Novel sulfonamide-indolinone hybrids targeting mitochondrial respiration of breast cancer cells.

Breast cancer (BC) still poses a threat worldwide which demands continuous efforts to present safer and efficacious treatment options via targeted therapy. Beside kinases' aberrations as Aurora B kinase which controls cell division, BC adopts distinct metabolic profiles to meet its high energy demands. Accordingly, targeting both aurora B kinase and/or metabolic vulnerability presents a promising approach to tackle BC. Based on a previously reported indolinone-based Aurora B kinase inhibitor (III), and guided by structural modification and SAR investigation, we initially synthesized 11 sulfonamide-indolinone hybrids (5a-k), which showed differential antiproliferative activities against the NCI-60 cell line panel with BC cells displaying preferential sensitivity. Nonetheless, modest activity against Aurora B kinase (18-49% inhibition) was noted at 100 nM. Screening of a representative derivative (5d) against 17 kinases, which are overexpressed in BC, failed to show significant activity at 1 µM concentration, suggesting that kinase inhibitory activity only played a partial role in targeting BC. Bioinformatic analyses of genome-wide transcriptomics (RNA-sequencing), metabolomics, and CRISPR loss-of-function screens datasets suggested that indolinone-completely responsive BC cell lines (MCF7, MDA-MB-468, and T-47D) were more dependent on mitochondrial oxidative phosphorylation (OXPHOS) compared to partially responsive BC cell lines (MDA-MB-231, BT-549, and HS 578 T). An optimized derivative, TC11, obtained by molecular hybridization of 5d with sunitinib polar tail, manifested superior antiproliferative activity and was used for further investigations. Indeed, TC11 significantly reduced/impaired the mitochondrial respiration, as well as mitochondria-dependent ROS production of MCF7 cells. Furthermore, TC11 induced G0/G1 cell cycle arrest and apoptosis of MCF7 BC cells. Notably, anticancer doses of TC11 did not elicit cytotoxic effects on normal cardiomyoblasts and hepatocytes. Altogether, these findings emphasize the therapeutic potential of targeting the metabolic vulnerability of OXPHOS-dependent BC cells using TC11 and its related sulfonamide-indolinone hybrids. Further investigation is warranted to identify their precise/exact molecular target.

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies.

A new class of benzimidazole-based derivatives (4a-j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a-j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.

Design, molecular modelling and synthesis of novel benzothiazole derivatives as BCL-2 inhibitors.

Apoptosis plays a crucial role in cancer pathogenesis and drug resistance. BCL-2 family of enzymes is considered as one of the key enzymes which is involved in apoptosis. When there is disruption in the balance between anti-apoptotic and pro-apoptotic members of the BCL-2 family apoptosis is dysregulated in the affected cells. Herein, 33 novel benzothiazole-based molecules 7a-i, 8a-f, 9a-b, 12a-e, 13a-d, 14a,b, and 17a-j were designed, synthesized and tested for their BCL-2 inhibitory activity. Scaffold hopping strategy was applied in designing of the target compounds. Compounds 13c and 13d showed the highest activity with IC50 values equal to 0.471 and 0.363 µM, respectively. Molecular docking studies of the synthesized compounds showed comparable binding interactions with the lead compound. Structure activity relationship study was performed to show the effects of structural modifications on the inhibitory activities on BCL-2.

Novel 1,3-diaryl pyrazole derivatives bearing methylsulfonyl moiety: Design, synthesis, molecular docking and dynamics, with dual activities as anti-inflammatory and anticancer agents through selectively targeting COX-2.

