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The present study details the design, synthesis, and bio-evaluation of indoles 3-16 as dual inhibitors of aromatase and inducible nitric oxide synthase (iNOS) with antiproliferative activity. The study evaluates the antiproliferative efficacy of 3-16 against various cancer cell lines, highlighting hybrids 12 and 16 for their exceptional activity with GI50 values of 25 nM and 28 nM, respectively. The inhibitory effects of the most active hybrids 5, 7,12, and 16, on both aromatase and iNOS were evaluated. Compounds 12 and 16 were investigated for their apoptotic potential activity, and the results showed that the studied compounds enhance apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking studies are intricately discussed to confirm most active hybrids' 12and 16-binding interactions with the aromatase active site. Additionally, our novel study discussed the ADME characteristics of derivatives 8-16, highlighting their potential as therapeutic agents with reduced toxicity. [ABSTRACT FROM AUTHOR]

The emergence of antibiotic-resistant Streptococcus pneumoniae necessitates the discovery of novel therapeutic agents. This study investigated the antimicrobial potential of green-synthesized gold nanoparticles (AuNPs) fabricated using Arthrospira platensis extract. Characterization using Fourier transform infrared spectroscopy revealed the presence of functional groups such as ketones, aldehydes, and carboxylic acids in the capping agents, suggesting their role in AuNP stabilization. Transmission electron microscopy demonstrated the formation of rod-shaped AuNPs with a mean diameter of 134.8 nm, as determined by dynamic light scattering, and a zeta potential of −27.2 mV, indicating good colloidal stability. The synthesized AuNPs exhibited potent antibacterial activity against S. pneumoniae, with a minimum inhibitory concentration (MIC) of 12 μg/mL, surpassing the efficacy of the control antibiotic, tigecycline. To elucidate the underlying mechanisms of action, an untargeted metabolomic analysis of the A. platensis extract was performed, identifying 26 potential bioactive compounds belonging to diverse chemical classes. In silico studies focused on molecular docking simulations revealed that compound 22 exhibited a strong binding affinity to S. pneumoniae topoisomerase IV, a critical enzyme for bacterial DNA replication. Molecular dynamics simulations further validated the stability of this protein–ligand complex. These findings collectively highlight the promising antimicrobial potential of A. platensis-derived AuNPs and their constituent compounds, warranting further investigation for the development of novel anti-pneumococcal therapeutics. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of mortality worldwide, making it a public health concern. A novel series of pyrrolidine‐carboxamide derivatives 7a‐q were developed and examined in a cell viability assay utilizing a human mammary gland epithelial cell line (MCF‐10A), where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 μM. Antiproliferative activity was evaluated in vitro against four panels of cancer cell lines A‐549, MCF‐7, Panc‐1, and HT‐29. Compounds 7e, 7g, 7k, 7n, and 7o were the most active as antiproliferative agents capable of triggering apoptosis. Compound 7g was the most potent of all the derivatives, with a mean IC50 of 0.90 μM compared to IC50 of 1.10 μM for doxorubicin. Compound 7g inhibited A‐549 (epithelial cancer cell line), MCF‐7 (breast cancer cell line), and HT‐29 (colon cancer cell line) more efficiently than doxorubicin. EGFR inhibitory assay results of 7e, 7g, 7k, 7n, and 7o demonstrated that the tested compounds inhibited EGFR with IC50 values ranging from 87 to 107 nM in comparison with the reference drug erlotinib (IC50 = 80 nM). 7e, 7g, 7k, 7n, and 7o inhibited CDK2 efficiently in comparison to the reference dinaciclib (IC50 = 20 nM), with IC50 values ranging from 15 to 31 nM. The results of inhibitory activity assay against different CDK isoforms revealed that the tested compounds had preferential inhibitory activity against the CDK2 isoform. [ABSTRACT FROM AUTHOR]

A novel series of hybrid compounds comprising quinazolin-4-one and 3-cyanopyridin-2-one structures has been developed, with dual inhibitory actions on both EGFR and BRAFV600E. These hybrid compounds were tested in vitro against four different cancer cell lines. Compounds 8, 9, 18, and 19 inhibited cell proliferation significantly in the four cancer cells, with GI50 values ranging from 1.20 to 1.80 µM when compared to Doxorubicin (GI50 = 1.10 µM). Within this group of hybrids, compounds 18 and 19 exhibited substantial inhibition of EGFR and BRAFV600E. Molecular docking investigations provided confirmation that compounds 18 and 19 possess the capability to inhibit EGFR and BRAFV600E. Moreover, computational ADMET prediction indicated that most of the newly synthesized hybrids have low toxicity and minimal side effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• A series of novel quinoline-based derivatives 3a-d and 4a-d as antiproliferative agents targeting EGFR and BRAFV600E have been developed. • Antiproliferative activities were evaluated against four human cancer cell lines. • Molecular docking studies were carried out against EGFR, and BRAFV600E. New quinoline-based derivatives 3a-d and 4a-d have been designed and synthesized as promising antiproliferative candidates. The designed compounds were tested for their antiproliferative activity against a panel of four human cancer cell lines with GI 50 values ranging from 1.40 µM to 5.00 µM relative to doxorubicin (GI 50 = 1.20 µM). Compound 4a was the most potent derivative against the four examined cancer cell lines (GI 50 = 1.40 µM) relative to the reference doxorubicin (GI 50 = 1.20 µM), indicating the role of the oxime moiety in the antiproliferative activity. The inhibitory impact on EGFR and BRAFV600E as potential molecular targets was investigated for the most effective antiproliferative derivatives, 3c, 4a , and 4b. Compound 4a exhibited the highest EGFR and BRAFV600E inhibitory activity with IC 50 values of 105±10 nM and 140±12 nM, respectively, which is comparable to the reference erlotinib with IC 50 values of 80±10 nM and 60±10, respectively. Docking computations were utilized to analyze the docking modes and scores of compounds 3c, 4a , and 4b with respect to EGFR and BRAFV600E. The results of the docking computations revealed a favorable affinity of compound 4a towards both EGFR and BRAFV600E, with values of -7.05 kcal/mol and -7.67 kcal/mol, respectively. [ABSTRACT FROM AUTHOR]

