Normal Vero Cells Research Articles

Bioguided antiplasmodial isolation of six new labdane-type diterpenoids from the stem bark of Croton sylvaticus Hochst. Ex. Krauss

The CH2Cl2-MeOH (1:1, v/v) extract of Croton sylvaticus stem bark selectively exhibited good antiplasmodial activity during preliminary screening against the multidrug-resistant (Dd2) and chloroquine sensitive (3D7) strains of Plasmodium falciparum with IC50 values of 10.57 and 18.47 μg/mL, respectively. After fractionation, the fractions exhibited moderate to good activity with IC50 values ranging from 4.31 to 25.49 μg/mL. The purification of these fractions led to the isolation of six new labdane-type diterpenoids named sylvacrotonins AF (16), alongside seven known compounds (713). Their structures were determined based on the analysis of their NMR and MS data. The isolated compounds were assessed in vitro for their antiplasmodial activity against Pf3D7 and PfDd2. The new labdane-type diterpenoids showed moderate antiplasmodial activity against the two P. falciparum strains, with compound 6 being the most active, with IC50 values of 11.26 and 21.80 μg/mL against PfDd2 and Pf3D7, respectively. Cytotoxic assays were performed on African green monkey kidney Vero cells to ensure that the obtained activity was specific to the parasites. Interestingly, all the tested extracts, fractions, and isolated compounds showed acceptable selectivity (SI > 10) against both Plasmodium strains, except fractions CSB-E (SI = 3.93) and CSB-C (SI = 9.22) against Pf3D7. Globally, with resistance indexes (RIs) lower than 1, all the tested samples were found to be more active against multidrug-resistant (PfDd2) than sensitive (Pf3D7) strains. Furthermore, all the isolated compounds exhibited cell cytotoxicity in the normal Vero cell line. The results from this study confirm the use of C. sylvaticus in malaria-endemic countries for its management and suggest that further lead-optimization studies on hit compounds could drive to the identification of potential lead molecules for antimalarial control and eradication.

Effect of new antitumor compounds based on azoloazine derivatives on the level of DNA damage in normal Vero cells in the DNA comet test

The aim of the work is to study the effect of new azoloazine derivatives on the level of DNA damage to Vero cells (DNA comet test) in vitro by alkaline gel electrophoresis.Material and methods. The objects of the study are 8-(piperidinocarbonyl)3-cyclohexylimidazo[5,1-d][1,2,3,5]tetrazine-4(3H)-one (1), diethyl ether 4-aminoimidazo[5,1-c][1,2,4]triazine3,8-dicarboxylic acid (2), 4-amino-8-ethoxycarbonylimidazo[5,1-c][1,2,4]triazine-3-N-(p-toluyl)carboxamide (3). Epirubicin was chosen as a comparison drug. The compounds were used in doses of 1/2, 1/10 and 1/50 IC50. The Vero cell line cultured according to the standard protocol was selected as the cell model. To assess genotoxicity, an alkaline version of the DNA comet method was used, which has a high sensitivity and allows detecting DNA damage.Results. Analysis of the data obtained indicates that the tested compounds 1-3 enhance DNA damage in non-tumor cells. Compound 1 has the most pronounced genotoxic effect. Thus, the use of this substance in a dose of ½ IC50 led to a significant increase in the length of the comet’s tail by 1.5 times. It was noted that DNA damage under the action of compound 1 in the studied doses and of epirubicin was on the same level.Conclusions. The results obtained prove that compounds 1-3 may have a potentially carcinogenic effect. However, this assumption requires further in-depth experimental studies.

Rationale, in silico docking, ADMET profile, design, synthesis and cytotoxicity evaluations of phthalazine derivatives as VEGFR-2 inhibitors and apoptosis inducers.

New phthalazine derivatives as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors were synthesized joined to different spacers including pyrazole, α,β-unsaturated ketonic fragment, pyrimidinone and/or pyrimidinthione. A docking study was carried out to explore the suggested binding orientations of the novel derivatives inside the active site of VEGFR-2. The obtained biological data were extremely interrelated to that of the docking study. In particular, compounds 4b and 3e showed the highest activities against Michigan Cancer Foundation-7 (MCF-7) and Hepatocellular carcinoma G2 (HepG2) with half maximal inhibitory concentration (IC50) = 0.06, 0.06 μM and 0.08, 0.19 μM respectively. Our derivatives 3a-e, 4a,b and 5a,b were evaluated for their cytotoxicity against normal VERO cells. Our compounds exhibited low toxicity concerning normal VERO cells with IC50 = 3.00-4.75 μM. In addition, our final derivatives 3a-e, 4a, 4b, 5a and 5b were investigated for their VEGFR-2 inhibitory activities. Derivative 4b exhibited the highest VEGFR-2 inhibitory activities at an IC50 value of 0.09 ± 0.02 μM. Derivatives 3e, 4a and 5b demonstrated good activities with IC50 values = 0.12 ± 0.02, 0.15 ± 0.03 and 0.13 ± 0.03 μM respectively. Furthermore, the activities of 4b were assessed against MCF-7 cancer cells for apoptosis induction, cell cycle distribution and growth inhibition. Compound 4b caused cell growth arrest in growth 2-mitosis (G2-M) phase; accumulation of cells at that phase became 6.92% after being 13.2 in control cells. Moreover, our derivatives 3e, 4b and 5b revealed a good in silico considered absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile in comparison to sorafenib.

