Anti-inflammatory activity of novel derivatives of pyrazolo [3,4d] pyridazine against digestive system inflammation.

The digestive system is exposed to severe inflammation as a result of taking some medications that have gastrointestinal side effects. Sixty Swiss-albino male mice were randomly distributed into six groups to treat inflammations of the colon, stomach, and small intestine caused by taking high doses of diclofenac (D), with two novel synthesized compounds, pyrazolo [3,4 d] pyridazine derivatives (Co1 and Co2). Myeloperoxidase enzyme activity was determined in the colon and small intestinal tissues. Serum contents of TNF-α, IL-22, IgG, and IgM were determined by ELISA. Histopathological examinations of the colon, small intestinal, and stomach tissues were microscopically analyzed. TNF-α, IL-22, and TNFSF11 gene expression were measured in the colon, intestinal, and spleen using qRT-PCR. Diclofenac caused surface columnar epithelial cell loss, focal necrosis of the gastric mucosa, inflammatory cell infiltration, and congested blood vessels in the stomach, colon, and small intestinal tissues. Co1 component was found to be better than Co2 component in reducing the focal necrosis of gastric mucosa and improving the histological structures of the stomach, colon, and small intestinal tissues. After 14 days, the activity of the myeloperoxidase enzyme was increased in group D and decreased in groups DCo1, DCo2, Co1, and Co2. Serum concentrations of TNF-α and IgG were increased, while IL-22 and IGM were reduced in the D, DCo1, and DCo2 groups compared with the Co1 and control groups. TNF-α gene was upregulated in the D group and downregulated in the Co1 group, while the IL-22 gene was downregulated in the D group and upregulated in the Co1 group compared with the control group. The CO1 component may be useful in reducing digestive system inflammation.

Determination of anticancer potential of a novel pharmacologically active thiosemicarbazone derivative against colorectal cancer cell lines.

Thiosemicarbazones have received noteworthy attention due to their numerous pharmacological activities. Various thiosemicarbazone derivatives have been reported to play a key role as potential chemotherapeutic agents for the management of cancer. Herein, we aimed to establish the anticancer efficacy of novel thiosemicarbazone derivative C4 against colon cancer in vitro. The MTT viability assay identified C4 as a promising anticancer compound in a panel of cancer cell lines with the most potent activity against colon cancer cells. Further, anticancer potential of C4 was evaluated against HT-29 and SW620 colon cancer cell lines considering the factors like cell adhesion and migration, oxidative stress, cell cycle arrest, and apoptosis. Our results showed that C4 significantly inhibited the migration and adhesion of colon cancer cells. C4 significantly increased the intracellular reactive oxygen species (ROS) and induced apoptotic cell death. Cell cycle analysis revealed that C4 interfered in the cell cycle distribution and arrested the cells at the G2/M phase of the cell cycle. Consistent with these results C4 also down-regulated the Bcl-XL and Bcl-2 and up-regulated the caspase-3 expression. These findings introduced C4 as the potential anticancer agent against colon cancer.

Pomegranate peel induced biogenic synthesis of silver nanoparticles and their multifaceted potential against intracellular pathogen and cancer.