Three series of novel 1-aryl-3-(4-methylsulfonylphenyl) pyrazole derivatives were synthesized, characterized by several spectroscopic techniques, and investigated as potential anti-inflammatory and anticancer agents. The biological evaluation showed that almost all the synthesized compounds have significant potency and selectivity for the COX-2 enzyme over COX-1 with noticeable anti-inflammatory activity compared to celecoxib and indomethacin. Accordingly, compounds 8a, 8b, 8e, 8j, 8l, 9a, 9b, 9c, and 10b showed the best COX-2 inhibition (IC50 ranged from 0.059 to 0.079 µM) with good anti-inflammatory activity (% of edema inhibition ranged from 87.9 to 67.5). Moreover, compound 8b possessed the highest selectivity index regarding COX-2 isozyme (SI = 211) in comparison to celecoxib (SI = 312) with good in vivo anti-inflammatory activity (% edema inhibition = 77.70 after 5 h). Also, compounds 8a, 8b, 8j, 8l, and 9a showed ulcerogenic liability and histopathological changes close to celecoxib. Molecular docking and dynamics simulations were also conducted to illustrate the binding modes inside the COX-2 active site. Furthermore, all compounds were screened against three cancer cell line panels to determine their antiproliferative properties by MTT assay. Compounds 8a, 8b, and 8e along with their cyclized forms 9a, 9b, and 9c exhibited a considerable antiproliferative effect on liver (IC50: 6.81-19.71 µM), colon (IC50: 7.64-15.34 µM), and breast (IC50: 6.77-18.41 µM) cancer cell lines. More importantly, compounds 8a, 8e, 9a, and 9b were found to be safe on normal HEK-293T kidney cells in comparison to cancer. cells, especially compound 8e with IC50 value of 66.45 µM. Mechanistic studies demonstrated the apoptotic activity of the most active compounds 8a, 8e, 9a, and 9b on MCF-7 cancer cells by inducing a strong S phase cell cycle arrest suggesting that the mechanism of its antiproliferative activity may be through COX-2 inhibition. Finally, the hit compounds 8a, 8b and 9a were discovered to have selective COX-2 inhibitory activity and good anti-inflammatory activity with minimal ulcerogenic effect as well as potent anticancer activity.

The natural isoflavone Biochanin-A synergizes 5-fluorouracil anticancer activity in vitro and in vivo in Ehrlich solid-phase carcinoma model.

Isoflavones are considered one of the most extensively studied plant-derived phytoestrogenic compounds. Of these, Biochanin A (Bio-A), a natural isoflavone abundant in cabbage, alfalfa, and red clover, has drawn a lot of attention. As reported in multiple studies, Bio-A possesses a promising anticancer activity against estrogen receptor-positive (ER+) breast cancer. The current study investigated the working hypothesis that Bio-A could synergistically enhance the potency of 5-fluorouracil (5-FU) in ER+ breast cancer. The hypothesis was tested both in vitro on hormone receptor-positive (MCF-7) and triple-negative breast cancer cells (MDA-MB231). Additionally, in vivo studies were performed in the Ehrlich solid-phase carcinoma mouse model. The in vitro cytotoxicity studies revealed that Bio-A synergistically increased the potency of 5-FU in both MCF-7 and MDA-MB231 cell lines. The synergistic effect of 5-FU/Bio-A combination was verified in vivo. The combination therapy (where 5-FU was used at one fourth its full dose) led to a significant 75% reduction in tumor volume after two treatment cycles. This was in addition to producing a significant 2.1-fold increase in tumor necrosis area% compared to mock-treated control. In conclusion, the current study presents the first preclinical evidence for the potential merit of 5-FU/Bio-A combination for the treatment of ER+ breast cancer. The synergistic antitumor effect of Bio-A/ 5-FU combination can be, at least partly, attributed to Bio-A-mediated suppression of ER-α/Akt axis and the augmentation of 5-FU-mediated proapoptotic effects. © 2022 John Wiley & Sons, Ltd.

Discovery of potent thieno[2,3-d]pyrimidine VEGFR-2 inhibitors: Design, synthesis and enzyme inhibitory evaluation supported by molecular dynamics simulations.

