Exploring effects of Simvastatin on coagulation mediators to alleviate the advancement of high cholesterol diet triggered neurodegeneration.

The objectives of our study were to investigate the possible effect of Simvastatin in ameliorating high cholesterol diet (HCD)-induced neurodegeneration and to also investigate its possible action on coagulation mediators. In silico and in vitro studies were performed to evaluate the impact of Simvastatin on prime coagulation mediators. HCD was used to induce neuropathology in wistar rats and histopathological and immunohistochemical studies were performed to evaluate the efficacy of Simvastatin in preventing the advancement of neurodegeneration in obese rats. Biochemical analyses were used to estimate changes in lipid profile, oxidative stress, inflammatory and coagulation markers. Simvastatin showed good theoretical affinity to coagulation proteins, significantly reversed changes in inflammatory and coagulation biomarkers which were induced by HCD. Enhanced fibrinolytic activity of Simvastatin was revealed through in vitro analysis. Immunohistoanalysis showed raised level of Nrf2. Histopathological studies also supported neuroprotective potential of Simvastatin in HCD fed rats. Simvastatin demonstrated reduced hypercoagulation, enhanced fibrinolysis and reversed neurodegeneration in HCD exposed rats suggesting its potential role in preventing the progression of neurodegeneration in obesity.

Design and synthesis of pyrazole-pyrazoline hybrids as cancer-associated selective COX-2 inhibitors.

In continuation of our previous work on cancer and inflammation, 15 novel pyrazole-pyrazoline hybrids (WSPP1-15) were synthesized and fully characterized. The formation of the pyrazoline ring was confirmed by the appearance of three doublets of doublets in 1 H nuclear magnetic resonance spectra exhibiting an AMX pattern for three protons (HA , HM , and HX ) of the pyrazoline ring. All the synthesized compounds were screened for their in vitro anticancer activity against five cell lines, that is, MCF-7, A549, SiHa, COLO205, and HepG2 cells, using the MTT growth inhibition assay. 5-Fluorouracil was taken as the positive control in the study. It was observed that, among them, WSPP11 was found to be active against A549, SiHa, COLO205, and HepG2 cells, with IC50 values of 4.94, 4.54, 4.86, and 2.09 µM. All the derivatives were also evaluated for their cytotoxicity against HaCaT cells. WSPP11 was also found to be nontoxic against normal cells (cell line HaCaT), with an IC50 value of more than 50 µM. The derivatives were also evaluated for their in vitro anti-inflammatory activity by the protein (egg albumin) denaturation assay and the red blood cell membrane stabilizing assay, using diclofenac sodium and celecoxib as standard. Compounds that showed significant anticancer and anti-inflammatory activities were further studied for COX-2 inhibition. The manifestation of a higher COX-2 selectivity index of WSPP11 as compared with other derivatives and an in vitro anticancer activity against four cell lines further established that compounds that were more selective toward COX-2 also exhibited a better spectrum of activity against various cancer cell lines.

Methylene-bearing sulfur-containing cyanopyrimidine derivatives for treatment of cancer: Part-II.

In continuation of our previous work on anticancer and anti-inflammatory agents, a series of 22 novel methylene-bearing sulfur-containing cyanopyrimidine derivatives was synthesized by Biginelli condensation reaction, which was followed by nucleophilic substitution of the chloro group with secondary or tertiary amines. Structural confirmation of these derivatives was attained through different spectral techniques. Then, anticancer evaluation of these compounds was done at the National Cancer Institute. Compounds 4g, 4j, 4k, and 4v demonstrated appreciable results against different cell lines. Among the synthesized compounds, 4g (NSC: 795475) exhibited a growth inhibition (GI) of 81.34% against the NCI-H460 lung cancer cell line, 72.64% against the ACHN renal cancer cell line, and 112.17% against the OVCAR-4 ovarian cancer cell line. Compound 4j (NSC: 795746) was active against U-251 CNS cancer, OVCAR-4 ovarian cancer, and 786-0 and ACHN renal cancer cell lines, with GI of 78.84%, 150.38%, 75.64%, and 86.45%, respectively. The literature supporting the association between cancer and underlying inflammation prompted us to evaluate the four compounds, 4g, 4j, 4k, and 4v, with appreciable anticancer activity for their in vitro anti-inflammatory activity. Cyclooxygenase (COX)-2 inhibition studies were also performed to study the molecular target. To validate the target study, molecular docking studies in the ligand-binding domain of COX-2 (PDB ID: 1CX2) were also performed. Compounds 4g, 4j, and 4k did not show cytotoxicity on RAW 264.7 cells up to 10 µM concentration; however, compound 4v showed cytotoxic effects at 10 µM concentration.

Synthesis of pyrazole acrylic acid based oxadiazole and amide derivatives as antimalarial and anticancer agents.

