Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction

Abstract

This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.

In Silico Evaluation of a Promising Key Intermediate Thieno [2,3-d] Pyrimidine Derivative with Expected JAK2 Kinase Inhibitory Activity

“…However, it showed moderate activity against both HT-29 and MCF-7, as expressed by IC 50 values of 4.526 ± 0.130 µM and 15.055 ± 0.785 µM, respectively, in comparison to doxorubicin that demonstrated IC 50 values of 1.358 ± 1.156 and 8.434 ± 0.522 µM, respectively. In addition, in reference to our previously reported work [11], the compound under investigation shows a comparable antiproliferative effect.…”

“…The gradient was set to 0.05 for energy minimization, and MMFF94X was the selected force field. According to the published procedures [11], the starting aminothiophene ester 1 was prepared using a mixture of cyclohexanone (~5 mL, 50 mmol), ethyl cyanoacetate (6.35 mL, 50 mmol), elemental sulfur (1.6 g, 50 mmol), and morpholine (4.35 mL, 50 mmol), that was heated at 60 • C, while stirring in absolute ethanol (20 mL) for 6 h (Gewald reaction). The mixture was left at room temperature overnight.…”

“…Thienopyrimidines, with a heterocyclic core derivatized from pyrimidine and resembling purines, are of unique importance as scaffolds for the preparation of a variety of biologically active compounds as enzyme inhibitors, including kinases [4,5], poly (ADPribose) polymerase (PARP) inhibitors [6], and as anticancer agents against some tumor cell lines [7][8][9][10][11], in addition to their antioxidant activity [12][13][14]. Meanwhile they are an interesting target for protein kinases (PKs), which are enzymes known to regulate proteinbiological activity, as they are responsible for protein phosphorylation that is involved in cell cycle proliferation, in addition to regulating cell progression and division [15][16][17].…”

Synthesis, Biocidal and Antibiofilm Activities of New Isatin–Quinoline Conjugates against Multidrug-Resistant Bacterial Pathogens along with Their In Silico Screening

“…The targeted enzyme was downloaded from Protein Data Bank along with its bounded co-crystallized ligand (PDB:4DKI). Preparation of the downloaded protein was performed following the literature [ 50 ]…”

Design, Synthesis, and Antiproliferative Activity of Novel Neocryptolepine–Rhodanine Hybrids

“…Hydrogen bond acceptors are between 2 and 5 acceptors while the donors are either 1 or 2 following LiPinski’s rule. As referenced [ 44 , 45 ], the blood brain barrier (BBB) score should range are between 0 and 6. The tested structures showed a minimum score of 2.16 and maximum one of 3.64, Table 2…”