Synthetic Approach to Diversified Imidazo[2,1-b][1,3]thiazines and Its Evaluation as Non-Steroidal Anti-Inflammatory Agents

Slyvka, Nataliia; Holota, Serhii; Saliyeva, Lesya; Vovk, Mykhailo

doi:10.3390/ecsoc-25-11692

Open AccessProceeding Paper

Synthetic Approach to Diversified Imidazo[2,1-b][1,3]thiazines and Its Evaluation as Non-Steroidal Anti-Inflammatory Agents^†

¹

Department of Organic Chemistry and Pharmacy, Lesya Ukrainka Volyn National University, Volya Avenue 13, 43025 Lutsk, Ukraine

²

Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska, 79010 Lviv, Ukraine

³

Department of Mechanism of Organic Reactions, Institute of Organic Chemistry of National Academy of Sciences of Ukraine, 5 Murmanska, 02660 Kyiv, Ukraine

^*

Author to whom correspondence should be addressed.

^†

Presented at the 25th International Electronic Conference on Synthetic Organic Chemistry, 15–30 November 2021; Available online: https://ecsoc-25.sciforum.net/.

Chem. Proc. 2022, 8(1), 82; https://doi.org/10.3390/ecsoc-25-11692

Published: 14 November 2021

(This article belongs to the Proceedings of The 25th International Electronic Conference on Synthetic Organic Chemistry)

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Abstract

:

The present work is devoted to the synthesis of imidazo[2,1-b][1,3]thiazine derivatives as possible anti-inflammatory agents. The synthetic approach to (2-pyridinyloxy) substituted imidazo[2,1-b][1,3]thiazines based on the interaction of the polysubstituted 2-chloropyridines with 3-hydroxy-imidazo[2,1-b][1,3]thiazines was proposed. Selective nucleophilic substitution in position 2 of a pyridine ring was observed in the mentioned reaction. The synthesized (2-pyridinyloxy) substituted imidazo[2,1-b][1,3]thiazines drug-like properties were studied in silico using SwissADME and anti-inflammatory activity in the carrageenan test in vivo. Hit-compounds with satisfactory drug-like and pharmacological features were identified as promising objects for forthcoming structure optimization and in-depth studies.

Keywords:

imidazo[2,1-b][1,3]thiazine; pyridine; small molecules; alkylation; drug-like; anti-inflammatory activity; NSAIDs

1. Introduction

Imidazo[2,1-b][1,3]thiazine scaffold is the attractive matrix for the design of small molecules with a wide activity spectrum. The application of modern drug design methodologies and strategies allowed the identification of the mentioned heterocycles’ potential agents with trypanocidal [1,2], anti-tuberculosis [3,4,5], antioxidant [6] antiviral [7,8], antitumor [9] and antifungal [10] activities (Figure 1).

Inflammation is an important part of many pathology processes and an attractive pathway/target in modern drug design for the modulation and obtaining of the appropriate and satisfactory therapeutic effects [11,12,13].

Taking into account the synthesis of the hybrid molecules containing two or more pharmacophores is a promising and interesting approach to the design of potential pharmacological active small molecules, it was interesting to work out the straightforward and convenient protocol for the synthesis of new hybrid molecules containing diversified imidazo[2,1-b][1,3]thiazine scaffolds linked with a potential pharmacophore–pyridine ring and evaluate their drug-like and anti-inflammatory properties.

2. Methods

2.1. General Information

Melting points were measured in open capillary tubes on a BÜCHI B-545 melting point apparatus (BÜCHI Labortechnik AG, Flawil, Switzerland) and are uncorrected. The elemental analyses (C, H, N) were performed using the Perkin–Elmer 2400 CHN analyzer (PerkinElmer, Waltham, MA, USA) and were within ±0.4% of the theoretical values. The 400 MHz-¹H and 126 MHz-¹³C spectra were recorded on a Varian Unity Plus 400 (400 MHz) spectrometer (Varian Inc., Paulo Alto, CA, USA). All spectra were recorded at room temperature except where indicated otherwise and were referenced internally to solvent reference frequencies. Chemical shifts (δ) are quoted in ppm and coupling constants (J) are reported in Hz. LC–MS spectra were obtained on a Finnigan MAT INCOS-50 (Thermo Finnigan LLC, San Jose, CA, USA). The reaction mixture was monitored by thin layer chromatography (TLC) using commercial glass-backed TLC plates (Merck Kieselgel 60 F₂₅₄). Solvents and reagents that are commercially available were used without further purification. The 3-hydroxy-imidazo[2,1-b][1,3]thiazines 2a–c were prepared using the similar protocol described in [5].