Anticancer evaluations of iodoquinazoline substituted with allyl and/or benzyl as dual inhibitors of EGFRWT and EGFRT790M: design, synthesis, ADMET and molecular docking.

Fifteen new iodoquinazoline derivatives, 5a,b to 18, are reported in this study and their anticancer evaluation as dual inhibitors of EGFRWT and EGFRT790M. The new derivatives were designed according to the target of structural requirements of receptors. Cytotoxicity of our compounds was evaluated against MCF-7, A549, HCT116 and HepG2 cell lines using MTT assay. Compounds 18, 17 and 14b showed the highest anticancer effects with IC50 = 5.25, 6.46, 5.68 and 5.24 μM, 5.55, 6.85, 5.40 and 5.11 μM and 5.86, 7.03, 6.15 and 5.77 μM against HepG2, MCF-7, HCT116 and A549 cell lines, respectively. The eight highly effective compounds 10, 13, 14a, 14b, 15, 16, 17 and 18 were inspected against VERO normal cell lines to evaluate their cytotoxicity. Our conclusion was that compounds 10, 13, 14a, 14b, 15, 16, 17 and 18 possessed low toxicity against VERO normal cells with IC50 increasing from 43.44 to 52.11 μM. All compounds were additionally assessed for their EGFRWT and EGFRT790M inhibitory activities. Additionally, their ability to bind with EGFRWT and EGFR receptors was confirmed by molecular docking. Compound 17 exhibited the same inhibitory activity as erlotinib. Compounds 10, 13, 14b, 16 and 18 excellently inhibited VEGFR-2 activity with IC50 ranging from 0.17 to 0.50 μM. Moreover, compounds 18, 17, 14b and 16 remarkably inhibited EGFRT790M activity with IC50 = 0.25, 0.30, 0.36 and 0.40 μM respectively. As planned, compounds 18, 17 and 14b showed excellent dual EGFRWT/EGFRT790M inhibitory activities. Finally, our compounds 18, 17 and 14b displayed good in silico ADMET calculated profiles.

Design, synthesis and in vitro anti-proliferative evaluation of new pyridine-2,3-dihydrothiazole/thiazolidin-4-one hybrids as dual CDK2/GSK3β kinase inhibitors.

Herein, the molecular hybridization drug discovery approach was used in the design and synthesis of twelve novel pyridine-2,3-dihydrothiazole hybrids (2a,b-5a,b and 13a,b-14a,b) and fourteen pyridine-thiazolidin-4-one hybrids (6a,b-12a,b) as anti-proliferative analogues targeting CDK2 and GSK3β kinase inhibition. Almost all of the newly synthesized hybrids, including their precursors (1a,b), were evaluated for their anti-proliferative activity against three human cancer cell lines-MCF-7, HepG2 and HEp-2-as well as normal Vero cell lines. Both compounds 1a (pyridine-thiourea precursor) and 8a (pyridine-5-acetyl-thiazolidin-4-one hybrid) exhibited excellent anti-proliferative activity against HEp-2 (IC50 = 7.5 μg mL-1, 5.9 μg mL-1, respectively). Additionally, 13a (pyridine-5-(p-tolyldiazenyl-2,3-dihydrothiazole)) hybrid demonstrated excellent anti-proliferative activity against HepG2 (IC50 = 9.5 μg mL-1), with an acceptable safety profile against Vero (<45% inhibition at 100 μg mL-1) in the cases of 8a and 13a alone. The three promising anti-proliferative hybrids (1a, 8a, 13a) were selected for the assessment of their in vitro inhibitory kinase activity against CDK2/GSK3β using roscovitine (IC50 = 0.88 μg mL-1) and CHIR-99021 (IC50 = 0.07 μg mL-1) as references, respectively. Compound 13a was the most potent dual CDK2/GSK3β inhibitor (IC50 = 0.396 μg mL-1, 0.118 μg mL-1, respectively) followed by 8a (IC50 = 0.675 μg mL-1, 0.134 μg mL-1, respectively), and the weakest was 1a. To elucidate the mechanism of the most potent anti-proliferative 13a hybrid, further cell cycle analysis was performed revealing that it caused G1 cell cycle arrest and induced apoptosis. Moreover, it resulted in an increase in Bax and caspase-3 with a decrease in Bcl-2 levels in HepG2 cells compared with untreated cells. Finally, in silico drug likeness/ADME prediction for the three potent compounds as well as a molecular docking simulation study were conducted in order to explore the binding affinity and interactions in the binding site of each enzyme, which inspired their usage as anti-proliferative leads for further modification.

