CH2-N), 44.5 (Ar-CH2-CH2-N), 28.5 (Ar-CH2-CH2-N). UV λmax, MeOH: 232 (*ε* = 13500) nm, 272 (*ε* = 12,000) nm. HRMS Electrospray ionization (ESI) *m*/*z* calcd for [M+H]+ C14H14NO2 <sup>+</sup> = 228.1019, found 228.1015 (mass error Δ<sup>m</sup> = −1.75 ppm), calcd for [M+Na]+ C14H13NO2Na<sup>+</sup> = 250.0838, found 250.0835 (mass error Δ<sup>m</sup> = 2.80 ppm).