2.2. Synthesis and Characterization of Compounds 3a–m

To the mixture of compounds 2a–c and a 60% NaH in mineral oil (10 mmol) in the dry DMF (4 mL), 10 mmol of the appropriate substituted derivate of 2-chloropiridine was added and stirred at room temperature for 24 h. Then, the mixture was poured onto ice, the sediment was filtered off, washed with water, dried and recrystallized from MeOH.

6-[(5-Chloropyridin-2-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine (3a). M.p.: 150–151 °C. ¹H NMR: δ = 8.25 (s, 1H, Ar), 7.83 (d, ³J = 8.8 Hz, 1H, Ar), 7.16 (s, 1H, Ar), 6.90 (d, ³J = 8.8 Hz, 1H, Ar), 6.87 (s, 1H, Ar), 5.69–5.70 (m, 1H, CH), 4.32–4.33 (m, 2H, NCH₂), 3.57–3.60 (m, 1H, SCH₂), 3.47 (dd, ²J = 13.2 Hz, ³J = 5.4 Hz, 1H, SCH₂). ¹³C NMR: δ = 160.80 (Py), 145.32 (Py), 140.04 (Py), 135.83 (C^8a), 128.20 (C²), 124.54 (Py), 121.80 (C³), 113.35 (Py), 65.33 (C⁶), 48.56 (C⁵), 28.86 (C⁷). LC-MS: m/z = 268 [M + 1] (100%). Anal. Calcd. for C₁₁H₁₀ClN₃OS, %: C, 49.35; H, 3.76; N, 15.69. Found, %: C, 49.48; H, 3.77; N, 15.54.

6-{[5-(Trifluoromethyl)pyridin-2-yl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine (3b). M.p.: 130–131 °C. ¹H NMR: δ = 8.64 (s, 1H, Ar), 8.09 (d, ³J = 8.8 Hz, 1H, Ar), 7.18 (s, 1H, Ar), 7.05 (d, ³J = 8.4 Hz, 1H, Ar), 6.88 (s, 1H, Ar), 5.82–5.85 (m, 1H, CH), 4.37–4.38 (m, 2H, NCH₂), 3.61–3.65 (m, 1H, SCH₂), 3.52 (dd, ²J = 13.4 Hz, ³J = 5.4 Hz, 1H, SCH₂). ¹³C NMR: δ = 168.58 (Py), 145.31 (q, ³J_CF = 4.5 Hz, Py), 137.42 (q, ⁴J_CF = 3.0 Hz, Py), 135.80 (C^8a), 128.21 (C²), 124.42 (d, ¹J_CF = 270.0 Hz, CF₃), 121.82 (C³), 119.93 (q, ²J_CF = 33.0 Hz, Py), 112.45 (Py), 65.73 (C⁶), 48.52 (C⁵), 28.80 (C⁷). LC-MS: m/z = 302 [M + 1] (100%). Anal. Calcd. for C₁₂H₁₀F₃N₃OS, %: C, 47.84; H, 3.35; N, 13.95. Found, %: C, 48.02; H, 3.32; N, 13.89.

6-[(6,7-Dihydro-5H-imidazo[2,1-b][1,3]thiazin-6-yl)oxy]nicotinonitrile (3c). M.p.: 182–183 °C. ¹H NMR: δ = 8.74 (s, 1H, Ar), 8.18 (d, ³J = 8.8 Hz, 1H, Ar), 7.17 (s, 1H, Ar), 7.04 (d, ³J = 8.8 Hz, 1H, Ar), 6.87 (s, 1H, Ar), 5.81–5.85 (m, 1H, CH), 4.35–4.36 (m, 2H, NCH₂), 3.60–3.64 (m, 1H, SCH₂), 3.44 (dd, ²J = 13.6 Hz, ³J = 5.2 Hz, 1H, SCH₂). ¹³C NMR: δ = 164.24 (Py), 152.49 (Py), 143.20 (Py), 135.76 (C^8a), 128.24 (C²), 121.82 (C³), 117.59 (Py), 112.66 (Py), 103.11 (CN), 65.97 (C⁶), 48.50 (C⁵), 28.80 (C⁷). LC-MS: m/z = 259 [M + 1] (100%). Anal. Calcd. for C₁₂H₁₀N₄OS, %: C, 55.80; H, 3.90; N, 21.69. Found, %: C, 56.02; H, 3.92; N, 21.60.