Vascular endothelial growth factor receptor (VEGFR) is one of the well-known targets that control angiogenesis and cancer progression. In this study, we are reporting the design, synthesis and biological evaluation of a series of 4-substituted thieno[2,3-d]pyrimidine derivatives as VEGFR-2 inhibitors. The design of these compounds was based on interactions extracted from crystal structure of potent pyrrolo[3,2-d]pyrimidine inhibitor VIII with VEGFR-2 (PDB: 3VHE). In addition to these interactions, the new compounds were also designed to interact with residues in the solvent accessible region such as Asn923. Accordingly, the thienopyrimidine target compounds were synthesized and subjected to VEGFR-2 enzyme inhibition assay. Several target compounds (7d-f, 8b-c, 8e-g and 15c) exhibited potent inhibitory activities against VEGFR-2 with IC50 values in low nanomolar range. Compounds 8b and 8e revealed exceptionally potent inhibitory activity with IC50 of 5 and 3.9 nM, respectively. The molecular docking analysis and molecular dynamics simulation were also performed to further investigate these findings.

Green analysis of newly approved binary omeprazole/aspirin mixture in presence of aspirin impurity using ultra-high-performance liquid chromatography and thin-layer chromatography methods.

Two green, simple, and accurate chromatographic methods were developed and validated for the simultaneous determination of omeprazole and aspirin mixture in the presence of salicylic acid, a major impurity of aspirin. Method A is a reversed-phase ultra-high-performance liquid chromatography; the separation was performed on a C18 column, with a mobile phase composed of ethanol:0.1% aqueous solution of triethylamine acidified with orthophosphoric acid (pH 3) (30:70, v/v) at 0.15 mL/min flow rate and 230 nm. Omeprazole, aspirin, and aspirin impurity retention times were 7.47, 4.40, and 5.13 min, respectively. Good linearity was achieved in the concentration ranges of 5-80, 5-85, and 3-50 µg/mL for the three mentioned components, respectively. Method B is thin-layer chromatography (TLC) where silica gel TLC F254 plates were utilized to achieve separation using ethanol:ethyl acetate (2:8, v/v) as a developing system at 240 nm. The resulted Rf values were 0.83, 0.65, and 0.23 for omeprazole, aspirin, and impurity, respectively. The concentration ranges of 0.1-3 µg/band for the three drugs showed good linearity. The proposed methods are eco-friendly and greener when compared to the already reported method (Microchemical Journal, 152, 104350). This is the first use of TLC method for the determination of the three drugs. International Council for Harmonization (ICH) guidelines were followed to ensure the validity of developed methods.

Design, synthesis, mechanistic studies and in silico ADME predictions of benzimidazole derivatives as novel antifungal agents.

Herein, novel three series of benzimidazole scaffold bearing hydrazone, 1,2,4-triazole and 1,3,4-oxadiazole moieties 1-3, 4a-j, 6a-c and 7 derivatives were designed, synthesized and evaluated for their antimicrobial activity. The structures of the prepared compounds were assigned using different spectroscopic techniques such as IR, 1H NMR, 13C NMR and elemental analyses. Compounds 3, 4a, 4e and 4f exhibited remarkable antifungal activity against C. albicans and C. neoformans var. grubii with MIC values ranging from 4 to 16 µg/mL. Furthermore, they were not cytotoxic against red blood cells and human embryonic kidney cells at concentration up to 32 µg/mL. The study was expanded to forecast the mechanism of action of the prepared compounds and determine sterol quantitation method (SQM) by spectrophotometric assay. On the other hand, compound 4e showed the highest inhibitory activity against lanosterol 14α-demethylase (CYP51) with IC50 value = 0.19 µg/mL compared to fluconazole as reference IC50 value = 0.62 µg/mL. Also, compounds 4d and 4f exhibited mild to moderate antibacterial activity. Moreover, molecular docking of the active target compound 4e in active site of lanosterol 14α-demethylase (CYP51) revealed that docking scores and binding mode are comparable to that of co-crystallized ligand confirming their antifungal activity. In silico ADME prediction investigations also forecasting the drug-like characters of these compounds.

