Design, synthesis, and molecular docking of novel 2-arylbenzothiazole multiangiokinase inhibitors targeting breast cancer.

A novel series of 2-arylbenzothiazoles 9, 10, and 12 were designed and synthesized as VEGFR-2/FGFR-1/PDGFR-β multiangiokinase inhibitors targeting breast cancer. Structural elongation of the known 2-phenylbenzothiazole scaffold (type I protein kinase inhibitor [PKI]), was carried out to afford series of type II PKIs 9, 10, and 12. Compounds 9d, 9f, 9i, and 9k exhibited potent multikinase inhibitory activity with IC50 values of 0.19, 0.18, 0.17, and 0.13 μM, respectively, against VEGFR-2; IC50 values of 0.28, 0.37, 0.19, and 0.27 μM, respectively, against FGFR-1; and IC50 values of 0.07, 0.04, 0.08, and 0.14 μM, respectively, against PDGFR-β. Moreover, the synthesized benzothiazoles demonstrated promising cytotoxic activity against the MCF-7 cell line. The most potent benzothiazoles 9d and 9i exhibited IC50 values of 7.83 and 6.58 μM, respectively, on the MCF-7 cell line in comparison to sorafenib (III), which showed IC50  = 4.33 μM. Additionally, 9d and 9i showed VEGFR-2 inhibitory activity in MCF-7 cells of 81% and 83% when compared with sorafenib (III), which showed 88% inhibition. Molecular docking of the designed compounds in the VEGFR-2 and FGFR-1 active sites showed the accommodation of the 2-phenylbenzothiazole moiety, as reported, in the hinge region of the receptor tyrosine kinase (RTK)-binding site, while the amide moiety is involved in hydrogen bond interactions with the key amino acids in the gate area; this in turn directs the aryl group to the hydrophobic allosteric back pocket of the RTKs in a type II-like binding mode. The synthesized benzothiazoles showed satisfactory ADME properties for further optimization in drug discovery.

Abdel-Mohsen HT ，Abd El-Meguid EA ，El Kerdawy AM ，Mahmoud AEE ，Ali MM ... -  《-》

Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors.

Inhibition of angiogenesis through inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) has been applied in cancer therapy because of its important role in promoting cancer growth and metastasis. In the presented study, a series of benzimidazol-furan hybrids was designed and synthesized through facile synthetic pathways. Evaluation of the synthesized compounds for their in vitro cytotoxic activity against breast (MCF-7) and hepatocellular (HepG2) carcinoma cell lines was performed. Two of the synthesized conjugates, 10b and 15, showed potent antiproliferative properties against MCF-7 cell line (IC50 = 21.25, 21.35 μM, respectively) in comparison to tamoxifen (IC50 = 21.57 μM). Additionally, compounds 10a, 10b, 15 and 17 showed promising potency (IC50 = 25.95, 22.58, 26.94 and 31.06 μM, respectively) against liver carcinoma cell line HepG2 in contrast to cisplatin (IC50 = 31.16 μM). Moreover, in vitro evaluation of the synthesized compounds for their effect on the level of VEGFR-2 in MCF-7 cell line showed their potent inhibitory activity relative to control untreated cells. Four compounds 10a, 10b, 14 and 15 showed 92-96% reduction in VEGFR-2 level, compared with tamoxifen and sorafenib which showed inhibition percentage of 98% and 95.75%, respectively. Compound 10a was found to have promising VEGFR-2 inhibitory activity (IC50 = 0.64 μM) in comparison to sorafenib (IC50 = 0.1 μM). Molecular docking was performed to study the binding pattern of the newly synthesized compounds with VEGFR-2 active site. Molecular docking attributed their good VEGFR-2 inhibitory activity to their hydrogen bonding interaction with the key amino acids in VEGFR-2 active site, Glu885 and Asp1046, and their hydrophobic interaction by their 2-furylbenzimidazole moiety with the allosteric hydrophobic back pocket in a type III inhibitors-like binding mode. The binding interaction is augmented by a ring substituent with long chain extension at position 1 of the benzimidazole due to its hydrophobic interaction with the hydrophobic side chains of the amino acids at the interface between the ATP binding site and the allosteric back pocket. Structure-activity relationship (SAR) was inferred for future optimization based on the performed biological and docking studies.