Isolation of active compounds from Streptomyces sennicomposti GMY01 and cytotoxic activity on breast cancer cells line

The occurrence of resistance to anticancer and the emergence of serious side effects due to chemotherapy is one of the main problems in cancer treatment, including breast cancer. The need for effective anticancer with a specific target is urgently required. Streptomyces are widely known as the potential producers of new anticancer molecules. Previously reported that the methanol extract of Streptomyces sennicomposti GMY01 isolated from Krakal Coast, Gunungkidul had very strong cytotoxic activity against MCF-7 and T47D breast cancer cells with IC50 values of 0.6 and 1.3 μg/mL, respectively. The following study aimed to isolate and identify active compounds of the S. sennicomposti GMY01 and evaluate its cytotoxic activity. The study was started by re-culturing and re-fermented optimization of S. sennicomposti GMY01 in a larger volume, then the bacteria were extracted using methanol following the bioassay-guided isolation of the extract obtained. The active compounds obtained were then structurally determined using UV/Vis spectroscopy, Fourier Transform-Infrared (FT-IR), Liquid Chromatography-Mass Spectroscopy (LC-MS), 1H NMR, and 13C NMR and analyzed for their cytotoxic activity using MTT assay on MCF-7 and normal Vero cells line. The results showed that the culture of the S. sennicomposti GMY01 using Starch Nitrate Broth (SNB) media yields the best results compared to other culture media. An active anticancer compound namely mannotriose was successfully isolated from the methanol extract with an IC50 value of 5.6 μg/mL and 687 μg/mL against the MCF-7 and Vero cells lines, respectively, indicating that this compound showed strong cytotoxic activity with high selectivity.

Computational design, synthesis, and assessment of 3-(4-(4-(1,3,4-oxadiazol-2-yl)-1H-imidazol-2-yl)phenyl)-1,2,4-oxadiazole derivatives as effective epidermal growth factor receptor inhibitors: a prospective strategy for anticancer therapy.

The epidermal growth factor receptor (EGFR) enzyme plays a critical role in governing the cell cycle, positioning it as a promising target for the development of anticancer drugs. In this study, we endeavored to design and synthesize innovative EGFR inhibitors with potential applications in anticancer therapy. A novel series of compounds, namely 3-(4-(4-(1,3,4-oxadiazol-2-yl)-1H-imidazol-2-yl)phenyl)-1,2,4-oxadiazoles (30a-j), were meticulously designed using FBDD efforts and synthesized. The synthesized compounds underwent thorough characterization using 1HNMR, 13CNMR, HRMS, and mass spectrum analyses. The in vitro anticancer activities of the newly developed compounds (30a-j) were evaluated against four human cancer cell lines such as prostate cancer (PC3 & DU-145), lung cancer (A549), and liver cancer (HEPG2) using the MTT method. The results, expressed as IC50 values, demonstrated significant anticancer activity for several compounds, with five compounds (30a, 30b, 30c, 30i, and 30j) exhibiting superior potency compared to the established anticancer drug etoposide. Notably, compound 30a emerged as the most promising compound, displaying potent cytotoxicity. We also conducted a screening of the compounds on the normal Vero cell line, revealing a pronounced selectivity of the compounds against cancer cell lines, with no observable impact on the normal cell lines. Moreover, the synthesized compounds were investigated for their impact on enzyme EGFR activity. The findings revealed a robust inhibitory effect against the EGFR wild-type enzyme and a 10-fold inferior potency against the mutant form of EGFR. This observation underscores the potential of the new derivatives as effective EGFRWT inhibitors with substantial anticancer efficacy. Further studies, including cell cycle analysis and apoptosis assays in HEPG2 cell lines, revealed cell cycle arrest at G1/G0 and G2 phases. We also evaluated the potential influence of compound 30a on the EGFR pathway using western blot analysis, revealing a significant inhibition of EGFR autophosphorylation in HEPG2 cells. In conclusion, our findings highlight the promise of these novel compounds as potent EGFR inhibitors, encouraging further investigation and development for the creation of novel and effective anticancer therapeutics.