Design and Synthesis of New Quinoxaline Derivatives as Anticancer Agents and Apoptotic Inducers.

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line.

Design, synthesis, biological evaluation and dynamics simulation of indazole derivatives with antiangiogenic and antiproliferative anticancer activity.

VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b, 11c and 11e exhibited the most potent action, with IC50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 µM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI50) and safety (LC50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action.

Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells.

Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for its significant role in the progression of different types of malignant tumors, where development of small molecules targeting EGFR is well known strategy for design of antitumor agents. Herein, we report the design and synthesis of two series of 6-(2-substitutedacetamido)-4-anilinoquinazolines (6a-x and 13a-d) as EGFR inhibitors. All the newly synthesized quinazoline derivatives were in vitro evaluated for their anti-proliferative activity towards MCF-7 (Breast Cancer) and HepG2 (Hepatocellular carcinoma) cell lines. In particular, compound 6n showed significant inhibitory activity against MCF-7 and HepG2 cell lines (IC50 = 3 and 16 µM, respectively), compared to that of Erlotinib (IC50 = 20 and 25 µM, respectively). Western blotting of 6n at MCF-7 cell line revealed the dual inhibitory activity of 6n towards diminishing the phosphorylated levels for EGFR and ERK. Also, ELISA assay confirmed the anti-EGFR activity of compound 6n (IC50 = 0.037 µM). Finally, a molecular docking study showed the potential binding mode of 6n within the ATP catalytic binding site of EGFR, exhibiting similar binding mode to EGFR inhibitor Erlotinib.

Synthesis and biological evaluation of novel 2-oxo-1,2-dihydroquinoline-4-carboxamide derivatives for the treatment of esophageal squamous cell carcinoma.

No new and effective treatments have been approved for the treatment of esophageal squamous cell carcinoma (ESCC) in the past decade. Cisplatin and 5-fluoruracil are the most commonly used drugs for this disease. In order to develop a new class of drugs effective in our ESCC phenotypic screens, we began a systematic approach to generate novel compounds based on the 2-oxo-1,2-dihydroquinoline-4-carboxamide fragment. Herein, we report on the synthesis and initial assessment of 55 new analogues in two ESCC cell lines. Some of the active analogues with IC50 values around 10 µM were tested in three additional cell lines. Our structure-activity relationships revealed remarkable alterations in the anti proliferative activities upon modest chemical modifications and autophagy modulation is a suggested mechanism of action.

Imidazo[2',1':2,3]thiazolo[4,5-d]pyridazinone as a new scaffold of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study.

New series of thiazolo[4,5-d]pyridazin and imidazo[2',1':2,3]thiazolo[4,5-d]pyridazin analogues were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activity. Compounds 13 and 43 proved to be DHFR inhibitors with IC50 0.05 and 0.06 µM, respectively. 43 proved lethal to OVCAR-3 Ovarian cancer and MDA-MB-435 Melanoma at IC50 0.32 and 0.46 µM, respectively. The active compounds formed hydrogen bond at DHFR binding site between N1-nitrogen of the pyridazine ring with Glu30; the carbonyl group with Trp24, Arg70 or Lys64; π-cation interaction with Arg22 and π-π interaction with Phe31 residues. Ring annexation of the active 1,3-thiazole ring analogue 13 into the bicyclic thiazolo[4,5-d]pyridazine (18,19) or imidazo[2,1-b]thiazoles (23-25) decreased the DHFR inhibition activity; while the formation of the tricyclic imidazo[2',1':2,3]-thiazolo[4,5-d]pyridazine (43-54) increased potency. The obtained model could be useful for the development of new class of DHFR inhibitors.

Design, synthesis and biological evaluation of some novel quinazolinone derivatives as potent apoptotic inducers.

