SYNTHESIS AND CHARACTERIZATION OF NEW COUMARIN DERIVATIVES CONTAINING VARIOUS MOIETIES WITH ANTIBACTERIAL ACTIVITIES

Objective: The purpose of this research is to evaluate the antibacterial activity of different moieties (Schiff bases, chalcones, hydrazones and hydrazinyl thiazole) derivatives, inserted at carbon 8 of 7-hydroxy-4-methyl coumarin, using in vitro, serial broth dilution method.Methods: A series of new coumarin derivatives, including (Schiff bases, chalcones, hydrazones and hydrazinyl thiazole), were prepared from 7-hydroxy-4-methyl coumarin, by insertion of the formyl group, at carbon number 8 using Duff reaction. The structure of the new synthesized derivatives elucidated and confirmed utilizing the corresponding analytical and spectroscopic data; including FT-IR, 13C-NMR, and mass spectroscopy. All new coumarin derivatives have been screened for their preliminary antibacterial activity, by serial broth dilution method against two Gram-positive bacteria (Staphylococcus epidermidis and Staphylococcus hemolyticus) and two Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae).Results: All the synthesized compounds have been found to exhibit considerable antibacterial activity in vitro. Among all the derivatives, compound (5a), showed the highest rate of inhibition, against (Escherichia coli), while compound (6a), showed the greatest anti-bacterial activity against (Staphylococcus hemolyticus), each with minimum inhibitory concentration of (25µg/ml), and the highest MIC of 200 µg/ml for compound 2, against. Klebsiella pneumoniae.Conclusion: Our results displayed a substantial preliminary antibacterial activity of the new coumarin moieties, especially some hydrazones and chalcones at C8 of the coumarin nucleus, against Gram-positive and a Gram-negative bacteria with distinguished MIC.Â

SYNTHESIS, ANTIMICROBIAL EVALUATION, DENSITY FUNCTIONAL THEORY, AND DOCKING STUDIES OF SOME NEW 2-MERCAPTO PYRIMIDINE SCHIFF BASES

Objective: Pyrimidine derivatives are reported to possess antibacterial, antifungal, anticancer, and anticonvulsant activities. Encouraged by this remarks, we decided to synthesize novel compounds of new 2-macraptopyrimidine linked to Schiffs̕ bases. Methods: The present work involves the synthesis of new 2-mercaptopyrimidine linked to Schiffs̕ bases. The starting, 2-mercaptopyrimidine, compound (1) reacted with thiourea to afford the corresponding 1-(pyrimidin-2-yl) thiourea (2). Then compound (2) was used as the key intermediate to prepare the -1-(2-hydroxy benzylidene)-3-(pyrimidin-2-yl) thiourea (3), and (1-benzylidine)-3-(pyrimidin-2-yl) thiourea (4), through the reaction with 2-hydroxybenzaldehyde, and benzaldehyde, respectively. Results: All the synthesized compounds were characterized by Fourier-transform infrared and1H-nuclear magnetic resonance spectroscopy. The synthesized derivatives were screened for their in vitro, antibacterial activity against two Gram-positive bacteria: Bacillus subtilis and Staphylococcus aureus and four Gram-negative bacteria: Klebsiella pneumoniae, Escherichia coli, and Salmonella typhi, and the results showed that most of them have good antibacterial activity. While their antifungal activity against three fungi species (Aspergillus fumigates, Aspergillus niger, Aspergillus terrus and Rhizopus) revealed that compounds (2-4) displayed the most potent antifungal activity. Density functional theory (DFT) calculations for the synthesized 2-mercapto pyrimidine derivatives were conducted, using a molecular structure with optimized geometry. Highest occupied molecular orbital/lowest unoccupied molecular orbital energies and structures are demonstrated. Conclusion: The antimicrobial activity indicates that compounds (3) and (4) are the most active than the compounds (1) and (2). Molecular docking revealed that compounds (3) and (4), with bulky phenyl groups are essential to blocking the active centers of glucose -6-phosphate synthase in the bacteria and fungi

Design and Synthesis of Novel Derivatives of 4-(6-(4-Substituted Phenyl)-7H-[1,2,4] Triazolo[3,4-b][1,3,4]Thiadiazin-3- yl) Phenol as a Potent Inhibitor of Tubulin with Antitumor Activity

A new series of 4-(6-(4-substituted phenyl)-7H[1,2,4] triazolo[3,4b][1,3,4]thiadiazin-3-yl) phenol was synthesized and explored for anti-tubulin activity  using in silico and in vitro assay models. The starting nucleus, ethyl-4-hydroxybenzoate was treated with hydrazine hydrated, and converted to 4-hydroxybenzohydrazide (1). Then, (1) was stirred with CS2 and KOH in dry EtOH  to afford 2-(4-. hydroxyl benzoyl)hydrazine-1-carbodithioate, as a potassium salt (2). Compound (2) was used directly and refluxed with hydrazine hydrate to yield a parent nucleus, 4-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)phenol (3). The target compounds (4-7), were synthesized by refluxing compound (3) with various substituted phenacyl bromides  using  sodium acetate as  a abase, The new compounds (3-7) were characterized using different spectroscopic analysis  techniques including IR, and 1HNMR.  The anticipated  modes  of binding to α- tubulin were also investigated by means of a molecular docking experiment. The binding mode revealed good agreement with the in vitro work with binding energies of (-38.77 and  -37.50 kcal/ mol) for the most potent compounds 7 and 4, respectively. The effect of synthetic novel compounds on cancer cell lines proliferation was screened  by MTT assay. The ability of the synthetic compounds to induce apoptosis process was tested using acridine orange/ ethidium  bromide staining. The synthetic novel compounds exhibited potent inhibitory effects on the growth and viability of cancer cell lines SKOV-3 and AMJ-13 cells. They inhibited  the proliferation and growth  of cancer cell lines at low concentrations, with IC50 values ranging from10.44 to 19.67 µg/mL against SKOV-3 cells, and for AMJ-13 cells,  the IC50 values were11.35 to 20.52 µg/mL. The effect of  the synthetic compounds on  the cell growth, and proliferation of cancer cell lines was associated with increased apoptosis.Our results demonstrated that the target compounds inhibited cancer cell lines proliferation, with a mechanism of action parallel to that of other tubulin inhibitor