Abdullaziz MA ，Abdel-Mohsen HT ，El Kerdawy AM ，Ragab FAF ，Ali MM ，Abu-Bakr SM ，Girgis AS ，El Diwani HI ... -  《-》

Type IIA - Type IIB protein tyrosine kinase inhibitors hybridization as an efficient approach for potent multikinase inhibitor development: Design, synthesis, anti-proliferative activity, multikinase inhibitory activity and molecular modeling of novel ind

Pursuing on our efforts regarding development of novel multikinase inhibitors, herein we report the design and synthesis of novel 2-indolinone-based ureides 6a-u and amides 10a-j. In this work we adopt a hybridization strategy between type IIA PTK inhibitor (sorafenib) and type IIB PTK inhibitors (sunitinib and nintedanib). This was implemented via linking the indolinone core, in both sunitinib and nintedanib, which is well-fitted in the hinge region in the kinase domain front cleft and the biaryl urea extension, in sorafenib, which is accommodated in the gate area and the hydrophobic back pocket. Molecular docking of the designed hybrid compounds in VEGFR-2 and FGFR-1 active sites revealed, as planned, their ability to establish the binding interactions achieved by both original type IIA and type IIB inhibitors. The designed compounds were evaluated for their multikinase inhibitory activity towards VEGFR-2, PDGFR-b and FGFR-1 and anti-proliferative activity towards HepG2, MCF-7, A549 and A498 cancer cell lines. The ureido analogue 6u emerged as the most potent multikinase inhibitor in the ureido series with VEGFR-2, FGFR-1 and PDGFR-b IC50 of 0.18, 0.23 and 0.10 μM, respectively. Whereas, the amido congener 10j emerged as the most potent multikinase inhibitor in the amide series with VEGFR-2, FGFR-1 and PDGFR-b IC50 of 0.28, 0.46 and 0.09 μM, respectively. While, indolinone 6u was the most potent derivative towards HepG2 cells (IC50 = 2.67 ± 0.14 μM), 6r stood out as the most potent indolinone against A498 cells (IC50 = 0.78 ± 0.02 μM). Additionally, the target indolinones displayed non-significant cytotoxic impact towards human normal melanocyte (HFB4). ADME prediction study of the designed compounds showed that they are not only with promising multikinase inhibitory activity but also with favorable pharmacokinetic and drug-likeness properties. Compounds 6r and 10j are revealed to be the best compounds in terms of multikinase activity and pharmacokinetics.

Eldehna WM ，El Kerdawy AM ，Al-Ansary GH ，Al-Rashood ST ，Ali MM ，Mahmoud AE ... -  《-》

Novel potent substituted 4-amino-2-thiopyrimidines as dual VEGFR-2 and BRAF kinase inhibitors.

In the present study, we report the discovery of a novel class of substituted 4-amino-2-thiopyrimidines as antiangiogenic and antiproliferative agents. Structural hybridization between 4-substituted aminopyrimidines (VEGFR-2 inhibitors) and 2-thioxopyrimidines (BRAF inhibitors) was carried out to afford substituted 4-amino-2-thiopyrimidines as type II dual VEGFR-2/BRAF inhibitors. Our design strategy was tailored such that the 4-amino-2-thiopyrimidine scaffold is to be accommodated in the central gate area of the inactive DFG-out conformation of both enzymes. On one side, the hydrophobic substituent on the 4-amino group would occupy the hydrophobic back pocket and on the other side the substituent on the sulfide moiety should extend to fit in the hinge region (front pocket). Molecular docking simulations confirmed the ability of the designed compounds to accomplish the key interactions in VEGFR-2 and BRAF active sites. Most of the synthesized substituted 4-amino-2-thiopyrimidines demonstrated potent VEGFR-2 inhibitory activity at submicromolar concentrations. Compounds 8a, 8d, 9c and 9e showed IC50 = 0.17, 0.12, 0.17 and 0.19 μM, respectively against VEGFR-2 in comparison to sorafenib (I) IC50 = 0.10 μM and regorafenib (II) IC50 = 0.005 μM. While compounds 9c, 9d and 10a showed IC50 = 0.15, 0.22 and 0.11 μM, respectively against BRAF-WT. At 10 μM concentration 9c revealed promising in vitro broad-spectrum antiproliferative activity against cancer cell lines with growth inhibition percent ranging from 10 to 90%. Moreover, compounds 7b, 8d, 9a, 9b, 9c and 9d showed potent activity against MCF7 cell line (IC50 = 17.18, 17.20, 19.98, 19.61, 13.02 and 16.54 μM, respectively). On the other hand, compounds 9c, 9d and 10d were found to be the most potent compounds against T-47D cell line (IC50 = 2.18, 8.09 and 4.36 μM, respectively). Studying the effect of the most potent compounds on VEGFR-2 level in MCF7 cell line revealed that 9c and 9d showed inhibition percent of 84 and 80%, respectively, in comparison to sorafenib (I) (% inhibition = 90%).

