Development of 1,5-diarylpyrazoles as EGFR/JNK-2 dual inhibitors: design, synthesis, moleecular docking, and bioactivity evaluation.

The eradication of multifactorial diseases, such as cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun N-terminal kinase 2 (JNK-2) for possible anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 cancer cell lines, with minimum concentration required to inhibit half of the cellular growth (IC50) values of 2.7-63 µM. The tests confirmed that 5b and 5d were potent JNK-2 inhibitors, with IC50 of 2.0 and 0.9 µM, respectively, whereas 6 h selectively inhibited EGFR protein kinase (EGFR-PK) (IC50 = 1.7 µM). Notably, 6c inhibited both kinases, with IC50 values of 2.7 and 3.0 µM against EGFR-PK and JNK-2, respectively, offering a reference for designing mutual inhibitors of EGFR/JNK-2. The docking studies revealed the ability of the pyrazole ring to bind to the hinge region of the ATP binding site, thereby supporting the experimental inhibitory results. Furthermore, the developed compounds could induce apoptosis and induce cell cycle arrest at different cell phases.

Synthesis of New D-π-A Phenothiazine-Based Fluorescent Dyes: Aggregation Induced Emission and Antibacterial Activity.

Highly solid-state fluorescent dyes based on phenothiazine bearing sulfa-drug derivatives were successfully prepared and fully characterized by NMR, mass spectra, and elemental analysis. The prepared phenothiazine dyes bearing sulfadiazine and sulfathiazole 4-(((10-hexyl-10 H-phenothiazin-3-yl)methylene)amino)-N-(pyrimidin-2yl) benzenesulfonamide (PTZ-1) and 4-(((10-hexyl-10 H-phenothiazin-3-yl) methylene) amino)-N-(thiazol-2-yl)benzenesulfonamide (PTZ-2), showed strong emission in polycrystalline form, and significant emission in solution was observed. The quantum yield of the prepared dyes varied and decreased by increasing the solvent polarity, with the maximum recorded value being 0.63 and 0.6 in dioxane. Aggregation-induced emission (AIE) and the effect of the solvent polarity on absorption and emission spectra were investigated. The dyeing application of polyester fabrics using the prepared phenothiazine-based dyes was studied, showing very good affinity to dyed fabrics. The antibacterial affinity against gram-positive and gram-negative bacteria for the dye powder as well as the dyed PET fabric was investigated, with PTZ-2 showing better affinity against bacteria compared to PTZ-1. This multifunctional property highlights the potential uses of PTZ-1 and PTZ-2 for advanced applications in biomedicine and optoelectronics.

Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kß kinases.

Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds 5, 4b, and 4a possessed potent cytotoxic activity against PC-3 cells with IC50 3.56, 8.99, and 10.22 µM, respectively. Compound 4c displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC50 8.5 µM. Moreover, compound 5 exhibited potent inhibitory activity on EFGR with IC50 0.1812 µM, as well as PI3Kß inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kß inhibiting activity. Docking aligns with the in vitro results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound 5 decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound 5 caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.

Quinazoline-chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in-silico studies of potential anticancer activity against multiple myeloma.

Two new series of quinazoline-chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5-trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer cell lines. Thus, it was selected for further investigation for NCI 5 log doses. Interestingly, this trimethoxy-substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)-8226 cells by 96%, at 10 µM with IC50 = 9.09 ± 0.34 µM and selectivity index = 7.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC50 = 0.41 ± 0.015, 0.61 ± 0.027, and 0.09 ± 0.004 µM, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax/Bcl-2 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI-8226 cells showed that the trimethoxy-substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc-containing binding site of HDAC6 and HDAC8.

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.

Diagnostic accuracy of point-of-care knee ultrasound for evaluation of meniscus and collateral ligaments pathology in comparison with MRI.