Synthesis, docking study, and in vitro anticancer evaluation of new flufenamic acid derivatives

Novel compounds (6–10) were synthesized and confirmed by spectroscopic analysis, including AT-IR, 1HNMR and CHNS. Their cytotoxic effect was evaluated by MTT assay against two cancer cell lines and two normal cell types. Compound 7 exhibited anticancer activity against MCF-7 breast cancer cell line (GI50 = 63.9 µg/ml, 148 µM), without any effect against A549 lung cancer cells, or the normal cells. Compound 7 caused cytotoxicity in MCF-7 breast cancer cells by apoptotic cell death, as suggested by fragmented nuclei after DAPI staining and agarose gel electrophoresis. In addition, treating MCF-7 cells with compound 7 resulted in an increase in the level of caspase 9 mRNA level, and its activation. Moreover, compound 7-treated MCF-7 cells showed enhanced cytochrome c release from the mitochondria to the cytosol, signifying an induction of the intrinsic apoptotic pathway. Finally, compound 7 exhibited epidermal growth factor receptor (EGFR) kinase inhibitory activity at (EC50 = 0.13 µM), which was matched by molecular docking studies that showed compound 7 might be an important EGFR kinase inhibitor

In silico and in vitro evaluation of novel carbothioamide-based and heterocyclic derivatives of 4-(tert-butyl)-3-methoxybenzoic acid as EGFR tyrosine kinase allosteric site inhibitors

Cancer is an elaborate sequence of disease grades that include uncontrolled cell growth and division, invasion, and metastasis. Overexpression of the epidermal growth factor receptor (EGFR) causes an abnormal signal transduction and is directly linked to cancer development. Most EGFR tyrosine kinase inhibitors (TKIs) are ATP-competitive inhibitors that frequently cause EGFR mutations or chemoresistance. Therefore, targeting the EGFR TK allosteric site has become a highly sought after cancer treatment strategy. Ten new derivatives of 4-(tert-butyl)-3-methoxybenzoic acid containing carbothioamide (compounds 3a-e), triazole (compounds 4a-d) or oxadiazole (compound 5) moieties were designed as EGFR TK allosteric site inhibitors as deduced in silico. The structures of these derivatives were characterized by chemical spectroscopic methods (ATR-FTIR, 1HNMR, 13CNMR and HRESI-MS). According to the molecular docking studies, compounds 3e and 3d showed the highest docking scores (ΔG), which was confirmed by molecular dynamic (MD) simulation studies. The synthesized derivatives, specifically compounds 3d and 3e, exhibited favorable pharmacokinetic profile. In vitro, the newly synthesized derivatives were evaluated for their cytotoxicity against A549 (lung adenocarcinoma), HepG2 (hepatocellular carcinoma), and HCT-116 (colorectal) cancer cell lines via the MTT assay, flow cytometry, RT-PCR, immunoblotting, and kinase inhibition assay. The cytotoxicity results showed that compound 3d was cytotoxic to the three tested cell lines, achieving the lowest IC50 concentration against A549 cancer cells. Compound 3d targeting EGFR tyrosine kinase caused cell cycle arrest at the G2/M phase and induction of the ER-mediated apoptosis pathway. In silico and in vitro antitumor activity findings of compound 3d demonstrated that it is a promising EGFR tyrosine kinase allosteric site inhibitor

The Essential Oil of <i>Petroselinum crispum</i> (Mill) Fuss Seeds from Peru: Phytotoxic Activity and In Silico Evaluation on the Target Enzyme of the Glyphosate Herbicide

Petroselinum crispum (Mill) Fuss is an aromatic plant belonging to the Apiaceae family and used in gastronomy as a spice. Several studies have been developed in leaves but studies are limited in seeds, especially the essential oils obtained from seeds. The aim of this study was to determine the phytochemical profile of the volatile compounds of this essential oil by gas-chromatography–mass spectrometry (GC-MS) in order to evaluate its phytotoxic activity on Lactuca sativa seeds and to carry out an in silico analysis on the target enzyme of the herbicide glyphosate 5-enolpyruvylshikimate 3-phosphate synthase (EPSP). The essential oil was obtained by steam distillation for two hours and then was injected into a GC-MS, the phytotoxic assay was carried out on Lactuca seeds and the in silico evaluation on the EPSP synthase focused on the volatile compounds similar to glyphosate, docking analysis, and molecular dynamics to establish the protein–ligand stability of the most active molecule. The chromatographic analysis revealed 47 compounds, predominated by three compounds with the most abundant percentage in the total content (1,3,8-ρ-menthatriene (22.59%); apiole (22.41%); and β-phellandrene (15.02%)). The phytotoxic activity demonstrated that the essential oil had a high activity at 5% against L. sativa seed germination, inhibition of root length, and hypocotyl length, which is comparable to 2% glyphosate. The molecular docking on EPSP synthase revealed that trans-p-menth-6-en-2,8-diol had a high affinity with the enzyme EPSP synthase and a better stability during the molecular dynamic. According to the results, the essential oil of P. crispum seeds presented a phytotoxic activity and might be useful as a bioherbicide agent against weeds