Some Thiazolopyrimidine Derivatives: Synthesis, DFT, Cytotoxicity, and Pharmacokinetics Modeling Study

Abdullah Y. A. Alzahrani; Eman A. E. El-Helw; Sayed K. Ramadan

doi:10.1055/a-2456-9620

Synlett, Table of Contents

Synlett 2025; 36(17): 2895-2905
DOI: 10.1055/a-2456-9620

letter

Small Molecules in Medicinal Chemistry

Some Thiazolopyrimidine Derivatives: Synthesis, DFT, Cytotoxicity, and Pharmacokinetics Modeling Study

Authors

Abdullah Y. A. Alzahrani

^aDepartment of Chemistry, Faculty of Science and Arts, King Khalid University, Abha, Mohail Assir, Saudi Arabia
Eman A. E. El-Helw

^bChemistry Department, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt
Sayed K. Ramadan ∗

^bChemistry Department, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt

Abstract

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Abstract

A pyrimidinethione candidate carrying pyrazole and thiophene scaffolds was produced by a Biginelli cyclocondensation reaction of a pyrazolecarbaldehyde with pentan-2,4-dione and thiourea. To create some heteroannulated thiazolopyrimidines, the pyrimidinethione was subjected to cyclocondensation reactions with ethyl chloroacetate, 1,2-dibromoethane, chloroacetonitrile, and oxalyl chloride. A DFT simulation was performed for a frontier-orbital analysis to determine the molecular geometry. Among the products, 6-acetyl-7-methyl-5-[1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl]-5H-[1,3]thiazolo[3,2-a]pyrimidine-2,3-dione displayed the highest softness and the lowest energy gap in the DFT calculations. Moreover, it had the highest electrophilicity index, suggesting possible biological impacts. The compounds obtained were evaluated against cell lines of breast adenocarcinoma (MCF7) and hepatocellular carcinoma (HepG2) as antiproliferative agents. A simulation of the molecular docking of our compounds with the epidermal growth factor receptor demonstrated the rationality of our design and identified the binding mode. A model pharmacokinetics analysis showed that the products have the expected and desirable drug-like and bioavailability properties.

Key words

cytotoxicity - density functional theory - pharmacokinetic modelling - pyrimidinethiones - thiazolopyrimidines