6-[(3,5-Dichloropyridin-2-yl)oxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine (3d). M.p.: 163–164 °C. ¹H NMR: δ = 8.24 (s, 1H, Ar), 8.17 (s, 1H, Ar), 7.17 (s, 1H, Ar), 6.87 (s, 1H, Ar), 5.75–5.77 (m, 1H, CH), 4.36–4.38 (m, 2H, NCH₂), 3.58–3.61 (m, 1H, SCH₂), 3.46–3.50 (m, 1H, SCH₂). ¹³C NMR: δ = 156.32 (Py), 143.54 (Py), 139.34 (Py), 135.82 (C^8a), 128.24 (C²), 124.35 (Py), 121.78 (C³), 118.58 (Py), 66.85 (C⁶), 48.42 (C⁵), 28.84 (C⁷). LC-MS: m/z = 302 [M + 1] (100%). Anal. Calcd. for C₁₁H₉Cl₂N₃OS, %: C, 43.72; H, 3.00; N, 13.91. Found, %: C, 43.88; H, 2.97; N, 14.04.

6-{[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine (3e). M.p.: 113–114 °C. ¹H NMR: δ = 8.57 (s, 1H, Ar), 8.37 (s, 1H, Ar), 7.16 (s, 1H, Ar), 6.86 (s, 1H, Ar), 5.85–5.88 (m, 1H, CH), 4.38–4.40 (m, 2H, NCH₂), 3.61–3.64 (m, 1H, SCH₂), 3.51 (dd, ²J = 10.6 Hz, ³J = 4.6 Hz, 1H, SCH₂). ¹³C NMR: δ = 159.97 (Py), 143.26 (q, ³J_CF = 3.75 Hz, Py), 136.87 (q, ⁴J_CF = 2.5 Hz, Py), 135.78 (C^8a), 128.23 (C²), 123.52 (d, ¹J_CF = 270.0 Hz, CF₃), 121.79 (C³), 120.83 (q, ²J_CF = 33.75 Hz, Py), 118.67 (Py), 67.34 (C⁶), 48.37 (C⁵), 28.77 (C⁷). LC-MS: m/z = 336 [M + 1] (100%). Anal. Calcd. for C₁₂H₉ClF₃N₃OS, %: C, 42.93; H, 2.70; N, 12.52. Found, %: C, 43.08; H, 2.67; N, 12.64.

2,3-Diphenyl-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine (3f). M.p.: 154–155 °C. ¹H NMR: δ = 8.54 (s, 1H, Ar), 8.05 (d, ³J = 9.0 Hz, 1H, Ar), 7.43–7.44 (m, 3H, Ar), 7.33–7.34 (m, 2H, Ar), 7.28–7.29 (m, 2H, Ar), 7.14–7.17 (m, 2H, Ar), 7.07–7.10 (m, 1H, Ar), 7.05 (d, ³J = 8.4 Hz, 1H, Ar), 5.80–5.82 (m, 1H, CH), 4.13–4.16 (m, 1H, NCH₂), 3.92–3.95 (m, 1H, NCH₂), 3.62–3.64 (m, 1H, SCH₂), 3.53–3.57 (m, 1H, SCH₂). ¹³C NMR: δ = 164.49 (Py), 145.22 (q, ³J_CF = 4.5 Hz, Py), 137.38 (q, ⁴J_CF = 3.0 Hz, Py), 137.01 (C^8a), 136.83 (C³), 134.62, 130.97, 130.19 (Ar), 129.85 (C²), 129.54, 129.22, 128.51, 126.67, 126.40 (Ar), 124.39 (d, ¹J_CF = 270.0 Hz, CF₃), 119.95 (q, ²J_CF = 33.0 Hz, Py), 112.47 (Py), 65.92 (C⁶), 47.33 (C⁵), 28.40 (C⁷). LC-MS: m/z = 454 [M + 1] (100%). Anal. Calcd. for C₂₄H₁₈F₃N₃OS, %: C, 63.57; H, 4.00; N, 9.27. Found, %: C, 63.75; H, 3.97; N, 9.19.