BACKGROUND: Although magnetic resonance imaging (MRI) is often the "gold standard" for diagnosing knee problems, it has many limitations. Therefore, ultrasonography has been suggested as an effective rapid alternative in many knee abnormalities, especially after injuries of the meniscus and collateral ligaments. PURPOSE: To determine the diagnostic accuracy of point-of-care ultrasound (POCUS) in detecting injuries of the meniscus and collateral ligament compared to MRI. MATERIAL AND METHODS: An observational cross-sectional blinded study was conducted of 60 patients with clinically suspicious meniscus and collateral ligament injuries who were planned for an arthroscopy and or operative procedure. These patients underwent both blinded POCUS and MRI of the knees before the intervention procedure and results of both imaging modalities were compared according to the operative and arthroscopic findings. RESULTS: The preoperative reliability of POCUS compared to MRI for the assessment of meniscus injuries was sensitivity (92.9% vs. 90.5%), specificity (88.9% vs. 83.3%), positive predictive value (PPV; 95.1% vs. 92.7%), negative predictive value (NPV; 84.2% vs. 79%), and overall accuracy (91.7% vs. 88.3%). However, for diagnosing collateral ligament injures, POCUS versus MRI assessed sensitivity (92.3% vs. 88.5%), specificity (100% vs. 97.1%), PPV (100% vs. 95.8%), NPV (94.4% vs. 91.7%), and overall accuracy (96.7% vs. 93.3%). CONCLUSION: Ultrasonography is a useful screening tool for the initial diagnosis of meniscal and collateral ligament pathology compared to or even with potential advantages over MRI, especially when MRI is unavailable or contraindicated. As newly advanced portable ultrasonography becomes available, it could be considered as a point-of-injury diagnostic modality.

Harnessing pyrimidine as a building block for histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors are well-established multifaceted bioactive agents against tumors and neurodegenerative disorders. Pyrimidine and its fused and substituted derivatives were employed as a surface recognition moiety of HDAC inhibitors. De facto, the literature was loaded with different success stories of pyrimidine-based HDAC inhibitors that garnered much interest. Provoked by our continuous interest in HDAC inhibitors, we summarized and elaborated on the successful harnessing of the pyrimidine scaffold in this regard. Furthermore, we dissect our perspective that may guide medicinal chemists for an effective future design of more active chemotherapeutic agents with potential clinical applications.

New 1,3,4-oxadiazole-chalcone/benzimidazole hybrids as potent antiproliferative agents.

A series of new 1,3,4-oxadiazole-chalcone/benzimidazole hybrids 9a-o and 10a-k were designed and synthesized as potential antiproliferative agents. Hybrids 9a-o exhibited remarkable antiproliferative activities on different NCI-60 cell lines in a single-dose assay. The antiproliferative activities of the newly synthesized compounds were evaluated against a panel of four human cancer cell lines (A-549, MCF-7, Panc-1, and HT-29). Compounds 9g-i and their oxygen isosteres, 10f-h, exhibited promising antiproliferative activities with IC50 values ranging from 0.80 to 2.27 µM compared to doxorubicin (IC50 ranging from 0.90 to 1.41 µM). Furthermore, the inhibitory potency of these compounds against the epidermal growth factor receptor (EGFR) and BRAFV600E kinases was evaluated using erlotinib as a reference drug. Molecular modeling studies were done to investigate the binding mode of the most active hybrids in the ATP binding site of EGFR.

Discovery of new cyanopyridine/chalcone hybrids as dual inhibitors of EGFR/BRAFV600E with promising antiproliferative properties.

As dual EGFR and BRAFV600E inhibitors, 2-(3-cyano-4,6-bis(aryl)-2-oxo-1,2-dihydropyridine-1-yl)-N-(4-cinnamoylphenyl) acetamide derivatives 8-20 were developed. Compounds 8, 12, and 13 showed strong antiproliferative activity when the target compounds were synthesized and tested in vitro against four cancer cell lines. These hybrids have a dual inhibition activity on EGFR and BRAFV600E , according to in vitro studies. The EGFR was inhibited by compounds 8, 12, and 13 with IC50 values between 89 and 110 nM, which were equivalent to those of erlotinib (IC50 = 80 nm). Compound 13 was found to be an effective inhibitor of the proliferation of cancer cells (GI50 = 0.72 µM) and demonstrated hopeful inhibitory activity of BRAFV600E (IC50 = 58 nm), which is superior to erlotinib (IC50 = 65 nm). Compound 13 caused apoptosis and showed cell cycle arrest in the G0/G1phase in a study on the MCF-7 cell line. The new compounds can fit tightly into the active sites of EGFR and BRAFV600E kinases, according to molecular docking analyses.

