Quinazolinone-based rhodanine-3-acetic acids as potent aldose reductase inhibitors: Synthesis, functional evaluation and molecular modeling study

A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors

Phytochemical Investigation of <i>Cordia africana</i> Lam. Stem Bark: Molecular Simulation Approach

Background: The current work planned to evaluate Cordia africana Lam. stem bark, a traditionally used herb in curing of different ailments in Africa such as gastritis and wound infections, based on phytochemical and antibacterial studies of two pathogenic microorganisms: methicillin-resistant Staphylococcus aureus (MRSA) and Helicobacter pylori. Methods: High performance liquid chromatography (HPLC) profiling was used for qualitative and quantitative investigation of the ethanol extract. The minimum inhibitory concentration (MIC) of the ethanolic extract and isolated compounds was estimated using the broth microdilution method and evidenced by molecular dynamics simulations. Results: Four compounds were isolated and identified for the first time: α-amyrin, β-sitosterol, rosmarinic acid (RA) and methyl rosmarinate (MR). HPLC analysis illustrated that MR was the dominant phenolic acid. MR showed the best bacterial inhibitory activity against MRSA and H. pylori with MIC 7.81 ± 1.7 μg/mL and 31.25 ± 0.6, respectively, when compared to clarithromycin and vancomycin, respectively. Conclusion: The antibacterial activity of the stem bark of Cordia africana Lam. was evidenced against MRSA and H. pylori. Computational modeling of the studied enzyme-ligands systems reveals that RA and MR can potentially inhibit both MRSA peptidoglycan transpeptidases and H. pylori urease, thereby creating a pathway via the use of a double target approach in antibacterial treatment

Identification of Novel and Efficacious Chemical Compounds that Disturb Influenza A Virus Entry in vitro

Influenza A virus is a negative RNA stranded virus of the family Orthomyxoviridae, and represents a major public health threat, compounding existing disease conditions. Influenza A virus replicates rapidly within its host and the segmented nature of its genome facilitates re-assortment, whereby whole genes are exchanged between influenza virus subtypes during replication. Antiviral medications are important pharmacological tools in influenza virus prophylaxis and therapy. However, the use of currently available antiviral is impeded by sometimes high levels of resistance in circulating virus strains. Here, we identified novel anti-influenza compounds through screening of chemical compounds synthesized de novo on human lung epithelial cells. Computational and experimental screening of extensive and water soluble compounds identified novel influenza virus inhibitors that can reduce influenza virus infection without detectable toxic effects on host cells. Interestingly, the indicated active compounds inhibit viral replication most likely via interaction with cell receptors and disturb influenza virus entry into host cells. Collectively, screening of new synthesis chemical compounds on influenza A virus replication provides a novel and efficacious anti-influenza compounds that can inhibit viral replication via disturbing virus entry and indicates that these compounds are attractive candidates for evaluation as potential anti-influenza drugs

Design, Synthesis, Docking Studies and Biological Evaluation of Novel Benzochromenopyrimidines via Silica Sulfuric Acid Catalyzed Reaction on Apoptosis in Human Cancer Cells

Via one-pot reaction of 2-naphthol, thiobarbituric acid and aldehyde in the presence of silica sulfuric acid (SSA) as a catalyst to synthesis benzochromenopyrimidines derivatives. Then we studied the reaction of benzochromenopyrimidines derivatives with bromoacetic acid to obtain benzo[5,6]chromeno[2,3-d]thiazolo[3,2-a]pyrimidine-11,13(10H,14H)-dione derivatives. Meanwhile, dichloroethane was reacted with 12-(4-fluorophenyl)-9-thioxo-9,10-dihydro-8H-benzo[5,6]chromeno[2,3-d]pyrimidin-11(12H)-one to form 14-(4-fluorophenyl)-10,11-dihydrobenzo[5,6]chromeno[2,3-d]thiazolo[3,2-a]pyrimidin-13(14H)-one. All new products structure was elucidated based on analytical and spectroscopic analyses. Anti-cancer activity of newly synthesized structures was investigated. Cancer cells (MDA-MB-231 and HepG2) were used to evaluate the anti-cancer activity of tested compounds using neutral red uptake assay. Treatment of MDA-MB-231 and HepG2 cells with tested compound 6h revealed more inhibitory influence after 48 h. The expression levels of BCL2, BAX, Caspase3, Survivin and P53 genes were investigated using QRT-PCR. This study exhibited that compound 6h revealed significant pro-apoptotic effect via down regulation of BCL2 and Survivin genes and up-regulation of BAX, Caspase3 and P53 genes when treated with MDA-MB-231 and HepG2 cells as compared to control values. The biological studies of these compounds were proved through molecular docking studies with human cyclin-dependent kinase 2 (PDB code: 2A4L) and compound 6h showed low binding energy and shortage bond length with different amino acids. Noteworthy, the tested compound 6h exhibited the most pronounced effect in this respect.</p