Depravity of malaria in terms of morbidity and mortality in human beings makes it a major health issue in tropical and subtropical areas of the globe. Drug counterfeiting and non-adherence to the treatment regimen have significantly contributed to development and spread of multidrug resistance that has highlighted the need for development of novel and more efficient antimalarial drugs. Complexity associated with cancer disease and prevalence of diversified cell populations vindicates highly specific treatment options for treatment of cancer. Resistance to these anticancer agents has posed a great hindrance in successful treatment of cancer. Pondering this ongoing situation, it was speculated to develop novel compounds targeting malaria and cancer. Moving on the same aisle, we synthesized pyrazole acrylic acid based oxadiazole and amide derivatives using multi-step reaction pathways (6a-x; 6a'-h'). Schizont maturation inhibition assay was employed to determine antimalarial potential. Compound 6v emerged as the most potent antimalarial agent targeting falcipain-2 enzyme. Anticancer activity was done using sulforhodamine B assay. Compounds 6b' and 6g' demonstrated promising results against all the tested cell lines. Further, Microscopic view clearly indicated formation of apoptotic bodies, chromatin condensation, shrinkage of cells and bleb formation. Validation of the results was achieved using molecular docking studies. From the obtained results, it was observed that cyclization (oxadiazole) favored antimalarial activity while non-cyclized compounds (amides) emerged as better anticancer agents.

Identification of expression profiles and prognostic value of RFCs in colorectal cancer.

Colorectal cancer (CRC) ranks among the most prevalent cancers globally, with its incidence closely tied to DNA damage. The Replication Factor C (RFC) complexes comprises five protein subunits: RFC1, RFC2, RFC3, RFC4, and RFC5. These RFC complexes play crucial roles in DNA replication, repair pathways, activities post DNA damage, and ATP-dependent processes during DNA synthesis. However, the impact of RFC complexes proteins on CRC prognosis remains unclear. To explore this, we employed a computational analysis approach, utilizing platforms such as the DepMap portal, GEPIA, DAVID Bioinformatics for KEGG pathway analysis, Human Protein Atlas (HPA), STRING, and TIMER. Our results indicate that the mRNA levels of RFC1 and RFC5 were the least expressed among CRC cell lines compared to other RFC complex subunits. Notably, low RFC1 and RFC5 expression was correlated with poor prognosis in terms of CRC patients' overall survival (OS). Immunohistochemical results from the Human Protein Atlas demonstrated medium staining for RFC1, RFC2, and RFC5 in CRC tissues. Furthermore, the low expression of RFC1 and RFC5 showed a significant correlation with high expression levels of miR-26a-5p and miR-636, impacting cell proliferation through mismatch repair, DNA replication, and the nucleotide excision repair pathway. Although the precise functions of RFC1 in cancer are still unknown, our findings suggest that the small-molecule single target, CHEMBL430483, and multiple target molecules could be potential treatments for CRC. In conclusion, the elevated expression of miR-26a-5p and miR-636 targeting RFC1 and RFC5 expression holds promise as a potential biomarker for early-stage CRC detection. These insights provide novel directions and strategies for CRC therapies.

Microwave assisted one pot synthesis of some pyrazole derivatives as a safer anti-inflammatory and analgesic agents.

A series of pyrazolo[3,4-b]quinolines have been synthesized using one-pot water mediated synthetic route under microwave irradiation involving the condensation of 2-chloroquinoline-3-carbaldehydes with semicarbazide or 2,4-dinitrophenyl hydrazine. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. The pharmacological evaluation showed that the compounds are good at inhibiting edema induced by carrageenan and also showed prominent analgesic activity with lesser GI toxicity as indicated by severity index and LPO values.

Ameliorative effect of rubiadin-loaded nanocarriers in STZ-NA-induced diabetic nephropathy in rats: formulation optimization, molecular docking, and in vivo biological evaluation.

Diabetic nephropathy (DN) is a significant source of end-stage renal illness all over the world in both developed and developing countries. The aim of the study was to optimize rubiadin-loaded niosomes (RLN) using Box-Behnken design for the management of streptozotocin-nicotinamide (STZ-NA)-induced DN in Wistar rats. The RLN were formulated by a "thin-layer hydration technique." The optimization of RLN was done by Box-Behnken design; the independent variables were cholesterol (CHOL), Span 80, and methanol, while the dependent factors were the vesicle size, zeta potential, and entrapment efficiency. The optimized formulation was characterized for various biochemical parameters including anti-diabetic activity in Wistar rats. The optimized RLN presented vesicle size of 238 nm, zeta potential -68 mV, and entrapment efficiency 85%. A noteworthy decreased in blood glucose level was detected in STZ-NA-induced DN rats when orally treated with RLN (100 mg/kg/week and 200 mg/kg/week). Oral administration of RLN formulation considerably decreased the levels of urea, uric acid, and creatinine in DN rats. In addition, treatment of DN rats with RLN formulation considerably improves the level of TBARS, GSH, SOD, and CAT. The lipid profile of DN rats was also improved on treatment with RLN formulation. This study revealed that the prepared RLN formulation was successfully optimized by Box-Behnken design and found to be useful for the management of STZ-NA-induced DN in Wistar rats.