Design, Synthesis, Antiproliferative Actions, and DFT Studies of New Bis-Pyrazoline Derivatives as Dual EGFR/BRAFV600E Inhibitors.

Some new Bis-pyrazoline hybrids 8-17 with dual EGFR and BRAFV600E inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI50 values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAFV600E. Compounds 12, 15, and 17 inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound 12 is the most potent inhibitor of cancer cell proliferation and BRAFV600E. Compounds 12 and 17 induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds 12, 15, and 17 have the potential to be dual EGFR/BRAFV600E inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, 12 and 15, were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study.

Development and Assessment of 1,5-Diarylpyrazole/Oxime Hybrids Targeting EGFR and JNK-2 as Antiproliferative Agents: A Comprehensive Study through Synthesis, Molecular Docking, and Evaluation.

New 1,5-diarylpyrazole oxime hybrid derivatives (scaffolds A and B) were designed, synthesized, and then their purity was verified using a variety of spectroscopic methods. A panel of five cancer cell lines known to express EGFR and JNK-2, including human colorectal adenocarcinoma cell line DLD-1, human cervical cancer cell line Hela, human leukemia cell line K562, human pancreatic cell line SUIT-2, and human hepatocellular carcinoma cell line HepG2, were used to biologically evaluate for their in vitro cytotoxicity for all the synthesized compounds 7a-j, 8a-j, 9a-c, and 10a-c. The oxime containing compounds 8a-j and 10a-c were more active as antiproliferative agents than their non-oxime congeners 7a-j and 9a-c. Compounds 8d, 8g, 8i, and 10c inhibited EGFR with IC50 values ranging from 8 to 21 µM when compared with sorafenib. Compound 8i inhibited JNK-2 as effectively as sorafenib, with an IC50 of 1.0 µM. Furthermore, compound 8g showed cell cycle arrest at the G2/M phase in the cell cycle analysis of the Hela cell line, whereas compound 8i showed combined S phase and G2 phase arrest. According to docking studies, oxime hybrid compounds 8d, 8g, 8i, and 10c exhibited binding free energies ranging from -12.98 to 32.30 kcal/mol at the EGFR binding site whereas compounds 8d and 8i had binding free energies ranging from -9.16 to -12.00 kcal/mol at the JNK-2 binding site.

Design, Synthesis, and Biological Evaluation of Novel 3-Cyanopyridone/Pyrazoline Hybrids as Potential Apoptotic Antiproliferative Agents Targeting EGFR/BRAFV600E Inhibitory Pathways.

A series of novel 3-cyanopyridone/pyrazoline hybrids (21-30) exhibiting dual inhibition against EGFR and BRAFV600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI50 values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAFV600E pathways. Compounds 28 and 30, akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAFV600E. Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAFV600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects.

New potent ciprofloxacin-uracil conjugates as DNA gyrase and topoisomerase IV inhibitors against methicillin-resistant Staphylococcus aureus.

A series of ciprofloxacin-uracil conjugates 5a-t were synthesized and identified by 1H NMR, 13C NMR, mass spectroscopy and elemental analyses. The antibacterial results revealed that the new derivatives exhibited better activity against Gram-positive than the Gram-negative strains; most of the target compounds exhibited good activities against S. aureus ATCC 6538. Compounds 5b and 5g possess the highest activities with MICs of 1.25 and 2.37 µM, respectively, which are more potent than the parent drug ciprofloxacin, MIC, 7.58 µM. In addition, they also exhibited potent activities against MRSA AUMC 261 with MICs, 0.031 and 0.046 µM respectively, higher than ciprofloxacin with MIC, 0.57 µM. Moreover, compounds 5b and 5g showed potent inhibitory activities against DNA gyrase (IC50 = 1.72 and 5.72 µM) and topoisomerase IV (4.36 and 7.77 µM) compared to ciprofloxacin with IC50 values 0.66 and 8.16 µM, respectively. The molecular docking study revealed that compounds 5b and 5g may formed stable interaction with the active sites of DNA gyrase and topoisomerase IV similar to ciprofloxacin. Hence, 5b and 5g are considered promising antibacterial candidated against MRSA AUMC 261 strains that requires further optimization.