Anticancer potential of novel symmetrical and asymmetrical dihydropyridines against breast cancer via EGFR inhibition: molecular design, synthesis, analysis and screening.

A series of novel symmetrical and asymmetrical dihydropyridines (HD 1-15) were designed, subjected to in silico ADMET prediction, synthesized, analyzed by IR, NMR, Mass analytical techniques and evaluated against epidermal growth factor receptor (EGFR) as inhibitors against Breast cancer. The results of predicted ADMET studies demonstrated the drug-likeness properties of the reported compounds. The in vitro cytotoxicity assessment of the synthesized compounds revealed that all of them showed good activity (IC50 ranging from 16.75 to 66.54 μM) towards MCF-7 breast cancer cells compared to the standard drug, Lapatinib (IC50 = 2.02 μM). Among these, compounds HD-6, HD-7, and HD-8 displayed the most potent activity with IC50 value of 21.26, 16.75, and 18.33 μM, respectively. Cytotoxicity of all compounds was tested on normal vero cells for comparison at different concentrations using the MTT assay. In addition to the MTT assay, the potent dihydropyridines derivatives were screened for EGFRwt kinase inhibition assay at concentrations ranging from 1 nM to 360 nM. Among the three compounds tested, HD-8 showed reasonably good inhibition with an IC50 value of 15.90 ± 1.20 nM compared to a standard Lapatinib IC50 value of 10.28 ± 1.01 nM. Based on the molecular docking study against EGFR, the most active derivatives HD-7 and HD-8 were docked against the active site of the protein and showed better binding affinity than the standard lapatinib. Additionally, molecular dynamics (MD) simulations were performed to explore the stability of the protein-ligand complex, its dynamic behavior, and the binding affinity.

Anticancer and anti-angiogenic activities of mannooligosaccharides extracted from coconut meal on colorectal carcinoma cells in vitro

Colorectal carcinoma (CRC) is one of the most common malignancies, though there are no effective therapeutic regimens at present. This study aimed to investigate the inhibitory effects of mannooligosaccharides extracted from coconut meal (CMOSs) on the proliferation and migration of human colorectal cancer HCT116 cells in vitro. The results showed that CMOSs exhibited significant inhibitory activity against HCT116 cell proliferation in a concentration-dependent manner with less cytotoxic effects on the Vero normal cells. CMOSs displayed the ability to increase the activation of caspase-8, –9, and –3/7, as well as the generation of reactive oxygen species (ROS). Moreover, CMOSs suppressed HCT116 cell migration in vitro. Interestingly, treatment of human microvascular endothelial cells (HMVECs) with CMOSs resulted in the inhibition of cell proliferation, cell migration, and capillary-like tube formation, suggesting its anti-vascular angiogenesis. In summary, the results of this study indicate that CMOSs could be a valuable therapeutic candidate for CRC treatment.

Design of Azomethine based Metalloorganic Complexes and their Binding Interactions with Nucleic Acid and Protein

Mononuclear nickel, copper, and zinc complexes based on salen type (ONNO) donor acting as a tetradentate ligand obtained by the condensation of 4-methyl-o-phenylenediamine and 5-fluoro salicylaldehyde in 1:2 ratios. The compounds are characterized using UV-visible, FT-IR, 1H, 13C-NMR, HR-MS, Elemental (CHN) analyses ESR spectral techniques, and single crystal X-ray diffraction studies (SC-XRD). The binding interactions of the metal complexes with deoxyribonucleic acid (DNA) and bovine serum albumin (BSA) are monitored using UV absorption titration and tryptophan emission quenching techniques, respectively. The complexes possess strong binding propensities with DNA and prefer groove binding, as indicated by the hyperchromic effect. The complexes quench the intrinsic fluorescence of BSA with increasing amounts of the complex concentration in a dose-dependent manner. The gel electrophoresis was carried out against pBR322 to analyze the cleaving ability of the complexes. The results of the NBO (natural bond orbitals) analysis performed in combination with the Time-dependent Density Functional Theory (TD-DFT) calculations provided a good explanation of their electronic and structural characteristics. Further, the predictions of molecular docking studies support the experimental observations. The Gel electrophoresis study reveals the cleaving ability of the complexes by their interactions with DNA. In addition, the cell viability of the complexes is assessed based on MTT assay and the results indicate that they have a good antiproliferative activity only on liver cancer cell-line HepG-2 and does not show cytotoxic effect on normal vero cell lines with 90% viability.