In the field of nano-biotechnology, silver nanoparticles (AgNPs) share a status of high repute owing to their remarkable medicinal values. Biological synthesis of environment-friendly AgNPs using plant extracts has emerged as the beneficial alternative approach to chemical synthesis. In the current study, we have synthesized biogenic silver nanoparticles (PG-AgNPs) using the peel extract of Punica granatum as a reducing and stabilizing agent. The as-synthesized PG-AgNPs were characterized and evaluated for their antibacterial and anticancer potential. UV-Visible spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering (DLS) confirmed the formation of biogenic PG-AgNPs. The antibacterial potential was assessed against the biofilm of Listeria monocytogenes. The PG-AgNPs were efficacious against sessile bacteria and their biofilm as well. The as-synthesized nanoparticles at sub-MIC values showed dose-dependent inhibition of biofilm formation. Corroborating results were observed under crystal violet assay, Congo red staining, Confocal microscopy and SEM analysis. The anticancer ability of the nanoparticles was evaluated against MDA-MB-231 metastatic breast cancer cells. As evident from the MTT results, PG-AgNPs significantly reduced the cell viability in a dose-dependent manner. Exposure of MDA-MB-231 cells led to the accumulation of reactive oxygen species (ROS). Morphological changes and DNA fragmentation showed the strong positive effect of PG-AgNPs on the induction of apoptosis. Collectively, the as-synthesized PG-AgNPs evolved with synergistically emerged attributes that were effective against L. monocytogenes and also inhibited its biofilm formation; moreover, the system displayed lower cytotoxic manifestation towards mammalian cells. In addition, the PG-AgNPs embodies intriguing anticancer potential against metastatic breast cancer cells.

ChCl: Gly (DESs) Promote Environmentally Benign Synthesis of Xanthene Derivatives and Their Antitubercular Activity.

A ChCl: Gly (DESs) promoted environmentally benign method was developed for the first time using the reaction of aryl aldehydes and dimedone to give excellent yields of xanthene analogues. The major application of this present protocol is the use of green solvent, a wide range of substrate, short reaction times, ease of recovery, the recyclability of the catalyst, high reaction yield, and ChCl: Gly as an alternative catalyst and solvent. In addition to this, all the synthesized compounds were evaluated for their in vitro antimycobacterial activity against M. tuberculosis H37Ra (MTB) and M. bovis BCG strains. The compounds 3d, 3e, 3f, and 3j showed significant antitubercular activity against MTB and M. bovis strains with minimum inhibitory concentration (MIC) values of 2.5-15.10 µg/mL and 0.26-14.92 µg/mL, respectively. The compounds 3e, 3f, and 3j were found to be nontoxic against MCF-7, A549, HCT 116, and THP-1 cell lines. All the prepared compounds were confirmed by 1H NMR and 13C NMR analysis.

Nα-1, 3-Benzenedicarbonyl-Bis-(Amino Acid) and Dipeptide Candidates: Synthesis, Cytotoxic, Antimicrobial and Molecular Docking Investigation.

PURPOSE: The objective of our work was to prepare a potent and safe antimicrobial and anticancer agents, through synthesis of several peptides and examine their biological activities, namely as, cytotoxically potent and antimicrobial and antifungal agents. INTRODUCTION: Multidrug-resistant microbial strains have arisen against all antibiotics in clinical use. Infections caused by these bacteria threaten global public health and are associated with high mortality rates. METHODS: The main backbone structure for the novel synthesized linear peptide is Nα-1, 3-benzenedicarbonyl-bis-(Amino acids)-X, (3-11). A computational docking study against DNA gyrase was performed to formulate a mode of action of the small compounds as antimicrobial agents. RESULTS: The peptide-bearing methionine-ester (4) exhibited potent antimicrobial activity compared to the other synthesized compounds, while, peptide (8), which had methionine-hydrazide fragment was the most potent as antifungal agent against Aspergillus niger with 100% inhibition percent. Compounds (6 and 7) showed the highest potency against breast human tumor cell line "MCF-7" with 95.1% and 79.8% of cell inhibition, respectively. The nine compounds possessed weak to moderate antiproliferative effect over colon tumor cell line. The docking results suggest good fitting through different hydrogen bond interactions with the protein residues. In silico ADMET study also evaluated and suggested that these compounds had promising oral bioavailability features. CONCLUSION: The tested compounds need further modification to have significant antimicrobial and antitumor efficacy compared to the reference drugs.

A potential anticancer dihydropyrimidine derivative and its protein binding mechanism by multispectroscopic, molecular docking and molecular dynamic simulation along with its in-silico toxicity and metabolic profile.