Functionalization of cotton fabrics with titanium oxide doped silver nanoparticles: Antimicrobial and UV protection activities.

The target of our current work was designed to prepare titanium oxide doped silver nanoparticles (Ag/TiO2 NPs) and their impact on the functionalization of cotton fabrics. Additionally, the effect of Ag/TiO2 NPs was compared with the individually prepared silver nanoparticles (AgNPs) and titanium oxide nanoparticles (TiO2 NPs). In this work, AgNPs were prepared in the solid state using arabic gum as efficient stabilizing and reducing agent. Then, two concentrations of the as-synthesized nanoparticles were used to functionalize the cotton fabrics by pad-dry-cure treatment in the presence of fixing agent to increase the durability of treated cotton fabrics against vigorous washing cycles. The findings implied that the as-prepared nanoparticles were successfully synthesized in nano-size with spherical shape and homogeneity. The efficacy of the functionalized cotton fabrics with those nanoparticles were evaluated in terms of multifunctional properties including antimicrobial and ultraviolet protection factor (UPF) and the mechanical features before and after many washing cycles; 10, 15 and 20 times. The resultant also proved that Ag/TiO2 NPs-treated cotton fabrics exhibited the greater values of both antimicrobial and UPF properties with enhancement in the tensile strength and elongation features. Thus, the combination between these two nanoparticles through doping reaction is suitable for imparting superior antimicrobial properties against the four tested microbial species (Staphylococcus aureus, Escherichia coli, Candida albicans, and Aspergillus niger) and good UPF properties. Depending on the promising obtained results of the multi-finishing fabrics, these nanoparticles of Ag/TiO2 NPs can be applied for the production of an efficient medical clothes for doctors, nurses and bed sheets for patients in order to kill and prevent the spread of bacteria and then, reduce the transmission of infection to others.

Effect of different surface treatments on the bond strength of milled polyetheretherketone posts.

STATEMENT OF PROBLEM: Polyetheretherketone (PEEK) can be used as a framework material for removable and fixed dental prostheses. However, information about the use of PEEK as a post-and-core restoration is scarce. PURPOSE: The purpose of this in vitro study was to evaluate the effect of different surface treatments on the push-out bond strength of milled polyetheretherketone posts to resin cement. MATERIAL AND METHODS: Sixty intact human maxillary central incisors were selected and endodontically treated, and standardized post spaces were prepared. Sixty PEEK posts were milled from a prefabricated PEEK blank by using a computer-aided design and computer-aided manufacturing (CAD-CAM) system and divided into 3 groups (n=15) according to the surface treatment: acid etching by using 98% sulfuric acid (AE); airborne-particle abrasion by using 50-µm Al2O3 (AA); nonthermal plasma treatment (NTP); in addition, PEEK posts (n=15) received no treatment (NT) and served as a control. All posts were bonded by using a self-adhesive resin cement. Three sections (coronal, middle, and apical) were obtained for each specimen. Push-out bond strength measurements (MPa) for each section were recorded by using a universal testing machine at a crosshead speed of 0.5 mm/min until failure occurred. The post-cement interfaces and failure modes were evaluated by using scanning electron microscopy. The data obtained were statistically analyzed by using 1-way ANOVA and the pair-wise Tukey (HSD) test to study the difference between group mean values (α=.05). RESULTS: The overall mean ±standard deviation of the push-out bond strength was 11 ±2 MPa for AE group, 6 ±1 MPa for AA group, 5 ±1 MPa for NTP group, and 3 ±1 MPa for NT group. A statistically significant difference was found among all groups subjected to different surface treatments as indicated by the ANOVA test (P<.001). The pair-wise Tukey honestly significant difference (HSD) test showed a significant difference among the AE group and all groups (P<.001); however, no significant difference was observed between the AA and NTP groups (P>.05). Moreover, a significant difference was observed among all root sections (P<.001). CONCLUSIONS: Surface treatment of PEEK posts with 98% sulfuric acid for 60 seconds showed significantly higher bond strength values than those in other groups. The bond strength of PEEK posts to resin cement was significantly higher in the coronal section than that in other sections.