Iodoquinazoline-derived VEGFR-2 and EGFRT790M dual inhibitors: Design, synthesis, molecular docking and anticancer evaluations

Herein, we report the synthesis of a series of new fourteen iodoquinazoline derivatives 7a-c to 13a-e and their evaluation as potential anticancer agents via dual targeting of EGFRT790M and VEGFR-2. The new derivatives were designed according to the target receptors structural requirements. The compounds were evaluated for their cytotoxicity against HepG2, MCF-7, HCT116 and A549 cancer cell lines using MTT assay. Compound 13e showed the highest anticancer activities with IC50 = 5.70, 7.15, 5.76 and 6.50 µM against HepG2, MCF-7, HCT116 and A549 cell lines correspondingly. Compounds 7c, 9b and 13a-d exhibited very good anticancer effects against the tested cancer cell lines. The highly effective six derivatives 7c, 10, 13b, 13c, 13d and 13e were examined against VERO normal cell lines to estimate their cytotoxic capabilities. Our conclusion revealed that compounds 7c, 10, 13b, 13c, 13d and 13e possessed low toxicity against VERO normal cells with IC50 prolonging from 41.66 to 53.99 μM. Also compounds 7a-c to 13a-e were further evaluated for their inhibitory activity against EGFRT790M and VEGFR-2. Also, their ability to bind with both EGFR and VEGFR-2 receptors was examined by molecular modeling. Compounds 13e, 13d, 7c and 13c excellently inhibited VEGFR-2 activity with IC50 = 0.90, 1.00, 1.25 and 1.50 µM respectively. Moreover, Compounds 13e, 7c, 10 and 13d excellently inhibited EGFRT790M activity with IC50 = 0.30, 0.35, 0.45 and 0.47 µM respectively. Finally, our derivatives 7b, 13d and 13e showed good in silico calculated ADMET profile.

Design, Synthesis and Biological Evaluation of Aryl Benzimidazole-Pyridones as Cytotoxic Agents

A new library of Aryl Benzimidazole-Pyridones (9a–j) has been synthesized, their structures were determined by 1HNMR,13CNMR and mass spectral data. Further, these compounds explored for their anticancer application on four human cancer cell lines such as human prostate cancer cell line (PC3), lung cancer (A549), breast cancer (MCF-7) and human ovarian cancer (A2780) by employing MTT assay and results were compared with known anticancer agent asetoposide. All these compounds displayed remarkable cytotoxic activity. Among them, five compounds 9a, 9b, 9c, 9h and 9i displayed more potent activity. All compounds exhibited a discerning cytotoxic effect on cancer cells while not affecting normal Vero cells (IC50 = >22 µM), so providing justification for the strategic design approach employed in the development of a targeted anticancer drug.

Computational Design, Synthesis, and Bioevaluation of 2-(Pyrimidin-4-yl)oxazole-4-carboxamide Derivatives: Dual Inhibition of EGFRWT and EGFRT790M with ADMET Profiling

The ongoing research in cancer treatment underscores the significance of dual epidermal growth factor receptor (EGFR) kinase inhibitors targeting both mutant and wild-type variants. In this study, employing in silico fragment-based drug design (FBDD) and computational analysis, we have successfully developed a novel chemical series of 2-(pyrimidin-4-yl)oxazole-4-carboxamide (16a-j) derivatives designed as dual EGFR kinase inhibitors. A comparative in vitro anticancer profile of the newly synthesized compounds (16a-j) was tested against a panel of five human cancer cell lines like prostate cancer (PC3 & DU-145), lung cancer (A549), human liver cancer (HEPG2), and breast cancer (MDA-MB-468) by employing MTT method. In this experiment a well-known anticancer agent, Etoposide was used as positive control. Most of the derivatives demonstrated significant cytotoxicity, ranging from excellent to moderate levels. The IC50 values for the synthesized compounds observed between 0.10 ± 0.052 to 9.83 ± 5.96 µM, while the positive control exhibited a range of 1.97 ± 0.45 µM to 3.08 ± 0.135 µM. These results indicate that the synthesized compounds demonstrate higher cytotoxic potency in comparison to the reference compound. Furthermore, all these compounds underwent screening against normal Vero cell lines to assess their cytotoxicity. In each case, the observed cytotoxicity values (IC50) were higher than 22 µM, affirming the compounds selectivity for cancer cell lines. Among the compounds investigated, three compounds (16a, 16e, and 16i) exhibited notable cytotoxicity, while two compounds (16g and 16h) demonstrated exceptional cytotoxicity. The selectivity index of the tested compounds indicates a pronounced preference for targeting cancer cell lines over normal cells. Furthermore, all the compounds 16a-j underwent assessment for their EGFR kinase inhibitory activity against both EGFRWT and mutated EGFRT790M. The results unveiled the potential eligibility of this new series of compounds as effective EGFR inhibitors. Moreover, compound 16h underwent additional testing for cell cycle analysis, revealing its capability to arrest the cell cycle in the G2/M phase and induce apoptosis at the IC50 concentration.