Human serum albumin (HSA) is the core protein in the systemic circulation and has a fundamental role in transportation and distribution of ligands in-vivo. In this study, a newly synthesized and patented anticancer dihydropyrimidine derivative; 4-(4-ethoxyphenyl)-5-(3,4,5- trimethoxybenzoyl)-3,4-dihydropyrimidin-2(1H)-one (DHP) was evaluated for its binding to HSA. Ligand-HSA interaction is significant factor to attribute the toxicity or therapeutic potential to a ligand. Multi-spectroscopic studies combined with molecular modelling and molecular dynamic simulation (MDS) were conducted to understand the HSA-DHP binding mechanism. In-silico evaluation of DHP for its toxicity and metabolism was also conducted. Reduction in the binding constants was observed from 6.71 × 104 - 4.5 × 103 at increased temperatures which indicates moderate binding and the interaction was found to follow a static quenching mechanism. Further, Site I on HSA for DHP was established by competition with site specific markers and the results were supported by molecular docking. The stability of the HSA-DHP complex was established with MDS studies. Thermodynamics parameters revealed involvement of hydrogen bonding and van der Waals forces for HSA-DHP binding. An in-silico evaluation of DHP for its toxicity and metabolism provided that the synthesized compound was potentially safe and could be a promising candidate for further studies.

Synthesis of Novel Sulfamethaoxazole 4-Thiazolidinone Hybrids and Their Biological Evaluation.

A search for potent antitubercular agents prompted us to design and synthesize sulfamethaoxazole incorporated 4-thiazolidinone hybrids (7a-l) by using a cyclocondensation reaction between 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide (4), aryl aldehyde (5a-l), and mercapto acetic acid (6) resulting in good to excellent yields. All the newly synthesized 4-thiazolidinone derivatives were screened for their in vitro antitubercular activity against M. Bovis BCG and M. tuberculosis H37Ra (MTB) strains. The compounds 7d, 7g, 7i, 7k, and 7l revealed promising antimycobacterial activity against M. Bovis and MTB strains with IC90 values in the range of 0.058-0.22 and 0.43-5.31 µg/mL, respectively. The most active compounds were also evaluated for their cytotoxicity against MCF-7, HCT 116, and A549 cell lines and were found to be non-cytotoxic. Moreover, the synthesized compounds were also analyzed for ADME (absorption, distribution, metabolism, and excretion) properties and showed potential as good oral drug candidates.

Biological Evaluation and Molecular Docking with In Silico Physicochemical, Pharmacokinetic and Toxicity Prediction of Pyrazolo[1,5-a]pyrimidines.

Pyrazolo[1,5-a]pyrimidines 5a-c, 9a-c and 13a-i were synthesized for evaluation of their in vitro antimicrobial properties against some microorganisms and their immunomodulatory activity. The biological activities of pyrazolo[1,5-a]pyrimidines showed that the pyrazolo[1,5-a]pyrimidines (5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h) displayed promising antimicrobial and immunomodulatory activities. Studying the in silico predicted physicochemical, pharmacokinetic, ADMET and drug-likeness properties for the pyrazolo[1,5-a]pyrimidines 5a-c, 9a-c and 13a-i confirmed that most of the compounds (i) were within the range set by Lipinski's rule of five, (ii) show higher gastrointestinal absorption and inhibition of some CYP isoforms, and (iii) have a carcinogenicity test that was predicted as negative and hERG test that presented medium risk. Moreover, the molecular docking study demonstrated that the compounds 5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h are potent inhibitors of 14-alpha demethylase, transpeptidase and alkaline phosphatase enzymes. This study could be valuable in the discovery of a new series of drugs.

Synthesis, characterization and antidiabetic effects of vanadyl(II) adenosine monophosphate amino acid mixed-ligand complexes.