Dual targeting of EGFR and HER2 is a valid anti-cancer approach for treating solid tumors. We designed and synthesized a new series of EGFR/HER-2 dual-target inhibitors based on quinoline derivatives. The structure of the newly synthesized compounds was verified using 1 H NMR, 13 C NMR, and elemental analysis. The targeted compounds were tested for antiproliferative efficacy against four cancer cell lines. All the compounds had GI 50 s ranging from 25 to 82 nM, with breast (MCF-7) and lung (A-549) cancer cell lines being the most sensitive. Compound 5a demonstrated the most significant antiproliferative action. With inhibitory (IC 50 ) values of 71 and 31 nM, respectively, compound 5a proved to be the most effective dual-target inhibitor of EGFR and HER-2, outperforming the reference erlotinib (IC 50 = 80 nM) as an EGFR inhibitor but falling short of the clinically used agent lapatinib (IC 50 = 26 nM) as a HER2 inhibitor. The apoptotic potential activity of 5a was examined, and the findings demonstrated that 5a promotes apoptosis by activating caspase-3, 8, and Bax while simultaneously reducing the expression of the anti-apoptotic protein Bcl-2. The docking studies provided valuable insights into the binding interactions of compounds 3e and 5a with EGFR, effectively rationalizing the observed SAR trends., Competing Interests: The authors reported no potential conflicts of interest(s)., (This journal is © The Royal Society of Chemistry.)

The current study focuses on developing a single molecule that acts as an antiproliferative agent with dual or multi-targeted action, reducing drug resistance and adverse effects. A new series of 4-pyrazolylquinolin-2-ones (5a-j) with apoptotic antiproliferative effects as dual EGFR/BRAF V600E inhibitors were designed and synthesized. Compounds 5a-j were investigated for their cell viability effect against a normal cell line (MCF-10A). Results showed that none of the compounds were cytotoxic, and all 5a-j demonstrated more than 90% cell viability at 50 μM concentration. Using erlotinib as a reference, the MTT assay investigated the antiproliferative impact of targets 5a-j against four human cancer cell lines. Compounds 5e, 5f, 5h, 5i, and 5j were the most potent antiproliferative agents with GI 50 values of 42, 26, 29, 34, and 37 nM, making compounds 5f and 5h more potent than erlotinib (GI 50 = 33 nM). Moreover, compounds 5e, 5f, 5h, 5i, and 5j were further investigated as dual EGFR/BRAF V600E inhibitors, and results revealed that compounds 5f, 5h, and 5i are potent antiproliferative agents that act as dual EGFR/BRAF V600E inhibitors. Cell cycle analysis and apoptosis detection revealed that compound 5h displaying cell cycle arrest at the G1 transition could induce apoptosis with a high necrosis percentage. Docking studies revealed that compound 5f exhibited a strong affinity for EGFR and BRAF V600E , with high docking scores of -8.55 kcal mol -1 and -8.22 kcal mol -1 , respectively. Furthermore, the ADME analysis of compounds 5a-j highlighted the diversity in their pharmacokinetic properties, emphasizing the importance of experimental validation., Competing Interests: The authors reported no potential conflicts of interest(s)., (This journal is © The Royal Society of Chemistry.)

As dual EGFR and BRAF V600E 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 BRAF V600E , according to in vitro studies. The EGFR was inhibited by compounds 8, 12, and 13 with IC 50 values between 89 and 110 nM, which were equivalent to those of erlotinib (IC 50  = 80 nm). Compound 13 was found to be an effective inhibitor of the proliferation of cancer cells (GI 50  = 0.72 µM) and demonstrated hopeful inhibitory activity of BRAF V600E (IC 50  = 58 nm), which is superior to erlotinib (IC 50  = 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 BRAF V600E kinases, according to molecular docking analyses., (© 2022 Deutsche Pharmazeutische Gesellschaft.)