Design, synthesis, biological evaluation, QSAR analysis and molecular modelling of new thiazol-benzimidazoles as EGFR inhibitors.

Heterocyclic rings such as thiazole and benzimidazole are considered as privileged structures, since they constitute several FDA-approved drugs for cancer treatment. In this work, a new set of 2-(2-(substituted) hydrazinyl)-4-(1-methyl-1H-benzo[d]imidazol-2-yl) thiazoles 4a-q were designed as epidermal growth factor receptor (EGFR) inhibitors and synthesized using concise synthetic methods. The new target compounds have been evaluated in vitro for their suppression activity against EGFR TK. Compounds 4n, 4h, 4i, 4a and 4d exhibited significant potency in comparison with erlotinib which served as a reference drug (IC50, 71.67-152.59 nM; IC50 erlotinib, 152.59 nM). Furthermore, MTT assay revealed that compounds 4j, 4a, 4f, 4h, 4n produced the most promising cytotoxic potency against the human breast cancer cell line (MCF-7) (IC50; 5.96-11.91 µM; IC50 erlotinib; 4.15 µM). Compound 4a showed promising activity as EGFR TK inhibitor as well as anti-breast cancer agent. In addition, 4a induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Moreover, 4a upregulated the oncogenic parameters; caspase-3, p53, Bax/Bcl-2 as well as it inhibited the level of PARP-1 enzyme. QSAR study was carried out for the new derivatives and it revealed the goodness of the models. Furthermore, molecular docking studies represented the binding modes of the promising compounds in the active pocket of EGFR.

Srour AM ，Ahmed NS ，Abd El-Karim SS ，Anwar MM ，El-Hallouty SM ... -  《-》

Novel 2-(5-Aryl-4,5-Dihydropyrazol-1-yl)thiazol-4-One as EGFR Inhibitors: Synthesis, Biological Assessment and Molecular Docking Insights.

Epidermal growth factor receptor (EGFR) regulates several cell functions which include cell growth, survival, multiplication, differentiation, and apoptosis. Currently, EGFR kinase inhibitors are of increasing interest as promising targeted antitumor therapeutic agents. Different thiazolyl-pyrazoline derivatives (7a-o) were synthesized and were first tested for anti-proliferative effect towards the A549 lung cancer cell line and the T-47D breast cancer cell line in MTT assay. Thereafter, thiazolyl-pyrazolines (7b, 7g, 7l, and 7m) were subsequently evaluated for their PK inhibition for EGFR. Moreover, representative promising derivatives (7g and 7m) in cytotoxic and PK inhibition assays were tested to investigate their impact on the apoptosis and cell cycle phases in T-47D cells in order to explore more insights into the antitumor actions of the target thiazolyl-pyrazolines. Furthermore, docking studies were accomplished to evaluate the patterns of binding of thiazolyl-pyrazolines 7b, 7g, 7l, and 7m in the EGFR active pocket (PDB ID: 1M17). Testing the thiazolyl pyrazoline compounds 7a-o on A549 and T-47D cell lines showed IC50 arrays between 3.92 and 89.03 µM, and between 0.75 and 77.10 µM, respectively. Also, the tested thiazolyl-pyrazolines (7b, 7g, 7l, and 7m) demonstrated significant sub-micromolar EGFR inhibitory actions with IC50 values 83, 262, 171 and 305 nM, respectively, in comparison to erlotinib (IC50 =57 nM). Generally, it was observed that the tested thiazolyl pyrazolines showed more potent antiproliferative activity toward breast cancer cells T-47D than toward lung cancer cell lines A549. In particular, thiazolyl pyrazolines 7g and 7m showed the best activity against A549 cells (IC50 = 3.92 and 6.53 µM) and T-47D cells (IC50 = 0.88 and 0.75 µM). Compounds 7g and 7m provoked a sub-G1 phase arrest and cell apoptosis which are in agreement with the expected outcome of EGFR inhibition. Finally, the molecular docking of 7g and 7m in the active site of EGFR revealed a common binding pattern similar to that of erlotinib which involves the accommodation of the 1,3 thiazol-4-one ring and pyrazoline ring of target compounds in the binding region of erlotinib's quinazoline ring and anilino moiety.

Al-Warhi T ，El Kerdawy AM ，Said MA ，Albohy A ，Elsayed ZM ，Aljaeed N ，Elkaeed EB ，Eldehna WM ，Abdel-Aziz HA ，Abdelmoaz MA ... -  《Drug Design Development and Therapy》

New thieno[3,2-d]pyrimidine-based derivatives: Design, synthesis and biological evaluation as antiproliferative agents, EGFR and ARO inhibitors inducing apoptosis in breast cancer cells.