Synthesis and Identification of New N,N-Disubstituted Thiourea, and Thiazolidinone Scaffolds Based on Quinolone Moiety as Urease Inhibitor.

Synthesis of thiazolidinone based on quinolone moiety was established starting from 4-hydroxyquinol-2-ones. The strategy started with the reaction of ethyl bromoacetate with 4-hydroxyquinoline to give the corresponding ethyl oxoquinolinyl acetates, which reacted with hydrazine hydrate to afford the hydrazide derivatives. Subsequently, hydrazides reacted with isothiocyanate derivatives to give the corresponding N,N-disubstituted thioureas. Finally, on subjecting the N,N-disubstituted thioureas with dialkyl acetylenedicarboxylates, cyclization occurred, and thiazolidinone derivatives were obtained in good yields. The two series based on quinolone moiety, one containing N,N-disubstituted thioureas and the other containing thiazolidinone functionalities, were screened for their in vitro urease inhibition properties using thiourea and acetohydroxamic acid as standard inhibitors. The inhibition values of the synthesized thioureas and thiazolidinones exhibited moderate to good inhibitory effects. The structure-activity relationship revealed that N-methyl quinolonyl moiety exhibited a superior effect, since it was proved to be the most potent inhibitor in the present series achieving (IC50 = 1.83 ± 0.79 µM). The previous compound exhibited relatively much greater activity, being approximately 12-fold more potent than thiourea and acetohydroxamic acid as references. Molecular docking analysis showed a good protein-ligand interaction profile against the urease target (PDBID: 4UBP), emphasizing the electronic and geometric effect of N,N-disubstituted thiourea.

Design, synthesis, and biological evaluation of new series of pyrrol-2(3H)-one and pyridazin-3(2H)-one derivatives as tubulin polymerization inhibitors.

A potential microtubule destabilizing series of new thirty-five Pyrrol-2-one, Pyridazin-3(2H)-one and Pyridazin-3(2H)-one/oxime derivatives has been synthesized and tested for their antiproliferative activity against a panel of 60 human cancer cell lines. Compounds IVc, IVg and IVf showed a broad spectrum of growth inhibitory activity against cancer cell lines representing renal, cancer of lung, colon, central nervous system, ovary, and kidney. Among them, compound IVg was found to have broad spectrum anti-tumor activity against the tested nine tumor subpanels with selectivity ratios ranging between 0.21 and 3.77 at the GI50 level. In vitro assaying revealed tubulin polymerization inhibition by all active compounds IVc, IVg and IVf. The results of the docking study revealed nice fitting of compounds IVc, IVf, and IVg into CA-4 binding site in tubulin. The three compounds exhibited high binding affinities (ΔGb = -12.49 to -12.99 kcal/mol) toward tubulin compared to CA-4 (-8.87 kcal/mol). Investigation of the binding modes of the three compounds IVc, IVf, and IVg revealed that they interacted mainly hydrophobically with tubulin and similar binding orientations to that of CA-4. These observations suggest that tubulin is a possible target for these compounds.

Design and synthesis of novel quinoline/chalcone/1,2,4-triazole hybrids as potent antiproliferative agent targeting EGFR and BRAFV600E kinases.

New quinoline / chalcone hybrids containing 1,2,4-triazole moiety have been designed, synthesized and their structures elucidated and confirmed by various spectroscopic techniques. The designed compounds showed moderate to good activity on different NCI 60 cell lines in a single-dose assay with a growth inhibition rate ranging from 50% to 94%. Compounds 7b, 7d, 9b, and 9d were the most active compounds in most cancer cell lines with a growth inhibition percent between 77% and 94%. Newly synthesized hybrids were evaluated for their anti-proliferative activity against a panel of four human cancer cell lines. Compounds 7a, 7b, 9a, 9b, and 9d showed promising antiproliferative activities. These compounds were further tested for their inhibitory potency against EGFR and BRAFV600E kinases with erlotinib as a reference drug. The molecular docking study of compounds 7a, 7b, 9a, 9b, and 9d revealed nice fitting into the active site of EGFR and BRAFV600E kinases. Compounds 7b, 9b, and 9d displayed the highest binding affinities and similar binding pattern to those of erlotinib.