6-[(2,3-Diphenyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-6-yl)oxy]nicotinonitrile (3g). M.p.: 235–236 °C. ¹H NMR: δ = 8.69 (s, 1H, Ar), 8.16–8.19 (m, 1H, Ar), 7.45–7.49 (m, 5H, Ar), 7.33–7.35 (m, 4H, Ar), 7.17–7.20 (m, 1H, Ar), 7.06–7.13 (m, 1H, Ar), 5.79–5.85 (m, 1H, CH), 4.14–4.17 (m, 1H, NCH₂), 3.90–3.94 (m, 1H, NCH₂), 3.63–3.66 (m, 1H, SCH₂), 3.52–3.57 (m, 1H, SCH₂). ¹³C NMR: δ = 164.22 (Py), 152.50 (Py), 143.19 (Py), 136.99 (C^8a), 136.88 (C³), 134.65, 131.05, 130.22 (Ar), 129.90 (C²), 129.65, 129.32, 128.61, 126.77, 126.47 (Ar), 117.64 (CN), 112.76, 103.19 (Py), 66.15 (C⁶), 47.41 (C⁵), 28.39 (C⁷). LC-MS: m/z = 411 [M + 1] (100%). Anal. Calcd. for C₂₄H₁₈N₄OS, %: C, 70.22; H, 4.42; N, 13.65. Found, %: C, 70.32; H, 4.44; N, 13.58.

6-[(3,5-Dichloropyridin-2-yl)oxy]-2,3-diphenyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine (3h). M.p.: 165–166 °C. ¹H NMR: δ = 8.20 (s, 2H, Ar), 7.46–7.49 (m, 3H, Ar), 7.30–7.35 (m, 5H, Ar), 7.16–7.20 (m, 2H, Ar), 7.11–7.13 (m, 1H, Ar), 5.72–5.76 (m, 1H, CH), 4.09–4.12 (m, 1H, NCH₂), 3.93–3.98 (m, 1H, NCH₂), 3.61–3.64 (m, 1H, SCH₂), 3.50–3.55 (m, 1H, SCH₂). ¹³C NMR: δ = 155.86, 143.23, 138.86 (Py), 136.65 (C^8a), 136.39 (C³), 134.23, 130.57, 129.84 (Ar), 129.45 (C²), 129.16, 128.83, 128.10, 126.24, 125.92 (Ar), 124.00, 118.17 (Py), 66.98 (C⁶), 46.63 (C⁵), 28.17 (C⁷). LC-MS: m/z = 455 [M + 1] (100%). Anal. Calcd. for C₂₃H₁₇Cl₂N₃OS, %: C, 60.80; H, 3.77; N, 9.25. Found, %: C, 60.94; H, 3.73; N, 9.16.

6-{[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}-2,3-diphenyl-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine (3i). M.p.: 159–160 °C. ¹H NMR: δ = 8.49 (s, 1H, Ar), 8.36 (s, 1H, Ar), 7.42–7.44 (m, 3H, Ar), 7.29–7.34 (m, 4H, Ar), 7.08–7.15 (m, 3H, Ar), 5.83–5.87 (m, 1H, CH), 4.12–4.14 (m, 1H, NCH₂), 3.98–4.00 (m, 1H, NCH₂), 3.64–3.66 (m, 1H, SCH₂), 3.54–3.56 (m, 1H, SCH₂). ¹³C NMR: δ = 159.47 (Py), 142.79 (q, ³J_CF = 3.75 Hz, Py), 136.65 (C^8a + C³), 136.45 (q, ⁴J_CF = 2.5 Hz, Py), 134.20, 130.55, 129.81 (Ar), 129.47 (C²), 129.14, 128.83, 128.09, 126.24, 125.94 (Ar), 123.03 (d, ¹J_CF = 270.0 Hz, CF₃), 120.47 (q, ²J_CF = 33.75 Hz, Py), 118.28 (Py), 67.50 (C⁶), 46.61 (C⁵), 28.15 (C⁷). LC-MS: m/z = 488 [M + 1] (100%). Anal. Calcd. for C₂₄H₁₇ClF₃N₃OS, %: C, 59.08; H, 3.51; N, 8.61. Found, %: C, 59.25; H, 3.47; N, 8.49.