AIM: Novel quinazolinone and triazinoquinazolinone derivatives were designed and synthesized as apoptotic inducers. METHODOLOGY/RESULTS: Most of the synthesized compounds showed excellent antiproliferative activity against MCF-7 and HCT-116 cell lines, respectively. Compounds 7a, 8a, 8d, 14a and 14d were superior to doxorubicin as activators of caspases 3, 8 and 9 in HCT-116 cell line. The most potent caspase inducers, 8d and 14a showed cell cycle arrest mainly in G1 and S phase, respectively and increased the levels of p53, Bax and the Bax/Bcl-2 ratio compared with doxorubicin in HCT-116 cells with excellent selectivity against CCD-18Co human colon normal cell line. CONCLUSION: The synthesized compounds can be considered as potent apoptotic inducers interfering with extrinsic and intrinsic apoptotic pathways.

Novel quinoline-3-carboxamides (Part 2): Design, optimization and synthesis of quinoline based scaffold as EGFR inhibitors with potent anticancer activity.

EGFR has a key role in cell growth. Its mutation and overexpression share in epithelial malignancies and tumor growth. Quinazoline and quinoline derivatives are common anticancer intracellular inhibitors of EGFR kinase, and their optimization is an important issue for development of potent targeted anticancer agents. Based on these facts, different strategies were used for optimizing our reported quinoline-3-carboxamide compound III (EGFR IC50 = 5.283 µM and MCF-7 IC50 = 3.46 µM) through different molecular modeling techniques. The optimized compounds were synthesized and subjected to EGFR binding assay and accordingly some more potent inhibitors were obtained. The most potent quinoline-3-carboxamides were the furan derivative 5o; thiophene derivative 6b; and benzyloxy derivative 10 showing EGFR IC50 values 2.61, 0.49 and 1.73 µM, respectively. Furthermore, the anticancer activity of compounds eliciting potent EGFR inhibition (5o, 5p, 6b, 8a, 8b, and 10) was evaluated against MCF-7 cell line where they exhibited IC50 values 3.355, 3.647, 5.069, 3.617, 0.839 and 10.85 µM, respectively. Compound 6b was selected as lead structure for further optimization hoping to produce more potent EGFR inhibitors.

Thiazolo[4,5-d]pyridazine analogues as a new class of dihydrofolate reductase (DHFR) inhibitors: Synthesis, biological evaluation and molecular modeling study.

A new series of 1,3-thiazoles and thiazolo[4,5-d]pyridazine both bearing the 2-thioureido function were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activities. Compound 26 proved to be the most active DHFR inhibitor (IC50 of 0.06µM). Compound 4, 20 and 21 showed in vitro antitumor activity against a collection of cancer cell lines. Compound 26 proved lethal to HS 578T breast cancer cell line with IC50 value of 0.8µM, inducing cell cycle arrest and apoptosis. Molecular modeling studies concluded that recognition with key amino acids Phe 31 and Arg 22 is essential for DHFR binding. The obtained model could be useful for the development of new class of DHFR inhibitors.

Aromatase inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and molecular modeling studies of novel phenothiazine derivatives carrying sulfonamide moiety as hybrid molecules.

Hybrid molecules are used as anticancer agents to improve effectiveness and diminish drug resistance. So, the current study aimed to introduce twenty novel phenothiazine sulfonamide hybrids 5-22, 24 and 25 of promising anticancer activity. Compounds 11 and 13 revealed more potent anticancer properties (IC50 8.1 and 8.8 µM) than that of the reference drug (doxorubicin, IC50 = 9.8 µM) against human breast cancer cell line (T47D). To determine the mechanism of their anticancer activity, compounds 5, 6, 7, 11, 13, 14, 16, 17, 19 and 22 that showed promising activity on T47D, were evaluated for their aromatase inhibitory effect. The study results disclose that the most potent aromatase inhibitors 11 and 13 showed the lowest IC50 (5.67 µM and 6.7 µM), respectively on the target enzyme. Accordingly, the apoptotic effect of the most potent compound 11 was extensively investigated and showed a marked increase in Bax level up to 55,000 folds, and down-regulation in Bcl2 to 5.24*10-4 folds, in comparison to the control. Furthermore, the effect of compound 11 on caspases 3, 8 and 9 was evaluated and was found to increase their levels by 20, 34, and 8.9 folds, respectively, which indicates the activation of both intrinsic and extrinsic pathways. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking and computer aided ADMET studies were adopted to confirm their mechanism of action.

