Design and synthesis of new thiazolidinone/uracil derivatives as antiproliferative agents targeting EGFR and/or BRAFV600E

Abstract

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 GI50 values ranging from 1.10 µM to 10.00 µM. Compounds 3c, 5b, 5c, 5h, 5i, and 5j were the most potent derivatives, with GI50 values ranging from 1.10 µM to 1.80 µM. Compound 5b showed potent inhibitory activity against EGFR and BRAFV600E with IC50 of 91 ± 07 and 93 ± 08 nM, respectively, indicating that this compound could serve as a dual inhibitor of EGFR and BRAFV600E with promising antiproliferative properties. Docking computations revealed the great potency of compounds 5b and 5j towards EGFR and BRAFV600E with docking scores of −8.3 and −9.7 kcal/mol and −8.2 and −9.3 kcal/mol, respectively.

Design, Synthesis, and Antiproliferative Activity of New 5-Chloro-indole-2-carboxylate and Pyrrolo[3,4-b]indol-3-one Derivatives as Potent Inhibitors of EGFRT790M/BRAFV600E Pathways

“…The in vitro anti-BRAF V600E activity of compounds 3a–e was further investigated [ 38 ] using erlotinib and vemurafenib as reference compounds and results are shown in Table 2 . The enzyme assay revealed that the five compounds tested significantly inhibited BRAF V600E , with IC 50 ranges from 35 to 67 nM, Table 2 .…”

“…The activity of 3a–e against BRAF was investigated using a V 600E mutant BRAF kinase assay [ 38 ]. See Appendix SA (Supplementary Materials) .…”

Uracil: A Pharmacophore with Diverse Biological Potential

“…The synthesised derivatives were evaluated for its in vitro anti-proliferative activity against eight cancer cell lines cervical (Hela), colon (Colo-205), lung (A-549), leukaemia (HL-60), ovarian (SKOV-3) and breast (MDA-MB-231, MCF-7 and T47D) cancer cell lines. [55] It was observed that compound 71 c exhibited potent anti proliferative activity against T47D cells with IC 50 value 7.56 � 0.29 μM as compared to the control staurosporine with IC 50 value 4.52 � 0.9 μM.…”

One-Pot Synthesis of 1-Thia-4-azaspiro[4.4/5]alkan-3-ones via Schiff Base: Design, Synthesis, and Apoptotic Antiproliferative Properties of Dual EGFR/BRAFV600E Inhibitors

“…Following our previous study on dual targeting strategies and motivated by the findings above [ 40 , 41 , 42 ], we synthesized new spiro-compounds that combine quinolinone, thiazolidinone, and spiro-cyclic in a single molecule via the reaction of thioglycolic acid and 4-(2-cyclodenehydrazinyl)4uinoline-2(1 H )-one. As a result, two new compounds, 6a – e (Scaffold A) and 7a and 7b (Scaffold B), were developed to generate new potent antiproliferative agents targeting EGFR and/or BRAF V600E , as shown in Figure 3 .…”