Aim: This research paper is aimed at designing a novel insulin alternative for the treatment of diabetes. Materials & methods: Six novel vanadyl(II) compounds, [(AMP-2)(VO+2)(AA n -1)]·NH4 +1, were synthesized from an equimolar ratio of adenosine monophosphate, VOSO4 and amino acids (AA n ). Results: The magnetic moments and electronic spectra revealed the square pyramidal geometrical structure of the complexes. In an in vivo study, the insulin levels, blood glucose levels, lipid profiles and histology of the pancreas and liver of the animals treated with the complexes were similar to those of healthy control animals, unlike the untreated and vanadyl sulfate(II)-treated diabetic ones. Conclusion: The data gathered in the current research illustrated that vanadyl(II)-AMP-amino acid (AA) mixed-ligand complexes can function as antidiabetic agents.

Lead Optimization of 2-Cyclohexyl-N-[(Z)-(3-methoxyphenyl/3-hydroxyphenyl) methylidene]hydrazinecarbothioamides for Targeting the HER-2 Overexpressed Breast Cancer Cell Line SKBr-3.

Lead derivatives of 2-cyclohexyl-N-[(Z)-(3-methoxyphenyl/3-hydroxyphenyl) methylidene]hydrazinecarbothioamides 1-18 were synthesized, characterized and evaluated in vitro against HER-2 overexpressed breast cancer cell line SKBr-3. All the compounds showed activity against HER-2 overexpressed SKBr-3 cells with IC50 = 17.44 ± 0.01 µM to 53.29 ± 0.33 µM. (2Z)-2-(3-Hydroxybenzylidene)-N-(3-methoxyphenyl)hydrazinecarbothioamide (12, IC50 = 17.44 ± 0.01 µM) was found to be most potent compound of this series targeting HER-2 overexpressed breast cancer cells compared to the standard drug 5-fluorouracil (5-FU) (IC50 = 38.58 ± 0.04 µM). Compound 12 inhibited the cellular proliferation via DNA degradation.

Design and Synthesis of N-Arylphthalimides as Inhibitors of Glucocorticoid-Induced TNF Receptor-Related Protein, Proinflammatory Mediators, and Cytokines in Carrageenan-Induced Lung Inflammation.

N-Arylphthalimides (1-10P) derived from thalidomide by insertion of hydrophobic groups were evaluated for anti-inflammatory activity, and (4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N'-[(4-ethoxyphenyl)methylidene]benzohydrazide 6P was identified as a promising anti-inflammatory agent. Further testing confirmed that compared with the control, 6P treatment resulted in a considerable decrease in CD4(+), NF-κB p65(+), TNF-α(+), IL-6(+), GITR(+), and IL-17(+) cell populations and an increase in the Foxp3(+), CD4(+)Foxp3(+), and IκBα(+) populations in whole blood and pleural fluid of a mouse model of lung inflammation. Moreover, treatment with compound 6P decreased the proteins associated with inflammation including TNF-α, IL-6, IL-17, GITR, NF-κB, COX-2, STAT-3, and iNOS and increased the anti-inflammatory mediators such as IL-10 and IL-4. Further, histopathological examination confirmed the potent anti-inflammatory effects of compound 6P. Thus, the N-arylphthalimide derivative 6P acts as a potent anti-inflammatory agent in the carrageenan-induced lung inflammation model, suggesting that this compound may be useful for the treatment of inflammation in a clinical setting.

Steroidal pyrazolines evaluated as aromatase and quinone reductase-2 inhibitors for chemoprevention of cancer.

The aromatase and quinone reductase-2 inhibition of synthesized heterocyclic pyrazole derivatives fused with steroidal structure for chemoprevention of cancer is reported herein. All compounds were interestingly less toxic than the reference drug (Cyproterone(®)). The aromatase inhibitory activities of these compounds were much more potent than the lead compound resveratrol, which has an IC(50) of 80 µM. In addition, all the compounds displayed potent quinone reductase-2 inhibition. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). The aromatase and quinone reductase-2 inhibitors resulting from this study have potential value in the treatment and prevention of cancer.