Synthesis of some new 2-(substituted-phenyl)-5-(N,N-diphenylaminomethyl)-1,3,4-oxadiazoles: a safer anti-inflammatory and analgesic agents.

A series of 2-(substituted-phenyl)-5-(N,N-diphenylaminomethyl)-1,3,4-oxadiazoles (3-15) were synthesized. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. The percentage inhibition in edema at different time intervals indicated that compounds 8, 11, 12, 14 and 15 exhibited good anti-inflammatory potential. The results illustrate that 2-(2-acetoxyphenyl)-5-(N,N-diphenylaminomethyl)-1,3,4-oxadiazole (15) and 2-(3,4-dimethoxyphenyl)-5-(N,N-diphenylaminomethyl)-1,3,4-oxadiazole (12) showed best anti-inflammatory activity among the series tested. Furthermore, activity is higher in case of chloro substitution as compared to methyl substitution. The compounds synthesized were also evaluated for their ulcerogenic and lipid peroxidation action and showed superior GI safety profile along with reduction in lipid peroxidation as compared to that of ibuprofen.

Search for new pharmacophore as antimalarial agent: synthesis and antimalarial activity of some 2(3H)-furanones bearing quinoline moiety.

A series of substituted 3-[(substituted-2-chloroquinolin-3-yl)methylene]-5-(substituted-phenyl)-furan-2(3H)-ones (4a-p) have been synthesized and evaluated for their in vitro antimalarial activity against P. falciparum. The title compounds were synthesized by condensing 3-(substituted-benzoyl)propionic acids (3a-d) with substituted 2-chloroquinoline-3-carbaldehydes (2a-d) following modified Perkin's reaction. Compounds 3-[2-chloro-6-methylquinolin-3-yl)methylene]-5-(2,4-dimethyl-phenyl)-furan-2(3H)-one (4n) and 3-[2-chloro-6-methoxyquinolin-3-yl)methylene]-5-(2,4-dimethyl-phenyl)-furan-2(3H)-one (4p) showed promising antimalarial activity with MIC of 10 microg/mL.

A review exploring biological activities of hydrazones.

The development of novel compounds, hydrazones has shown that they possess a wide variety of biological activities viz. antimicrobial, anticonvulsant, antidepressant, anti-inflammatory, analgesic, antiplatelet, antimalarial, anticancer, antifungal, antitubercular, antiviral, cardio protective etc., Hydrazones/azomethines/imines possess-NHN = CH- and constitute an important class of compounds for new drug development. A number of researchers have synthesized and evaluated the biological activities of hydrazones. This review aims at highlighting the diverse biological activities of hydrazones.

3D-QSAR and molecular docking studies on 3-anilino-4-arylmaleimide derivatives as glycogen synthase kinase-3ß inhibitors.

Glycogen synthase kinase-3, a serine/threonine kinase, is a fascinating enzyme with diverse biological actions in intracellular signaling systems, making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar disorders, and Alzheimer's disease. It is important to inhibit glycogen synthase kinase-3 selectively, and the net effect of the glycogen synthase kinase-3 inhibitors thus should be target specific, over other phylogenetically related kinases such as CDK-2. In the present work, we have carried out three-dimensional quantitative structure-activity relationship studies on novel class of 3-anilino-4-arylmaleimide derivatives to have improved cellular activity. Docked conformation of the most active molecule in the series, which shows desirable interactions in the receptor, was taken as template for the alignment of the molecules. Statistically significant CoMSIA (r2(cv)=0.614, r2(ncv)=0.948) and comparative molecular field analysis (r2(cv) =0.652, r2(ncv)=0.958) models were generated using 57 molecules in training set. The predictive ability of CoMSIA and comparative molecular field analysis models was determined using a test set of 17 molecules, which gave predictive correlation coefficients (r2(pred)) of 0.87 and 0.82, respectively, indicating good predictive power. Based on the information derived from CoMSIA and comparative molecular field analysis contour maps, we have identified some key features that explain the observed variance in the activity and have been used to design new anilinoarylmaleimide derivatives. The designed molecules showed better binding affinity in terms of estimated docking scores with respect to the already reported systems, hence suggesting that newly designed molecules can be more potent and selective toward glycogen synthase kinase-3ß inhibition.

Synthesis of 6-aminomethyl derivatives of benzopyran-4-one with dual biological properties: anti-inflammatory-analgesic and antimicrobial.

A series of 6-aminomethyl-2-aryl-1-benzopyran-4-one derivatives (10-24) were synthesized. The compounds were tested for anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. Among the tested compounds, six compounds 11, 13, 16, 18, 21 and 23 showed higher degree of anti-inflammatory activity (>75% activity of standard drug ibuprofen). In addition to remarkable anti-inflammatory activity, analgesic activity was found to be comparable with that of the standard drug ibuprofen. Compounds 16 and 21 showed a significant GI protection (with respect to ulcerogenesis) and a marked decrease in lipid peroxidation values whereas compounds 11 and 16 were found to possess antimicrobial activity against Staphylococcus aureus, Escherichia coli, Rhizopus oryza and Penicillum citrum with an MIC of 10 microg/mL.