Design, Synthesis, and Bioactivity Assessment of Novel 2‐Phenyl Indole Derivatives Incorporating 4‐Thiazolidinone‐5‐carboxylic Acid as Promising Anti‐cancer Agents

AbstractWe conducted a study to create new chemical compounds using indole derivatives, specifically incorporating thiosemicarbazone (8 a–e) and 4‐thiozolidinone‐5‐carboxylic acid (9 a–e) structures. We then tested these compounds against various bacteria and cancer cells. In our antibacterial tests, the compounds showed moderate inhibitory effects on bacterial growth. However, when we examined their effects on cancer cells, we observed specific patterns of activity. Notably, compounds 9 c and 9 d were highly toxic to NCI‐H187 cancer cells, while compounds 8 c, 9 b, 9 c, 9 d, and 9 e exhibited moderate inhibitory activity against KB cancer cells. Compound 8 e displayed strong toxicity against MCF‐7 cancer cells. When we assessed the toxicity of these compounds on normal Vero cells, we found that compounds 8 e, 9 b, 9 c, 9 d, and 9 e were less toxic compared to ellipticine, a known anticancer drug. These results suggest that these newly synthesized compounds may have potential applications in cancer treatment, and further research is necessary to explore their therapeutic possibilities.

Design, synthesis, and characterization of 3-(2-(pyrimidin-5-yl)thiazol-4-yl)-1,2,4-oxadiazole derivatives: Anticancer and molecular docking investigations

Herein, we present a new library of 3-(2-(pyrimidin-5-yl)thiazol-4-yl)-1,2,4-oxadiazole (14a–j) as an anticancer agent designed based on in silico fragment-based drug design (FBDD). The derivatives were synthesized and characterized by 1HNMR,13CNMR, HRMS, and FT-IR. The library was named “pyrimidine-thiazole-1,2,4-oxadiazoles.” In addition, the MTT assay was used to test the compounds (14a–j) for their potential anticancer activity in a panel of four human cancer cell lines, such as PC3 & DU-145 (prostate cancer), A549 (lung cancer), MCF-7 (breast cancer), and the normal Vero cell lines, using the widely used anticancer drug etoposide acting as a reference drug and positive control. The value obtained was presented as IC50 (µM). The IC50 values of the reference standard ranged from 1.97 ± 0.45 µM to 3.08 ± 0.135 µM, while the library of tested compounds showed IC50 values ranging from 0.02 ± 0.0031 µM to 10.3 ± 6.25 µM. Among the tested compounds, six of them showed promising anticancer activity: 14a, 14b, 14c, 14d, 14e and 14j. Especially, one compound, 14a, showed excellent anticancer activity in all the tested cell lines. All compounds showed selective cytotoxicity against cancer cells but not against normal Vero cells (IC50 = >19 µM), justifying the designing approach to develop a selective anticancer agent. These compounds were also subjected to docking experiments to investigate potential binding site interactions, and the results were consistent with the in vitro results.

Inhibitory potential of rutin and rutin nano-crystals against Helicobacter pylori, colon cancer, hemolysis and Butyrylcholinesterase in vitro and in silico

Despite the vital activity of many compounds, they lack that effectiveness due to their low solubility in water. Unfortunately, for this reason, rutin often leads to low tissue permeability and insufficient bioavailability, which has greatly limited its pharmacological utility. Therefore, the present investigation is designed to overcome this problem by formulating the rotin to rotin nanocrystals (RNCs) with studying their some pharmacological applications in vitro and in silico. RNCs were created via the ultrasonication approach and showed a spherical shape via Transmission electron microscopy with a mean particle size of 27 nm. RNCs reflected inhibitory action against Helicobacter pylori with an inhibition zone (IZ) of 22.67 mm compared to rutin (IZ of 18 mm) and standard control (IZ of 19.5 mm). RNCs exhibited less minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) (7.8 µg/mL) than rutin (62.5 µg/mL). The MBC/MIC index of rutin and RNCs indicated their bactericidal properties. RNCs were more acutely (92.12%) than rutin (85.43%) for inhibition the H. pylori biofilm formation. A promising half maximal inhibitory concentration (IC50) (6.85 µg/mL) was recorded using RNCs for urease inhibition compared to the IC50 value of rutin (97.8 µg/mL). The activity of rutin and RNCs was tested against cancer cells of human colon cancer (HT-29) and normal Vero cells. IC50 values of RNCs were less 168.23 ± 1.15 µg/mL and 297.69 ± 4.23 µg/mL than the IC50 values of rutin 184.96 ± 4.33 µg/mL and 335.31 ± 2.02 µg/mL against HT-29 cells and normal Vero cells, respectively. Different percentages (72.2, 77.3, and 81.9%) of hemolysis inhibition were recorded using RNCs, but 63.6, 68.9, 73.6, and 80.6% were obtained using rutin at 600, 800, and 1000 µg/mL, respectively. Butyrylcholinesterase (BChE) inhibition % was documented at a lower IC50 value for RNCs (12.74 µg/mL) than the IC50 of rutin (18.15 µg/mL). The target molecule underwent molecular docking research against H. pylori [Protein Data Bank (PDB) code: 4HI0], HT-29 cells (PDB code: 2HQ6), and BChE (PDB code: 6EMI) in order to enhance the interactions between rutin and the chosen receptors and to estimate its molecular operating environment (MOE) affinity scoring. Rutin has predicted strong binding interactions and potent activity against the examined proteins 4HI0, 2HQ6, and 6EMI with low binding scores of − 7.47778 kcal/mol, − 7.68511 kcal/mol, and − 9.50333 kcal/mol, respectively.