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References

References and Notes
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FTIR (ν, cm^-1): 3285, 3190 (NH), 1706 (C=O), 1612 (C=N), 1180 (C=S) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.02 (s, 3 H, CH₃CO), 2.28 (s, 3 H, CH₃), 5.48 (s, 1 H, C4-H pyrimidine), 7.31–7.53 (m, 5 H, Ar-H), 7.81–7.88 (m, 3 H, Ar-H), 8.32 (s, 1 H, C5-H pyrazole), 9.72 (br s, 1 H, NH, exchangeable), 10.23 (br s, 1 H, NH, exchangeable). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 8.82, 30.66, 46.12, 111.71, 118.91, 124.93, 126.95, 128.46, 128.55, 128.88 (2 C), 128.96, 129.97 (2 C), 133.23, 139.71, 144.41, 150.78, 174.26 (C=O), 195.01 (C=S). MS (EI, 70 eV): m/z (%) = 394.43 (11.50) [M⁺]. Anal. calcd for C₂₀H₁₈N₄OS₂ (394.51): C, 60.89; H, 4.60; N, 14.20. Found: C, 60.78; H, 4.52; N, 14.19. 6-Acetyl-7-methyl-5-[1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-3(2H)-one (5) A mixture of pyrimidinethione 4 (2 mmol), ethyl chloroacetate (2 mmol), and fused NaOAc (2 mmol) in absolute EtOH (20 mL) was refluxed for 5 h. The solid that precipitated after cooling was collected and crystallized from EtOH to give brown crystals; yield: 74%; mp 243–245 °C. FTIR (ν, cm^-1): 1705, 1690 (C=O) cm^–1.¹H NMR (400 MHz, DMSO-d ₆): δ = 2.15 (s, 3 H, CH₃CO), 2.21 (s, 3 H, CH₃), 3.70 (s, 2 H, CH₂), 6.36 (s, 1 H, C4-H pyrimidine), 7.29–7.61 (m, 5 H, Ar-H), 7.78–8.04 (m, 3 H, Ar-H), 8.77 (s, 1 H, C5-H pyrazole). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 23.76, 31.10, 39.38, 48.15, 118.82, 119.90, 122.51, 123.42, 125.10, 126.34, 128.68 (2), 129.01, 129.17 (2), 129.94, 130.09, 134.20, 138.42, 150.31, 165.50, 176.61. Anal. calcd for C₂₂H₁₈N₄O₂S₂ (434.53): C, 60.81; H, 4.18; N, 12.89. Found: C, 60.72; H, 4.13; N, 12.88. 1-{7-Methyl-5-[1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl]-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-6-yl}ethanone (6) A mixture of pyrimidinethione 4 (2 mmol), 1,2-dibromoethane (2 mmol), and anhyd NaOAc (2 mmol) in absolute EtOH (20 mL) was refluxed for 6 h. The solid that precipitated after cooling was collected and crystallized from EtOH to give brown crystals; yield: 68%; mp 224–226 °C. FTIR (KBr): 1682 (C=O), 1625 (C=N) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.04 (s, 3 H, CH₃CO), 2.26 (s, 3 H, CH₃), 2.91–3.12 (t, J = 7.1 Hz, 2 H, S-CH₂), 3.71–3.92 (t, J = 7.1 Hz, 2 H, N–CH₂), 5.37 (s, 1 H, C₅-H thiazolopyrimidine), 7.20–8.02 (m, 8 H, Ar-H), 8.41 (s, 1 H, C₅-H pyrazole). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 21.2, 24.3, 27.3, 52.3, 65.5, 117.1, 118.8, 122.8, 124.2, 126.3, 127.4 (2), 128.6, 129.2 (2), 129.3, 131.2, 132.9, 139.5, 148.9, 150.7, 171.3. Anal. calcd for C₂₂H₂₀N₄OS₂ (420.55): C, 62.83; H, 4.79; N, 13.32. Found: C, 62.74; H, 4.73; N, 13.31. 1-{3-Amino-7-methyl-5-[1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl]-5H-[1,3]thiazolo[3,2-a]pyrimidin-6-yl}ethanone (7) A solution of pyrimidinethione 4 (2 mmol) and ClCH₂CN (2 mmol) in DMF (10 mL) was refluxed for 4 h. The mixture was allowed to cool to r.t. and then poured onto ice-cold H₂O. The precipitated solid was collected and crystallized from EtOH to afford brown crystals; yield: 62%; mp 245–247 °C. IR (ν, cm^-1): 3340, 3300 (NH₂), 1665 (C=O), 1628 (C=N) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.74 (s, 3 H, CH₃CO), 2.89 (s, 3 H, CH₃), 4.94 (s, 1 H, C₄-H pyrimidine), 5.02 (s, 1 H, C₅–H thiazolo), 7.13 (br s, 2 H, NH₂, exchangeable), 7.16–7.55 (m, 5 H, Ar-H), 7.75–8.74 (m, 3 H, Ar-H), 9.23 (s, 1 H, C₅-H pyrazole). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 31.2, 36.2, 40.6, 119.1, 124.3, 126.4, 127.4 (2), 128.4, 128.8, 128.9 (2), 129.3, 129.9, 130.1, 131.3, 133.2, 135.4, 149.3, 150.5, 162.7. Anal. calcd for C₂₂H₁₉N₅OS₂ (433.55): C, 60.95; H, 4.42; N, 16.15. Found: C, 60.81; H, 4.35; N, 16.12. 6-Acetyl-7-methyl-5-[1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl]-5H-[1,3]thiazolo[3,2-a]pyrimidine-2,3-dione (8) A solution of pyrimidinethione 4 (2 mmol) and oxalyl chloride (2 mmol) in anhyd benzene (20 mL) was refluxed for 6 h in the presence of EtN₃ (0.5 mL). The solid that formed on cooling was collected and crystallized from benzene to give pale-brown crystals; yield: 69%; mp 254–256 °C. FTIR (ν, cm^-1): 1703, 1673 (C=O), 1655 (C=N) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.02 (s, 3 H, CH₃CO), 2.37 (s, 3 H, CH₃), 5.47 (s, 1 H, C₅-H thiazolopyrimidine), 7.29–7.58 (m, 5 H, Ar-H), 7.72–8.02 (m, 3 H, Ar-H), 8.31 (s, 1 H, C₅-H pyrazole). ¹³C NMR (100 MHz, DMSO): δ = 1.5, 27.1, 66.8, 117.4, 119.7, 123.1, 126.1, 127.3 (2), 128.8, 129.1, 129.2 (2), 131.8, 133.1, 139.4, 149.7, 151.8, 153.1, 164.2, 171.1, 175.3. MS (EI, 70 eV): m/z (%) = 448.15 (36.70) [M⁺]. Anal. calcd for C₂₂H₁₆N₄O₃S₂ (448.52): C, 58.91; H, 3.60; N, 12.49. Found: C, 58.82; H, 3.55; N, 12.51.
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38 Cytotoxicity Assay
Cell lines: Hepatocellular carcinoma (HepG2) and mammary gland breast cancer (MCF7) cell lines were obtained from ATCC through a holding company for biological products and vaccines (VACSERA, Cairo, Egypt). Chemical reagents: The reagents used were RPMI-1640 medium, MTT, DMSO, doxorubicin (Sigma Co., St. Louis, USA), and fetal bovine serum (FBS; GIBCO, Paisley, UK). Doxorubicin was used as a standard anticancer drug for comparison. MTT assay: The inhibitory effects of the prepared compounds on the growth of the various cell lines were measured by an MTT assay. Cell lines were cultured in RPMI-1640 medium with 10% FBS containing 100 units/mL penicillin and 100 μg/mL streptomycin at 37 °C in a 5% CO₂ incubator. The cell lines were seeded into a 96-well plate at a density of 1.0 × 10⁴ cells/well at 37 °C for 48 h under 5% CO₂. After incubation, the cells were treated with various concentrations of the compounds and incubated for 24 h. After 24 h of drug treatment, MTT solution (20 μL) at 5 mg/mL was added and the mixture was incubated for a further 4 h. DMSO (100 μL) was added to each well to dissolve the purple formazan that formed. A colorimetric assay at λ = 570 nm was performed by using a plate reader (EXL 800, Bio-Tech, Winoosky, VT, USA). The relative cell viability as a percentage was calculated by using the expression (A₅₇₀ treated sample/A₅₇₀ untreated sample) × 100.
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