Synthesis, anticancer activity and molecular docking study of Schiff base complexes containing thiazole moiety

AbstractA Schiff base ligand 1 was prepared from condensation of salicyaldehyde with 2-amino-4-phenyl-5-methyl thiazole. The ligand forms complexes with CoII, NiII, CuII, and ZnII in good yield. The synthesized compounds were characterized by elemental analysis, magnetic susceptibility, molar conductance, infrared spectra, 1H and 13C NMR, mass, electronic absorption and ESR spectroscopy. The anticancer activity of the synthesized compounds was studied against different human tumor cell lines: breast cancer MCF-7, liver cancer HepG2, lung carcinoma A549 and colorectal cancer HCT116 in comparison with the activity of doxorubicin as a reference drug. The study showed that ZnII complex showed potent inhibition against human TRK in the four cell lines (HepG2, MCF7, A549, HCT116) by the ratio 80, 70, 61 and 64% respectively as compared to the inhibition in the untreated cells. Moreover, the molecular docking into TRK (PDB: 1t46) was done for the optimization of the aforementioned compounds as potential TRK inhibitors

Novel quinazolinone-based 2,4-thiazolidinedione-3-acetic acid derivatives as potent aldose reductase inhibitors

Aim: Targeting aldose reductase enzyme with 2,4-thiazolidinedione-3-acetic acid derivatives having a bulky hydrophobic 3-arylquinazolinone residue. Materials &amp; methods: All the target compounds were structurally characterized by different spectroscopic methods and microanalysis, their aldose reductase inhibitory activities were evaluated, and binding modes were studied by molecular modeling. Results: All the synthesized compounds proved to inhibit the target enzyme potently, exhibiting IC50 values in the nanomolar/low nanomolar range. Compound 5i (IC50 = 2.56 nM), the most active of the whole series, turned out to be almost 70-fold more active than the only marketed aldose reductase inhibitor epalrestat. Conclusion: This work represents a promising matrix for developing new potential therapeutic candidates for prevention of diabetic complications through targeting aldose reductase enzyme

Antiviral Potentialities of Chemical Characterized Essential Oils of Acacia nilotica Bark and Fruits against Hepatitis A and Herpes Simplex Viruses: In Vitro, In Silico, and Molecular Dynamics Studies

Acacia nilotica (synonym: Vachellia nilotica (L.) P.J.H.Hurter and Mabb.) is considered an important plant of the family Fabaceae that is used in traditional medicine in many countries all over the world. In this work, the antiviral potentialities of the chemically characterized essential oils (EOs) obtained from the bark and fruits of A. nilotica were assessed in vitro against HAV, HSV1, and HSV2. Additionally, the in silico evaluation of the main compounds in both EOs was carried out against the two proteins, 3C protease of HAV and thymidine kinase (TK) of HSV. The chemical profiling of the bark EOs revealed the identification of 32 compounds with an abundance of di- (54.60%) and sesquiterpenes (39.81%). Stachene (48.34%), caryophyllene oxide (19.11%), and spathulenol (4.74%) represented the main identified constituents of bark EO. However, 26 components from fruit EO were assigned, with the majority of mono- (63.32%) and sesquiterpenes (34.91%), where trans-caryophyllene (36.95%), Z-anethole (22.87%), and &gamma;-terpinene (7.35%) represented the majors. The maximum non-toxic concentration (MNTC) of the bark and fruits EOs was found at 500 and 1000 &micro;g/mL, respectively. Using the MTT assay, the bark EO exhibited moderate antiviral activity with effects of 47.26% and 35.98% and a selectivity index (SI) of 2.3 and 1.6 against HAV and HSV1, respectively. However, weak activity was observed via the fruits EO with respective SI values of 3.8, 5.7, and 1.6 against HAV, HSV1, and HSV2. The in silico results exhibited that caryophyllene oxide and spathulenol (the main bark EO constituents) showed the best affinities (&Delta;G = &minus;5.62, &minus;5.33, &minus;6.90, and &minus;6.76 kcal/mol) for 3C protease and TK, respectively. While caryophyllene (the major fruit EO component) revealed promising binding capabilities against both proteins (&Delta;G = &minus;5.31, &minus;6.58 kcal/mol, respectively). The molecular dynamics simulation results revealed that caryophyllene oxide has the most positive van der Waals energy interaction with 3C protease and TK with significant binding free energies. Although these findings supported the antiviral potentialities of the EOs, especially bark EO, the in vivo assessment should be tested in the intraoral examination for these EOs and/or their main constituents