3-{[5-(Trifluoromethyl)pyridin-2-yl]oxy}-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine (3j). M.p.: 140–141 °C. ¹H NMR: δ = 8.66 (s, 1H, Ar), 8.08 (d, ³J = 9.2 Hz, 1H, Ar), 7.48 (d, ³J = 7.6 Hz, 1H, Ar), 7.43–7.45 (m, 1H, Ar), 7.13–7.19 (m, 2H, Ar), 7.05 (d, ³J = 8.4 Hz, 1H, Ar), 6.87 (s, 1H, Ar), 6.00–6.04 (m, 1H, CH), 4.57–4.61 (m, 1H, NCH₂), 4.48–4.52 (m, 1H, NCH₂), 3.75–3.78 (m, 1H, SCH₂), 3.66 (dd, ²J = 13.4 Hz, ³J = 5.4 Hz, 1H, SCH₂). ¹³C NMR: δ = 164.50 (Py), 146.24 (C^10a), 145.33 (q, ³J_CF = 4.5 Hz, Py), 143.05 (C^9a), 137.47 (q, ⁴J_CF = 3.0 Hz, Py), 136.20 (C^5a), 124.42 (d, ¹J_CF = 270.0 Hz, CF₃), 122.42 (C⁸), 121.47 (C⁷), 120.02 (q, ²J_CF = 33.0 Hz, Py), 117.61 (Py), 112.47 (C⁹), 109.25 (C⁶), 65.06 (C³), 46.59 (C⁴), 28.48 (C²). LC-MS: m/z = 352 [M + 1] (100%). Anal. Calcd. for C₁₆H₁₂F₃N₃OS, %: C, 54.70; H, 3.44; N, 11.96. Found, %: C, 54.88; H, 3.47; N, 11.84.

6-[(3,4-Dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-3-yl)oxy]nicotinonitrile (3h). M.p.: 161–162 °C. ¹H NMR: δ = 8.74 (s, 1H, Ar), 7.46 (s, 1H, Ar), 7.40 (s, 1H, Ar), 7.00–7.13 (m, 4H, Ar), 5.97–6.00 (m, 1H, CH), 4.55–4.57 (m, 1H, NCH₂), 4.46–4.48 (m, 1H, NCH₂), 3.73–3.75 (m, 1H, SCH₂), 3.61–3.63 (m, 1H, SCH₂). ¹³C NMR: δ = 164.14 (Py), 152.49 (Py), 146.19 (C^10a), 143.14 (Py), 143.01 (C^9a), 136.16 (C^5a), 122.45 (C⁸), 121.51 (C⁷), 117.62 (Py), 117.60 (Py), 112.66 (C⁹), 109.24 (C⁶), 103.19 (CN), 65.26 (C³), 46.56 (C⁴), 28.48 (C²). LC-MS: m/z = 309 [M + 1] (100%). Anal. Calcd. for C₁₆H₁₂N₄OS, %: C, 62.32; H, 3.92; N, 18.17. Found, %: C, 62.45; H, 3.89; N, 18.29.

3-[(3,5-dichloropyridin-2-yl)oxy]-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine (3l). M.p.: 203–204 °C. ¹H NMR: δ = 8.25 (s, 1H, Ar), 8.14 (s, 1H, Ar), 7.41–7.46 (m, 2H, Ar), 7.11–7.16 (m, 2H, Ar), 5.90–5.94 (m, 1H, CH), 4.48–4.50 (m, 1H, NCH₂), 4.54–4.56 (m, 1H, NCH₂), 3.70–3.73 (m, 1H, SCH₂), 3.58–3.62 (m, 1H, SCH₂). ¹³C NMR: δ = 155.81 (Py), 145.83 (C^10a), 143.32 (Py), 142.64 (C^9a), 138.89 (Py), 135.78 (C^5a), 124.04 (Py), 121.99 (C⁸), 121.05 (C⁷), 118.19 (Py), 117.20 (C⁹), 108.87 (C⁶), 65.63 (C³), 46.07 (C⁴), 28.06 (C²). LC-MS: m/z = 352 [M + 1] (100%). Anal. Calcd. for C₁₅H₁₁Cl₂N₃OS, %: C, 51.15; H, 3.15; N, 11.93. Found, %: C, 51.36; H, 3.11; N, 11.82.