An array of newly synthesized thieno[3,2-d]pyrimidine-based derivatives and thienotriazolopyrimidines hybridized with some pharmacophoric anticancer fragments were designed, synthesized and assessed for their in vitro antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines using erlotinib and pictilisib as reference standards in the MTT assay. In general, many compounds were endowed with considerable antiproliferative activity (IC50 = 0.43-1.31 µM). Some of the tested compounds, namely 3c, 5b, 5c, 9d, 10, 11b and 13 displayed remarkable antiproliferative activity against both cell lines. Meanwhile, compounds 2c-e, 3b, 4a, 5a, 9c and 15b showed noticeable selectivity against MCF-7 cells while compounds 2b, 3a, 4b, 6a-c, 7, 8, 9b and 12 exhibited considerable selectivity against MDA-MB-231 cells. Further mechanistic evidences for their anticancer activities were provided by screening the most potent compounds against MCF-7 and/or MDA-MB-231 cells for EGFR and ARO inhibitory activities using erlotinib and letrozole as reference standards respectively. Results proved that, in general, tested compounds were better EGFRIs than ARIs. In addition, significant overexpression in caspase-9 level in treated MCF-7 breast cell line samples was observed for all tested compounds with the 4-fluorophenylhydrazone derivative 2d exhibiting the highest activation. In treated MDA-MB-231 breast cell line samples, 11b was found to highly induce caspase-9 level thereby inducing apoptosis. Cell cycle analysis and Annexin V-FITC/PI assay were also assessed for active compounds where results indicated that all tested compounds induced preG1 apoptosis and cell cycle arrest at G2/M phase. Compound 9d, as an inhibitor of ARO, was observed to downregulate the downstream signaling proteins HSP27 and p-ERK in MCF-7 cells. Furthermore, compound 11b downregulated EGFR expression as well as the downstream signaling protein p-AKT. Docking experiments on EGFR and ARO enzymes supported their in vitro results. Thus, the thienotriazolopyrimidines 11b and 12 showing good EGFR inhibition and the thieno[3,2-d]-pyrimidine derivatives 3b and 9d, eliciting the best ARO inhibition activity, can be considered as new candidates as anti-breast cancer agents that necessitate further development.

Farghaly AM ，AboulWafa OM ，Baghdadi HH ，Abd El Razik HA ，Sedra SMY ，Shamaa MM ... -  《-》

Design, synthesis and biological evaluation of a new series of thiazolyl-pyrazolines as dual EGFR and HER2 inhibitors.

Epidermal growth factor receptor (EGFR, also known as HER1) and HER2, prominent members of receptor tyrosine kinase (RTK) superfamily, have been reported as diagnostic or prognostic markers in tumor progression. Based on the importance of molecular hybridization of pyrazoline and thiazole scaffolds in the discovery of potent anticancer agents, new thiazolyl-pyrazoline derivatives (3a-v) were synthesized and screened for their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma and A375 human melanoma cell lines. 1-(4-(4-Fluorophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3c),1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3f) and 1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3q) were found as the most potent anticancer agents against A549 and MCF-7 cell lines compared to erlotinib. Compound 3q also showed moderate cytotoxic activity against A375 cell line. Moreover, these compounds exert a cancer cell-selective action against Jurkat cell line posing no toxicity on peripheral blood mononuclear cells (PBMCs). In order to enlighten the mechanism of action underlying anticancer activity, compounds 3c, 3f and 3q were investigated for their apoptotic effects on A549 and MCF-7 cell lines and inhibitory potencies against eight different RTKs including EGFR and HER2 compared to erlotinib. The results indicated that compounds 3f and 3q induced apoptosis in both cell lines and showed significant EGFR inhibitory activity with IC50 values of 4.34 ± 0.66 μM and 4.71 ± 0.84 μM, respectively when compared with erlotinib (IC50 = 0.05 ± 0.01 μM). Besides, compound 3f also inhibited HER2 notably with an IC50 value of 2.28 ± 0.53 μM making it a dual EGFR and HER2 inhibitor. Molecular docking studies, which were conducted to support the in vitro assays, pointed out that compound 3f showed high affinity into the ATP binding sites of EGFR and HER2.

Sever B ，Altıntop MD ，Radwan MO ，Özdemir A ，Otsuka M ，Fujita M ，Ciftci HI ... -  《-》

Novel Pyrazoloquinolin-2-ones: Design, synthesis, docking studies, and biological evaluation as antiproliferative EGFR-TK inhibitors.

Two new series of diethyl 2-[2-(substituted-2-oxo-1,2-dihydroquinolin-4-yl)hydrazono]-succinates 6a-g and 1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazoles 7a-f have been designed and synthesized. The structures of the synthesized compounds were proved by IR, mass, NMR (2D) spectra and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, seven compounds were further examined against the most sensitive cell lines, leukemia CCRF-CEM, and MOLT-4. 5-Amino-1-(6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazole-3,4-dicarbonitrile (7f) was the most active product, with IC50 = 1.35 uM and 2.42 uM against MOLT-4 and CCRF-CEM, respectively. Also, it showed a remarkable inhibitory activity compared to erlotinib on the EGFR TK with IC50 = 247.14 nM and 208.42 nM, respectively. Cell cycle analysis of MOLT-4 cells treated with 7f showed cell cycle arrest at G2/M phase (supported by Caspases, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking study indicated that both the pyrazole moiety and the quinolin-2-one ring showed good fitting into EGFR (PDB code: 1M17). In order to interpret SAR of the designed compounds, and provide a basis for further optimization, molecular docking of the synthesized compounds to known EGFR inhibitors was performed. The study illustrated the effect of several factors on the compounds' activity.

Elbastawesy MAI ，Aly AA ，Ramadan M ，Elshaier YAMM ，Youssif BGM ，Brown AB ，El-Din A Abuo-Rahma G ... -  《-》