Novel Mannich bases of ciprofloxacin with improved physicochemical properties, antibacterial, anticancer activities and caspase-3 mediated apoptosis.

The design, synthesis and identification of a novel series of Mannich bases of ciprofloxacin was reported. Naphthol derivatives 2a and 2b showed highly potent cytotoxic activity among the tested compounds. Compound 2a showed broad spectrum antiproliferative activity with GI50 of 2.5-6.79 µM with remarkable selectivity towards renal and prostate cancers with selectivity ratios ranging from 0.17 to 6.79. Independently, 2a showed outstanding activity against colon cancer HOP-92 cell lines with IC50 of 6.66 µM while 2b showed highly potent activity against ovarian cancer cell lines with IC50 of 0.97 µM. Results showed that 2b induced cell cycle arrest at G2/M phase and apoptosis; compound 2b showed over-expression of caspase-3 protein level (449.2 ± 7.95) compared to doxorubicin (578.7 ± 14.4 pg/mL). Meanwhile, compounds 2a and 2b experienced outstanding activity against both Gram-positive and Gram-negative microorganisms. Interestingly, compound 2j experienced high activity against Escherichia coli and Pseudomonas aeruginosa with MIC of 0.036 and 0.043, respectively. Compound 2d revealed 27 folds and 22 folds, respectively increasing of activity over ciprofloxacin against Staphylococcus aureus and MRSA(reference strain). Compound 2d showed high activity against Staphylococcus aureus, MRSA (reference strain) and MRSA (clinical strain) with MIC of 0.57, 0.52, 0.082 µg/mL, respectively. Interestingly, the most active tested compounds were found to have promising physicochemical and drug likeness properties. The Mannich bases 2j, 2d and 2g showed promising antibacterial activities, while naphthols 2a and 2b showed promising antiproliferative and antibacterial activities that require further optimization.

Development of 2'-aminospiro [pyrano[3,2-c]quinoline]-3'-carbonitrile derivatives as non-ATP competitive Src kinase inhibitors that suppress breast cancer cell migration and proliferation.

Src kinase activity controls diverse cellular functions, including cell growth, migration, adhesion, and survival. It is de-regulated in several cancers, including breast cancer, where it is highly expressed and phosphorylated. Thus, targeting Src by a small molecule is a feasible strategy for managing different breast cancer types. Several Src kinase inhibitors are available, including the FDA-approved drug (dasatinib). However, they are primarily ATP-competitive inhibitors that have been reported to lack specificity towards Src. We have a long-time interest in discovering protein kinase inhibitors that are non-competitive for ATP. In this project, three groups of 2'-aminospiro[pyrano[3,2-c]quinoline]-3'-carbonitrile derivatives were designed and synthesized, hypothesizing that small molecules with a spiro scaffold appended to a pyrano[3,2-c]quinoline analog could act as non-ATP competitive Src kinase inhibitors. 3b, 3c, and 3d inhibited Src kinase activity with IC50s of 4.9, 5.9, and 0.9 µM, respectively. At the same time, they did not impact the MDM2/p53 interaction in HEK293 cells, which has been reported to be affected by some spirocyclic compounds. 25 µM of 3b, 3c, or 3d did not inhibit the kinase activity of ERK2, JNK1, or p38-alpha in an in-vitro kinase assay. Steady-state kinetic studies for the effect of 3d on the ability of recombinant Src to phosphorylate its substrate (Srctide) revealed a non-ATP competitive inhibition mechanism. 1.6 µM of 3d was enough to diminish Src, Fak, and paxillin phosphorylation in the breast cancer cell lines MDA-MB-231 and MCF7. In the NCI screening, 3d induced broad tumor cytotoxicity for the NCI-60 cell lines, including all the breast cancer cell lines. The potency of 3b, 3c, and 3d to inhibit migration, proliferation, and colony formation of MDA-MB-231 and proliferation of MCF7 cells correlates with their potency to suppress Src kinase activity in the same cell line. Noticeably, the cell growth suppression and apoptosis induction in the tested cell lines can be attributed to the ability of the new derivatives to suppress the ERK and Akt survival pathways downstream of Src.