PDF herunterladen
Synlett
DOI: 10.1055/s-0043-1775488
letter
Small Molecules in Medicinal Chemistry

Synthesis of Novel Coumarin-Appended Dihydrothiopyrimidinones and Evaluation of Their Binding Interactions with Bovine Serum Albumin

Debojyoti Das
,
Juheli Sadhukhan
,
Pabitra Mandal
,
Smritimoy Pramanik
,
Alomgir Shah Kabir
,
Susanta Sekhar Adhikari  ∗

S.S.A. acknowledges SERB-DST, New Delhi, India (project No. EMR/2017/002140) for financial support. S. Р. is grateful for financial assistance to DST-INSPIRE (DST/INSPIRE/04/2015/000345). D.D. acknowledges CSIR, India for doctoral research fellowship (award no.: 09/028(1171)/2021-EMR-I). J.S. sincerely thanks the UGC for financial support (Fellowship ID - 201610097551). P.M. acknowledges CSIR, India (award no.: 09/028(1105)/2019-EMR-I) for his fellowship. A.S.K. is also thankful to UGC for the fellowship (Fellowship ID - 231610266490). We also thank the University of Calcutta for providing research infrastructures for this work.
› Weitere Informationen
   Lizenzen und Reprints Alle Artikel dieser Rubrik


Abstract

A novel one-pot, single-step multicomponent approach for the acid-catalyzed synthesis of coumarin-appended dihydrothiopyrimidinones is developed by utilizing a coumarin-based 1,3-biselectrophile, thiourea, and different aldehydes at reflux temperature. This method utilizes cheap solvents (ethanol/acetonitrile) and enables the construction of a library of highly substituted coumarin-based dihydrothiopyrimidinones (CDHTPs), demonstrating a wide range of substrate compatibility and affording very good yields of products. The coumarin ring is incorporated in the dihydrothiopyrimidinones due to its wide range of biological efficacy and its excellent fluorescence properties in the visible region of the spectrum. The binding interactions of the obtained CDHTPs to bovine serum albumin (BSA) protein are evaluated using spectroscopic techniques, with ethyl 6-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-4-(4-hydroxyphenyl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate exhibiting the strongest binding interaction (K d = 2.3 μM. Various site markers are used in displacement assays, revealing that the above compound is bound to the subdomain IB. The structures of the obtained CDHTPs are confirmed by NMR and mass spectrometry.

Key words

multicomponent reaction - Biginelli synthesis - BSA binding - coumarins - dihydrothiopyrimidinones

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0043-1775488.
  • Supporting Information


Publikationsverlauf

Eingereicht: 12. März 2025

Angenommen nach Revision: 10. April 2025

Artikel online veröffentlicht:
05. Juni 2025

© 2025. Thieme. All rights reserved

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

 