Antioxidant, antibacterial, and cytotoxic activities of cimemoxin derivatives and their molecular docking studies

PurposeThe cimemoxin derivatives and their biological importance in antioxidant, antibacterial, and cytotoxic activities were the main focus of this study. By using a one-step reaction and green chemistry method, this study was able to synthesise derivatives of cimemoxin-related Mannich base compounds. MethodsGreen chemistry can be used to prepare new, one-pot syntheses of cimemoxin derivatives (1a-i) Mannich base derivatives. FTIR, mass spectrometry, elemental analysis, and 1H and 13C NMR were used to analyse the newly synthesised compounds. The cytotoxic, antibacterial, and antioxidant activities of synthesized compounds (1a-i) were investigated. To test all synthesised compounds (1a–i) for cytotoxicity against normal Vero cell lines and MCF-7, the antioxidant activities were studied using DPPH, NO, H2O2, and ABTS•+ assays. The synthesised compounds were screened for anti-tyrosinase and antibacterial activities. Highly active compounds were investigated using molecular docking studies. ResultsThe compound 1h showed considerable activity in H2O2 (IC50: 13.79 µg/mL) and DPPH-scavenging was significantly active (IC50: 19.62 µg/mL) compared to the standard BHT (IC50: 27.16 and 33.88 µg/mL). Compound 1f was more effective than trolox (85.28 %) against ABTS and AAPH antioxidants. The most potent inhibitory activity was observed for compound 1h (IC50 = 15.16 µg/mL) which was more potent than kojic acid (IC50 = 17.79 ± 0.95 µg/mL). All synthetic substances were tested for their cytotoxic potential. Compound 1f (IC50 = 0.12 µg/mL) was extremely active compared to doxorubicin (IC50 = 0.74 µg/ml) and other compounds were lowly active compared to the MCF-7 cell line. In terms of anti-tyrosinase activity, compound 1h was highly active compared with the standard, and compound 1d was highly active against K. pneumonia. ConclusionIn this study, strong antioxidant, antibacterial, and cytotoxic activities were reported for all the compounds. In molecular docking studies, compounds 1d and 1h had higher binding affinities than the other compounds. Compounds 1d and 1h performed well in all tests. Additionally, this investigation successfully identified a number of intriguing compounds with cytotoxic and antioxidant properties.

Design, Molecular Modeling, MD Simulations, Essential Dynamics, ADMET, DFT, Synthesis, Anti-proliferative, and Apoptotic Evaluations of a New Anti-VEGFR-2 Nicotinamide Analogue.

This study aims to design and evaluate (in silico and in vitro) a new nicotinamide derivative as an inhibitor of VEGFR-2, a major mediator of angiogenesis Methods: The following in silico studies were performed; DFT calculations, molecular modelling, MD simulations, MM-GBSA, PLIP, and PCAT studies. The compound's in silico (ADMET) analysis was also conducted. Subsequently, the compound ((E)-N-(4-(1-(2-(4-(4-Chlorobenzamido)benzoyl)hydrazono)ethyl) phenyl)nicotinamide) was successfully synthesized and designated as compound X. In vitro, VEGFR-2 inhibition and cytotoxicity of compound X against HCT-116 and A549 cancer cell lines and normal Vero cell lines were conducted. Apoptosis induction and migration assay of HCT-116 cell lines after treatment with compound X were also evaluated. DFT calculations assigned stability and reactivity of compound X. Molecular docking and MD simulations indicated its excellent binding against VEGFR-2. Furthermore, MM-GBSA analysis, PLIP experiments, and PCAT studies confirmed compound X's correct binding with optimal dynamics and energy. ADMET analysis expressed its general likeness and safety. The in vitro assays demonstrated that compound X effectively inhibited VEGFR-2, with an IC50 value of 0.319 ± 0.013 μM and displayed cytotoxicity against HCT-116 and A549 cancer cell lines, with IC50 values of 57.93 and 78.82 μM, respectively. Importantly, compound X exhibited minimal toxicity towards the non-cancerous Vero cell lines, (IC50 = 164.12 μM). Additionally, compound X significantly induced apoptosis of HCT-116 cell lines and inhibited their potential to migrate and heal. In summary, the presented study has identified compound X as a promising candidate for the development of a novel apoptotic lead anticancer drug.

