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Design and synthesis of new thiazolidinone/uracil derivatives as antiproliferative agents targeting EGFR and/or BRAF$^{V600E}$

Alshammari, Mohammed B.; Aly, Ashraf A. ; Youssif, Bahaa G. M. ; Bräse, Stefan 1,2; Ahmad, Akil; Brown, Alan B.; Ibrahim, Mahmoud A. A.; Mohamed, Asmaa H.
1 Institut für Biologische und Chemische Systeme (IBCS), Karlsruher Institut für Technologie (KIT)
2 Institut für Organische Chemie (IOC), Karlsruher Institut für Technologie (KIT)


Thiourea derivatives of uracil were efficiently synthesized via the reaction of 5-aminouracil with isothiocyanates. Then, we prepared uracil-containing thiazoles via condensation of thioureas with diethyl/dimethyl acetylenedicarboxylates. The structures of the products were confirmed by a combination of spectral techniques including infra-red (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS) and elemental analyses. A rationale for the formation of the products is presented. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against four cancer cell lines. The compounds tested showed promising antiproliferative activity, with GI$_{50}$ values ranging from 1.10 µM to 10.00 µM. Compounds 3c, 5b, 5c, 5h, 5i, and 5j were the most potent derivatives, with GI$_{50}$ values ranging from 1.10 µM to 1.80 µM. Compound 5b showed potent inhibitory activity against EGFR and BRAF$^{V600E}$ with IC$_{50}$ of 91 ± 07 and 93 ± 08 nM, respectively, indicating that this compound could serve as a dual inhibitor of EGFR and BRAF$^{V600E}$ with promising antiproliferative properties. Docking computations revealed the great potency of compounds 5b and 5j towards EGFR and BRAF$^{V600E}$ with docking scores of −8.3 and −9.7 kcal/mol and −8.2 and −9.3 kcal/mol, respectively.

Verlagsausgabe §
DOI: 10.5445/IR/1000154657
Veröffentlicht am 18.01.2023
DOI: 10.3389/fchem.2022.1076383
Zitationen: 15
Web of Science
Zitationen: 11
Zitationen: 14
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Biologische und Chemische Systeme (IBCS)
Institut für Organische Chemie (IOC)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2022
Sprache Englisch
Identifikator ISSN: 2296-2646
KITopen-ID: 1000154657
HGF-Programm 43.33.11 (POF IV, LK 01) Adaptive and Bioinstructive Materials Systems
Erschienen in Frontiers in Chemistry
Verlag Frontiers Media SA
Band 10
Seiten Art.-Nr.: 1076383
Bemerkung zur Veröffentlichung Gefördert durch den KIT-Publikationsfonds
Vorab online veröffentlicht am 12.12.2022
Schlagwörter 5-AU, thiourea, thiazolidinone, EGFR, B-RAF, viability, molecular modeling
Nachgewiesen in Scopus
Web of Science
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