Analogue based drug design, synthesis, molecular docking and anticancer evaluation of novel chromene sulfonamide hybrids as aromatase inhibitors and apoptosis enhancers.

Twenty novel chromene derivatives carrying different sulfonamide moieties (3-22) were designed and synthesized. All the newly prepared compounds were evaluated for their in vitro anticancer activity against breast cancer cell line (T47D). Most of the synthesized compounds showed good to moderate activity (IC50 = 8.8-108.9 µM), where compound 16 (IC50 = 8.8 µM) exhibited higher activity compared to doxorubicin (IC50 = 9.8 µM). In order to determine the mechanism of the anticancer activity in T47D cells, the effect of the most potent compounds (5-8, 11-14, and 16-18) on the aromatase activity was tested. Most of the selected compounds showed significant inhibitory effect on the aromatase activity, with compound 18 showing IC50 = 4.66 µM. Furthermore, apoptosis studies were conducted on two of the most potent compounds (8 & 16) to estimate the proapoptotic potential of our compounds. Both induced the levels of active caspase 3, caspase 8 and caspase 9. Moreover, they surprisingly boosted the Bax/Bcl2 ratio 5936 & 33,000 folds, respectively compared to the control. Moreover, they showed mild cytotoxic effect (IC50 = 183.8 µM & 172.04 µM, respectively) in normal breast cells 184A1. Finally, a molecular docking study was performed to investigate the probable interaction with the aromatase enzyme.

Quinoxaline-Based Scaffolds Targeting Tyrosine Kinases and Their Potential Anticancer Activity.

Quinoxaline derivatives, also called benzopyrazines, are an important class of heterocyclic compounds. Quinoxalines have drawn great attention due to their wide spectrum of biological activities. They are considered as an important basis for anticancer drugs due to their potential activity as protein kinase inhibitors. In this review, we focus on the chemistry of the quinoxaline derivatives, the strategies for their synthesis, their potential activities against various tyrosine kinases, and on the structure-activity relationship studies reported to date.

Increasing the binding affinity of VEGFR-2 inhibitors by extending their hydrophobic interaction with the active site: Design, synthesis and biological evaluation of 1-substituted-4-(4-methoxybenzyl)phthalazine derivatives.

A series of anilinophthalazine derivatives 4a-j was initially synthesized and tested for its VEGFR-2 inhibitory activity where it showed promising activity (IC50 = 0.636-5.76 µM). Molecular docking studies guidance was used to improve the binding affinity for series 4a-j towards VEGFR-2 active site. This improvement was achieved by increasing the hydrophobic interaction with the hydrophobic back pocket of the VEGFR-2 active site lined with the hydrophobic side chains of Ile888, Leu889, Ile892, Val898, Val899, Leu1019 and Ile1044. Increasing the hydrophobic interaction was accomplished by extending the anilinophthalazine scaffold with a substituted phenyl moiety through an uriedo linker which should give this extension the flexibility required to accommodate itself deeply into the hydrophobic back pocket. As planned, the designed uriedo-anilinophthalazines 7a-i showed superior binding affinity than their anilinophthalazine parents (IC50 = 0.083-0.473 µM). In particular, compounds 7g-i showed IC50 of 0.086, 0.083 and 0.086 µM, respectively, which are better than that of the reference drug sorafenib (IC50 = 0.09 µM).