  • References and Notes

  • 1 Behera S, Mohanty P, Dash PP, Mohapatra P, Shubhadarshinee L, Behera R, Barick AK, Mohapatra P, Jali BR. Biointerface Res. Appl. Chem. 2023; 13: 555
    Suche in Google Scholar
  • 2 Matos LH. S, Masson FT, Simeoni LA, Homem-de-Mello M. Eur. J. Med. Chem. 2018; 143: 1779
    CrossrefPubMedSuche in Google Scholar
  • 3 Khasimbi S, Ali F, Manda K, Sharma A, Chauhan G, Wakode S. Curr. Org. Synth. 2021; 18: 270
    PubMedSuche in Google Scholar
  • 4 Jalali HS, Shahri FS. M, Moeinpour F. J. Mol. Struct. 2022; 1252-132222
    PubMedSuche in Google Scholar
  • 5 Annunziata F, Pinna C, Dallavalle S, Tamborini L, Pinto A. Int. J. Mol. Sci. 2020; 21: 4618
    PubMedSuche in Google Scholar
  • 6 Hussain MK, Khatoon S, Khan MF, Akhtar MS, Ahamad S, Saquib M. Phytomedicine 2024; 134: 155972
    PubMedSuche in Google Scholar
  • 7 Cao D, Liu L, Verwilst P, Koo S, Jangjili P, Kim JS. Chem. Rev. 2019; 119: 10403
    CrossrefPubMedSuche in Google Scholar
  • 8 Sun XY, Liu T, Sun J, Wang XJ. RSC Adv. 2020; 10: 10826
    CrossrefPubMedSuche in Google Scholar
  • 9 Paul S, Sepay N, Sarkar S, Roy P, Dasgupta S, Sardar SP, Majhi A. New J. Chem. 2017; 41: 15392
    Suche in Google Scholar
  • 10 Sharma K, Yadav P, Sharma B, Panday M, Awasthi SK. J. Mol. Recognit. 2020; 33: 2834
    Suche in Google Scholar
  • 11 Nagarajaiah H, Mukhopadhyay A, Moorthy JN. Tetrahedron Lett. 2016; 57: 5135
    CrossrefSuche in Google Scholar
  • 12 Vitorio F, Pereira TM, Castro RN, Guedes GP, Graebin CS, Kummerle AE. New J. Chem. 2015; 39: 2323
    Suche in Google Scholar
  • 13 Ghosh A, Upadhyay P, Sarkar S, Das S, Bhattacharjee M, Bhattacharjee S, Ahir M, Guria S, Gupta P, Chattopadhyay S, Ghosh S, Adhikari S, Adhikary A. Biomater. Sci. 2021; 9: 5665
    PubMedSuche in Google Scholar
  • 14 Guria S, Ghosh A, Upadhyay P, Das MK, Mishra T, Adhikary A, Adhikari S. ACS Appl. Bio Mater. 2020; 3: 3099
    PubMedSuche in Google Scholar
  • 15 Ethyl 3-(7-(Diethylamino)-2-oxo-2H-chromen-3-yl)-3-oxopropanoate (3) 4-(Diethylamino)-2-hydroxybenzaldehyde (1) (1 mmol, solid compound) and diethyl 3-oxopentanedioate (2) (2 mmol, 1.113 g/mL) were mixed in EtOH (5 mL) and piperidine (0.1 mmol, 0.862 g/mL) was added gradually. The resulting mixture was stirred at room temperature for 24 h. The obtained precipitate was filtered, washed with petroleum ether (60–80 °C) (3 × 10 ml) and dried to give product 3 as a yellow solid (215.3 mg, 65%). 1H NMR (300 MHz, CDCl3): δ = 8.49 (s, 1 H), 7.40 (d, J = 9.0 Hz, 1 H), 6.62 (dd, J = 9.0, 2.5 Hz, 1 H), 6.45 (d, J = 2.3 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 4.08 (s, 2 H), 3.46 (q, J = 7.1 Hz, 4 H), 1.24 (t, J = 7.4 Hz, 9 H). 13C NMR (75 MHz, CDCl3): δ = 189.96, 168.19, 160.69, 158.66, 153.14, 148.32, 131.98,114.40, 109.88, 108.09, 96.33, 60.75, 48.66, 44.98, 13.89, 12.19.
  • 16 De SK, Gibbs RA. Synth. Commun. 2005; 35: 2645
    Suche in Google Scholar
  • 17 Biginelli Multicomponent Reaction; General Procedure Coumarin β-keto ester 3 (1 mmol), thiourea (4) (1.5 mmol) and the appropriate aromatic aldehyde 5 (1.2 mmol) were mixed in EtOH (5 mL) with HCl (37%, 0.1 mol%) or in MeCN (5 mL) with Sc(OTf)3 (5 mol%) at room temperature. The resulting mixture was heated at reflux for 12 h until the reaction was complete (as monitored by TLC). The solvent was evaporated under vacuum and EtOAc (60 mL) was added to the residue. The organic phase was washed with brine (3 × 10 mL), dried over Na2SO4 and concentrated under vacuum and. Purification of the residue was accomplished by silica gel column chromatography. Elution of the final product 6 was achieved with 40% acetone/petroleum ether.
  • 18 Ethyl 6-(7-(Diethylamino)-2-oxo-2H-chromen-3-yl)-4-(4-hydroxyphenyl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6a) Yield: 389.9 mg (79%); yellow solid; Rf = 0.22 (silica gel; Petroleum Ether-Acetone, 3:2); mp 165 °C. 1H NMR (300 MHz, DMSO-d 6): δ = 10.41 (s, 1 H), 9.64 (s, 1 H), 9.47 (s, 1 H), 7.81 (s, 1 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 8.2 Hz, 2 H), 6.74 (dd, J = 8.8, 6.7 Hz, 3 H), 6.58 (d, J = 2.4 Hz, 1 H), 5.14 (d, J = 3.6 Hz, 1 H), 3.84 (q, J = 7.1 Hz, 2 H), 3.45 (q, J = 7.0 Hz, 4 H), 1.14 (t, J = 6.9 Hz, 6 H), 0.88 (t, J = 7.1 Hz, 3 H). 13C NMR (75 MHz, DMSO-d 6): δ = 174.45, 164.90, 159.73, 157.54, 156.67, 151.32, 143.06, 140.76, 133.88, 130.24, 128.48, 115.66, 115.24, 109.51, 107.82, 103.77, 96.76, 60.11, 54.18, 44.56, 14.16, 12.80. HRMS (TOF MS ES+): m/z [M + H]+ calcd for C26H28N3O5S: 494.1671; found: 494.1710.
  • 19 Lakowicz JR. Principles of Fluorescence Spectroscopy . Springer Science+Business Media; New York: 2006
    Suche in Google Scholar
  • 20 Likussar W, Boltz DF. Anal. Chem. 1971; 43: 1265
    Suche in Google Scholar
  • 21 Kumar S, Ghosh P, Roy P, Nair MS. J. Mol. Struct. 2025; 1323: 140765
    Suche in Google Scholar
  • 22 Rippe R. B.I.F. Futura 1997; 12: 20
    Suche in Google Scholar
  • 23 Tantimongcolwat T, Prachayasittikul S, Prachayasittikul V. Spectrochim. Acta, Part A 2019; 216: 25
    Suche in Google Scholar
  • 24 Zunszain PA, Ghuman J, McDonagh AF, Curry S. J. Mol. Biol. 2008; 381: 394
    PubMedSuche in Google Scholar
  • 25 Gupta R, Paul K. J. Mater. Chem. B 2024; 12: 9037
    PubMedSuche in Google Scholar