Design, synthesis and anticancer evaluation of novel half-sandwich Ru(II) complexes bearing pyrazalone moiety: Apoptosis inducers based on mitochondrial dysfunction and G0/G1 arrest

Six half-sandwich Ru(II) complexes (Ru1-Ru6), integrated with 5-phenyl-2-(pyridin-2-yl)-2,4-dihydro-3H-pyrazol-3-one (PDPO1-PDPO6) ligands, were synthesized and spectroscopically characterized. The structure of Ru3 that crystallized as a monoclinic crystal with P21/c space group was further confirmed by X-ray single crystal diffraction. Prototropic tautomerism within the complexes transformed OH-form ligands to NH-form, forming a hydrogen bond (Cl1---H-N3). The complexes and ligands' cytotoxicity was assessed against several cancerous (HepG2, A549, MCF-7) and normal Vero cell lines. Relative to the ligands and Cisplatin, complexes (Ru2, Ru3, Ru5, Ru6) exhibited potent cytotoxicity against cancer cells, with IC50 values from 2.05 to 15.69 μM/L, excluding Ru1 and Ru4. Specifically, Ru2, Ru3, and Ru5 demonstrated superior anti-HepG2 properties. Compared to Cisplatin, Ru2 and Ru5 were less toxic to Vero cells, highlighting their enhanced selectivity in toxicity. Structure-activity relationship (SAR) studies indicated that t-butyl substitution (in Ru2) or -Cl (in Ru5) on the benzene ring significantly improved the selective toxicity. These complexes manifested substantial lipophilicity, cellular uptake, and were quickly hydrolyzed to Ru-H2O species. Roughly positive correlations were observed between hydrolysis rate, lipophilicity, cellular uptake, and anticancer activities. Ru2, investigated specifically, induced apoptosis in HepG2 cells at concentrations of 10 and 20 μM/L through ROS-mediated mitochondrial dysfunction and G0/G1phase arrest, associated with altered P21, cyclin D, and CDK4 expression levels.

A novel class of pyrazole analogues as aurora kinase A inhibitor: design, synthesis, and anticancer evaluation

Pyrazole, as a small molecule, was discovered for higher cytotoxicity and affinity towards Aurora-A kinase. Based on these facts, a novel pyrazole substituted at the 4th position was designed, synthesized, and evaluated against MCF-7, MDA-MB-23, and Vero (non-cancerous kidney cell) cell lines. Compounds5hand5eexhibited greater cytotoxicity in the series against MCF-7 and MDA-MB-231, with GI50 values of 0.12 µM and 0.63 µM, respectively, as compared to Imatinib (GI50 values of 16.08 µM and 10.36 µM). All of the compounds displayed selective cytotoxicity against cancer cells but not on normal Vero cells, supporting the design strategy to be a selective anticancer agent. Furthermore, compounds 5h and 5e inhibited Aurora-A kinase with IC50 values of 0.78 µM (4.70-fold) and 1.12 µM (2.84-fold), respectively, as compared to alisertib (IC50 = 3.36 µM). In addition, compound 5h significantly arrested the cell cycle at G2/M (34.89 %, 5.56-fold) and the apoptotic phase (25.04 %, 11.81-fold) compared to the control. It also triggered an increase in early (7.43 %) and late (14.89 %) phase apoptosis compared to vehicle (0.235 and 0.36 %, respectively), causing 37.89-fold higher total apoptosis in the annexin-V assay. These data imply that Aurora-A kinase inhibition may be linked to apoptosis induction and cell cycle arrest. Furthermore, their higher docking score in the study confirmed evidence of Aurora-kinase suppression. It was observed that fluorine and imidazole increased the H-bond and lipophilic interactions with the binding residue. Also, the substitution of electron-rich and lipophilic groups increased hydrophobic interactions. Moreover, the three-atom linkage (CH2NHCH2) expanded compound 5h to fill the cavity. Based on current findings, it is concluded that compounds 5h and 5e with strong Aurora-A kinase suppression may be promising anticancer agents.