3-{[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-b][1,3]thiazine (3m). M.p.: 165–166 °C. ¹H NMR: δ = 8.61 (s, 1H, Ar), 8.39 (s, 1H, Ar), 7.42–7.47 (m, 2H, Ar), 7.11–7.16 (m, 2H, Ar), 6.04–6.07 (m, 1H, CH), 4.58–4.61 (m, 1H, NCH₂), 4.51–4.54 (m, 1H, NCH₂), 3.74–3.77 (m, 1H, SCH₂), 3.63–3.67 (m, 1H, SCH₂). ¹³C NMR: δ = 159.87 (Py), 146.19 (C^10a), 143.34 (q, ³J_CF = 3.75 Hz, Py), 143.05 (C^9a), 136.97 (q, ⁴J_CF = 2.5 Hz, Py), 136.19 (C^5a), 123.52 (d, ¹J_CF = 270.0 Hz, CF₃), 122.42 (C⁸), 121.47 (C⁷), 120.92 (q, ²J_CF = 33.75 Hz, Py), 118.68 (Py), 117.63 (C⁹), 109.31 (C⁶), 66.54 (C³), 46.50 (C⁴), 28.27 (C²). LC-MS: m/z = 386 [M + 1] (100%). Anal. Calcd. for C₁₆H₁₁ClF₃N₃OS, %: C, 49.81; H, 2.87; N, 10.89. Found, %: C, 50.01; H, 2.89; N, 10.97.

2.3. Anti-Inflammatory (Anti-Exudative) Activity

The male albino rats, weighing 180–220 g, were used for the anti-exudative activity studies. The animals were treated humanely throughout the study period, adhering to the guideline for the use and care of animals in the declaration of Helsinki (National Research Council, 2011). The experiment design and study protocol were approved by the Animal Ethics Committee of the Danylo Halytsky Lviv National Medical University, Lviv, Ukraine, protocol No.10, 17 March 2021. The carrageenin-induced hind paw edema was produced by the method of Winter et al. [14]. The synthesized compounds were intraperitoneally injected in a dose of 50 mg/kg (in saline solution with one drop of Tween-80™). Diclofenac (tablets “Diclofenac sodium”, “Zdorovja narodu”, Ukraine) in a dose of 8 mg/kg was used as reference drug. The antiexudative activity (inflammation inhibition) was expressed as a decrease in the rats’ paw edema and was calculated using the equation and was given in a percentage:

Inhibition = (∆V_control − ∆V_experiment)/∆V_control × 100%

where, ΔV_control and ΔV_experiment—the mean values of the volume difference for control and experimental animal hinds, respectively.

3. Results and Discussion

Used in the present work, the synthetic approach is based on the utilization of structure-modified imidazolinthiones as starting the building blocks for the formation of the imidazo[2,1-b][1,3]thiazine core. The interaction of the last ones in the soft conditions with epichlorohydrin led to the key 3-hydroxy-imidazo[2,1-b][1,3]thiazines 2a–c [5]. The various polysubstituted 2-chloropyridines were studied in the alkylation reaction with early synthesized compounds 2a–c (Scheme 1). As a result, the target (2-pyridinyloxy) substituted imidazo[2,1-b][1,3]thiazines 3a–m were obtained with satisfied yields (in the presence of equimolar amounts of 60% sodium hydride in an anhydrous DMF medium) at room temperature, and the selective nucleophilic substitution in position 2 of the pyridine ring was observed.

The control of reaction process and products formation was monitored by TLC. The compounds’ structure characterization and yield are presented in the Table 1.

The structure of compounds was studied and confirmed using 1H, 13C NMR spectroscopy and LC-MS spectrometry.

3.1. In Silico Evaluation of Drug-Likeness Properties

The drug-likeness properties of the derivatives 3a–m were determined based on Lipinski and Veber rules and evaluated in silico using the SwissAdme of the Swiss Institute of Bioinformatics website [15] (Table 2).

All tested compounds comply with Lipinski’s rules of five and Veber’s rules, except derivatives 3h and 3i, for which the calculated MlogP values were higher (4.69 and 4.28, accordingly) than limited for the Mlog P parameter (accepted ≤ 4.15), in line with the Lipinski’s rules.

3.2. Study of Anti-Inflammatory (Anti-Exudative) Activity of Synthesized Compounds 3a–m

The anti-inflammatory (anti-exudative) activity of all synthesized compounds 3a–m was investigated on the in vivo carrageenin model of the total edema of the hind paws of albino rats [14]. The study results are presented in Table 3.