Abdel-Mohsen HT ，Omar MA ，El Kerdawy AM ，Mahmoud AEE ，Ali MM ，El Diwani HI ... -  《-》

Design, Synthesis, In Vitro Anti-cancer Activity, ADMET Profile and Molecular Docking of Novel Triazolo[3,4-a]phthalazine Derivatives Targeting VEGFR-2 Enzyme.

Extensive studies were reported in the synthesis of several phthalazine derivatives as promising anticancer agents as potent VEGFR-2 inhibitors. Vatalanib (PTK787) was the first anilinophthalazine published derivative as a potent inhibitor of VEGFR. The discovery of vatalanib as a clinical candidate led to the design and synthesis of different anilinophthalazine derivatives as potent inhibitors for VEGFR-2. The objective of present research work is the synthesis of new agents with the same essential pharmacophoric features of the reported and clinically used VEGFR-2 inhibitors (e.g vatalanib and sorafenib). The main core of our molecular design rationale comprised bioisosteric modification strategies of VEGFR-2 inhibitors at four different positions. A correlation between structure and biological activity of our designed phthalazines was established using molecular docking and VEGFR-2 kinase assay. In view of their expected anticancer activity, novel triazolo[3,4-a]phthalazine derivatives 5-6a-o and 3-substituted-bis([1,2,4]triazolo)[3,4-a:4',3'-c]phthalazines 9a-b were designed, synthesized and evaluated for their anti-proliferative activity against two human tumor cell lines HCT-116 human colon adenocarcinoma and MCF-7 breast cancer. It was found that, compound 6o the most potent derivative against both HCT116 and MCF-7 cancer cell lines. Compounds 6o, 6m, 6d and 9b showed the highest anticancer activities against HCT116 human colon adenocarcinoma with IC50 of 7±0.06, 13±0.11, 15±0.14 and 23±0.22 µM respectively while compounds 6o, 6d, 6a and 6n showed the highest anticancer activities against MCF-7 breast cancer with IC50 of 16.98±0.15, 18.2±0.17, 57.54±0.53 and 66.45±0.67 µM respectively. Sorafenib as a highly potent VEGFR-2 inhibitor was used as a reference drug with IC50 of 5.47±0.3 and 7.26±0.3 µM respectively. Nine compounds were further evaluated for their VEGFR-2 inhibitory activity. Compounds 6o, 6m, 6d and 9b emerged as the most active counterparts against VEGFR-2 with IC50 values of 0.1±0.01, 0.15±0.02, 0.28±0.03 and 0.38±0.04 µM, respectively comparable to that of sorafenib (IC50 = 0.1±0.02) µM. Furthermore, molecular docking studies were carried out for all synthesized compounds to investigate their binding pattern and predict their binding affinities towards VEGFR-2 active site. In silico ADMET studies were calculated for the tested compounds. Most of our designed compounds exhibited good ADMET profile. The obtained results showed that, the most active compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective VEGFR-2 inhibitors with higher anticancer analogs.

El-Helby AA ，Sakr H ，Ayyad RRA ，El-Adl K ，Ali MM ，Khedr F ... -  《-》