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DOI: 10.1055/a-2456-9620
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Small Molecules in Medicinal Chemistry

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

Abdullah Y. A. Alzahrani
a   Department of Chemistry, Faculty of Science and Arts, King Khalid University, Abha, Mohail Assir, Saudi Arabia
,
Eman A. E. El-Helw
b   Chemistry Department, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt
,
Sayed K. Ramadan  ∗
b   Chemistry Department, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt
› Author AffiliationsThe authors received no funding for this work.
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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

Supporting Information



Publication History

Received: 07 August 2024

Accepted after revision: 29 October 2024

Accepted Manuscript online:
29 October 2024

Article published online:
04 December 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

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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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