The synthesized compounds 3a–m possess different levels of anti-inflammatory activity (inhibition index was in the range of 3.7 to 39.1%). From the point of view of the “structure—anti-inflammatory activity” derivatives 3a–d with an unsubstituted imidazole ring in the imidazo[2,1-b][1,3]thiazine core, they are characterized with a total higher activity level. The compound 3c containing cyano-group in the pyridine ring was the most active among derivatives 3a–d, whereas the change of cyano-group on the chlorine or threefluormethyl-group led to an insignificant activity decrease. Derivative 3l was found to be the most active inside the tested group, with an inflammation inhibition value of 39.1%, which is only 15.5% less compared to the same data for the reference drug, diclofenac.

4. Conclusions

In the present work, a synthetic approach to (2-pyridinyloxy) substituted imidazo[2,1-b][1,3]thiazines is described. The polysubstituted 2-chloropyridines were studied in the alkylation reaction with some 3-hydroxy-imidazo[2,1-b][1,3]thiazines, and the selective nucleophilic substitution in position 2 of pyridine ring was observed. The synthesized (2-pyridinyloxy) substituted imidazo[2,1-b][1,3]thiazines comply with Lipinski’s rules of five and Veber’s rules and possess promising anti-inflammatory properties in the carrageenan test in vivo. Such drug-like and pharmacological features of synthesized derivatives argue for forthcoming studies as potential non-steroidal anti-inflammatory agents.

Author Contributions

Conceptualization, N.S. and M.V.; methodology and experimental work, N.S., S.H., L.S. and M.V.; data analysis, N.S., S.H., L.S. and M.V.; writing—review and editing, N.S., S.H., L.S. and M.V.; project administration and supervision, N.S. and M.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethic Committee of the Danylo Halytsky Lviv National Medical University, Lviv, Ukraine (protocol No. 10 from 17 March 2021).

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in this article.

Acknowledgments

This research was supported by the Lesya Ukrainka Volyn National University, Danylo Halytsky Lviv National Medical University and Institute of Organic Chemistry of National Academy of Sciences of Ukraine, which is gratefully acknowledged.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Pharmacology profile of imidazo[2,1-b][1,3]thiazine scaffold.

Scheme 1. Synthesis of compounds 3a–m. Reagents and conditions: (i) 1a–c (10 mmol), 2-(chloromethyl)oxirane (10 mmol), NaOH (10 mmol), MeOH (25 mL), stirring, r.t. 24 h; (ii) 2a–c (10 mmol), 60% NaH in mineral oil (10 mmol), appropriate derivate of 2-chloropiridine (10 mmol), DMF (4 mL), stirring, r.t. 24 h.

Table 1. Structure characterization and yeilds of synthesized compounds 3a–m.

Compound	R	R¹	R²	R³	R⁴	Yield, %
3a	H	H	H	H	Cl	55
3b	H	H	H	H	CF₃	60
3c	H	H	H	H	CN	58
3d	H	H	Cl	H	Cl	59
3e	H	H	Cl	H	CF₃	62
3f	Ph	Ph	H	H	CF₃	67
3g	Ph	Ph	H	H	CN	57
3h	Ph	Ph	Cl	H	Cl	61
3i	Ph	Ph	Cl	H	CF₃	66
3j	(-CH=CH-)₂		H	H	CF₃	67
3k	(-CH=CH-)₂		H	H	CN	59
3l	(-CH=CH-)₂		Cl	H	Cl	62
3m	(-CH=CH-)₂		Cl	H	CF₃	65

Table 2. Drug-likeness parameters of derivatives 3a-m according to Lipinski and Veber rules.

Compounds	Lipinski Rules					Veber Rules	Violations of Rules
Compounds	MW ≤ 500	log P/Mlog P ≤ 5/≤ 4.15 ¹	NHD ≤ 5 ²	NHA ≤ 10 ³	NBR ≤ 10 ⁴	TPSA ≤ 140 ⁵	Violations of Rules
3a	267.73	2.09/1.41	0	3	2	65.24	0
3b	301.29	2.25/1.82	0	6	3	65.24	0
3c	258.30	1.94/0.23	0	4	2	89.03	0
3d	302.18	2.58/1.95	0	3	2	65.24	0
3e	353.73	2.41/2.34	0	6	3	65.24	0
3f	453.48	3.61/4.11	0	6	5	65.24	0
3g	410.49	3.03/2.63	0	4	4	89.03	0
3h	454.37	3.91/4.28	0	3	4	65.24	1
3i	487.92	3.65/4.69	0	6	5	65.24	1
3j	351.35	2.74/3.15	0	6	3	65.24	0
3k	308.36	2.33/1.62	0	4	2	89.03	0
3l	352.24	2.96/3.30	0	3	2	65.24	0
3m	385.79	2.84/3.66	0	6	3	65.24	0

¹ Mlog P: Moriguchi log P [16,17]; ² NHD: number of hydrogen bond donors; ³ NHA: number of hydrogen acceptors; ⁴ NBR: number of rotatable bonds; ⁵ TPSA: total polar surface area.

Table 3. In vivo anti-inflammatory activity of compounds 3a–m on carrageenin-induced paw edema in white rats (intraperitoneally use; doses: carrageenin 1%, 0.1 mL; Diclofenac sodium—8 mg/kg, tested compounds—50 mg/kg; M ± m; n = 6 in each group).

Compounds/Reference Drug, Doses	Rat Hind Limb Volume Increase, 4 h, %	Inflammation Inhibition, %
Carrageenin	122.9 ± 10.8	-
Diclofenac sodium	65.9 ± 5.3	46.3
3a	81.6	33.8
3b	82.1	33.2
3c	78.9	35.8
3d	84.8	31.0
3e	90.4	26.4
3f	96.2	21.7
3g	118.4	3.7
3h	114.9	6.5
3i	104.1	15.3
3j	105.8	13.9
3k	101.6	17.3
3l	74.8	39.1
3m	96.1	21.8

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Slyvka, N.; Holota, S.; Saliyeva, L.; Vovk, M. Synthetic Approach to Diversified Imidazo[2,1-b][1,3]thiazines and Its Evaluation as Non-Steroidal Anti-Inflammatory Agents. Chem. Proc. 2022, 8, 82. https://doi.org/10.3390/ecsoc-25-11692

AMA Style

Slyvka N, Holota S, Saliyeva L, Vovk M. Synthetic Approach to Diversified Imidazo[2,1-b][1,3]thiazines and Its Evaluation as Non-Steroidal Anti-Inflammatory Agents. Chemistry Proceedings. 2022; 8(1):82. https://doi.org/10.3390/ecsoc-25-11692

Chicago/Turabian Style

Slyvka, Nataliia, Serhii Holota, Lesya Saliyeva, and Mykhailo Vovk. 2022. "Synthetic Approach to Diversified Imidazo[2,1-b][1,3]thiazines and Its Evaluation as Non-Steroidal Anti-Inflammatory Agents" Chemistry Proceedings 8, no. 1: 82. https://doi.org/10.3390/ecsoc-25-11692

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Synthetic Approach to Diversified Imidazo[2,1-b][1,3]thiazines and Its Evaluation as Non-Steroidal Anti-Inflammatory Agents^†

Abstract

1. Introduction

2. Methods

2.1. General Information

2.2. Synthesis and Characterization of Compounds 3a–m

2.3. Anti-Inflammatory (Anti-Exudative) Activity

3. Results and Discussion

3.1. In Silico Evaluation of Drug-Likeness Properties

3.2. Study of Anti-Inflammatory (Anti-Exudative) Activity of Synthesized Compounds 3a–m

4. Conclusions

Author Contributions

Funding

Institutional Review Board Statement

Informed Consent Statement

Data Availability Statement

Acknowledgments

Conflicts of Interest

References

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Synthetic Approach to Diversified Imidazo[2,1-b][1,3]thiazines and Its Evaluation as Non-Steroidal Anti-Inflammatory Agents †

Abstract

1. Introduction

2. Methods

2.1. General Information

2.2. Synthesis and Characterization of Compounds 3a–m

2.3. Anti-Inflammatory (Anti-Exudative) Activity

3. Results and Discussion

3.1. In Silico Evaluation of Drug-Likeness Properties

3.2. Study of Anti-Inflammatory (Anti-Exudative) Activity of Synthesized Compounds 3a–m

4. Conclusions

Author Contributions

Funding

Institutional Review Board Statement

Informed Consent Statement

Data Availability Statement

Acknowledgments

Conflicts of Interest

References

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Synthetic Approach to Diversified Imidazo[2,1-b][1,3]thiazines and Its Evaluation as Non-Steroidal Anti-Inflammatory Agents^†