Synthesis, in-Silico studies and biological evaluation of pyrimidine based thiazolidinedione derivatives as potential anti-diabetic agent.

Despite the advancements in the management of Diabetes mellitus, the design and synthesis of drug molecule which ameliorates the hyperglycemia and associated secondary complications in diabetic patients, still remains a challenge. Herein, we report the synthesis, characterization and anti-diabetic evaluation of pyrimidine-thiazolidinedione derivatives. The synthesized compounds were characterized by 1H NMR, 13C NMR, FTIR and Mass Spectroscopic analytical techniques. The in-silico ADME studies depicted that the compounds were within the permissible limits of the Lipinski's rule of five. The compounds 6e and 6m showing the best results in OGTT were evaluated for in-vivo anti-diabetic evaluation in STZ induced diabetic rats. Administration of 6e and 6m for four weeks decreased the blood glucose levels significantly. Compound 6e (4.5 mg/kg p.o.) was the most potent compound of the series. It reduced the level of blood glucose to 145.2 ± 1.35 compared to the standard Pioglitazone (150.2 ± 1.06). Moreover, the 6e and 6m treated group did not show increase in bodyweight. The biochemical estimations showed that the levels of ALT, ASP, ALP, urea, creatinine, blood urea nitrogen, total protein and LDH restored to normal in 6e and 6m treated groups as compared to STZ control group. The histopathological studies supported the results obtained in biochemical estimations. Both the compounds did not show any toxicity. Moreover, the histopathological studies of pancreas, liver, heart and kidney revealed that the structural integrity of these tissues restored to almost normal in 6e and 6m treated groups as compared to STZ control group. Based upon these findings it can be concluded that the pyrimidine-based thiazolidinedione derivatives represent novel anti-diabetic agents with least side effects.

Computational Modelling, Functional Characterization and Molecular Docking to Lead Compounds of Bordetella pertussis Diaminopimelate Epimerase.

Bordetella pertussis, the causative agent of whooping cough, is an opportunistic virulent bacterial pathogen that is resistant to a wide range of antibiotics due to a variety of resistance mechanisms. Looking at the increasing number of infections caused by B. pertussis and its resistance to diverse antibiotics, it is essential to develop alternative strategies to fight against B. pertussis. Diaminopimelate epimerase (DapF) is an important enzyme of the lysine biosynthesis pathway in B. pertussis that catalyzes the formation of meso-2, 6-diaminoheptanedioate (meso-DAP), which is an important step in lysine metabolism. Therefore, Bordetella pertussis diaminopimelate epimerase (DapF) becomes an ideal target for antimicrobial drug development. In the present study, computational modelling, functional characterization, binding studies, and docking studies of BpDapF with lead compounds were carried out using different in silico tools. In silico prediction results in the secondary structure, 3-D structure analysis, and protein-protein interaction analysis of BpDapF. Docking studies further showed the respective amino acid residues for ligands in the phosphate­binding loop of BpDapF play a vital role in the formation of H­bonds with these ligands. The site where the ligand was bound is a deep groove, which is regarded as the binding cavity of the protein. Biochemical studies indicated that Limonin (binding energy - 8.8 kcal/mol), Ajmalicine (binding energy - 8.7 kcal/mol), Clinafloxacin (binding energy - 8.3 kcal/mol), Dexamethasone (binding energy - 8.2 kcal/mol), and Tetracycline (binding energy - 8.1 kcal/mol) exhibited promising binding towards the drug target DapF of B. pertussis in comparison with the binding between other drugs and act as the potential inhibitors of BpDapF that eventually can reduce the catalytic activity of BpDapF.

Role of NLRP3 Inflammasome and Its Inhibitors as Emerging Therapeutic Drug Candidate for Alzheimer's Disease: a Review of Mechanism of Activation, Regulation, and Inhibition.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders. The etiology and pathology of AD are complicated, variable, and yet to be completely discovered. However, the involvement of inflammasomes, particularly the NLRP3 inflammasome, has been emphasized recently. NLRP3 is a critical pattern recognition receptor involved in the expression of immune responses and has been found to play a significant role in the development of various immunological and neurological disorders such as multiple sclerosis, ulcerative colitis, gout, diabetes, and AD. It is a multimeric protein which releases various cytokines and causes caspase-1 activation through the process known as pyroptosis. Increased levels of cytokines (IL-1ß and IL-18), caspase-1 activation, and neuropathogenic stimulus lead to the formation of proinflammatory microglial M1. Progressive researches have also shown that besides loss of neurons, the pathophysiology of AD primarily includes amyloid beta (Aß) accumulation, generation of oxidative stress, and microglial damage leading to activation of NLRP3 inflammasome that eventually leads to neuroinflammation and dementia. It has been suggested in the literature that suppressing the activity of the NLRP3 inflammasome has substantial potential to prevent, manage, and treat Alzheimer's disease. The present review discusses the functional composition, various models, signaling molecules, pathways, and evidence of NLRP3 activation in AD. The manuscript also discusses the synthetic drugs, their clinical status, and projected natural products as a potential therapeutic approach to manage and treat NLRP3 mediated AD.

Glycolytic enzyme activities and gene expression in Cicer arietinum exposed to water-deficit stress.

The specific activities and transcript levels of glycolytic enzymes were examined in shoots of chickpea (Cicer arietinum L.) cultivars, Pusa362 (drought tolerant) and SBD377 (drought sensitive), subjected to water-deficit stress 30 days after sowing. Water-deficit stress resulted in decrease in relative water content, chlorophyll content, plant dry weight, and NADP/NADPH ratio and increase in NAD/NADH ratio in both the cultivars. A successive decline in the specific activities of fructose-1,6-bisphosphate aldolase (aldolase), 3-phosphoglycerate kinase (PGK), and NADP-glyceraldehyde-3-phosphate dehydrogenase (NADP-GAPDH) and elevation in the specific activities of phosphoglycerate mutase (PGM) and triosephosphate isomerase (TPI) was observed in both the cultivars under stress as compared to their respective control plants. The specific activities of hexokinase, fructose-6-phosphate kinase (PFK), and NAD-GAPDH were least affected. The transcript levels of PGK and NADP-GAPDH decreased and that of glucose-6-phosphate isomerase (GPI), PGM, and PFK increased in response to water-deficit stress while water-deficit stress had no effect on the steady-state transcript levels of hexokinase, aldolase, TPI, and NAD-GAPDH. The results suggest that under water-deficit stress, the activities and transcript levels of most of the glycolytic enzymes are not significantly affected, except the increased activity and transcript level of PGM and decreased activities and transcript levels of PGK and NADP-GAPDH. Further, the glycolytic enzymes do not show much variation between the tolerant and sensitive cultivars under water deficit.

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.

Molecular characterization of primary gene pool of chickpea based on ISSR markers.

Genetic diversity and relationships within and among members of the primary gene pool of chickpea, including 38 accessions of Cicer arietinum, six of C. reticulatum,, and four of C. echinospermum, were investigated using 31 ISSR markers. The study revealed moderate diversity, detecting 141 fragments, of which 79 (56%) were polymorphic. Averages were 0.125 for polymorphic information content, 0.350 for marker index, and 0.715 for resolving power. The UPGMA dendrogram and the principal coordinate analysis revealed a clear differentiation between wild and cultivated accessions. The clustering pattern did not strictly follow the grouping of accessions by geographic origin but was in good agreement with the pedigree data and the seed type. The study demonstrates that ISSRs provide promising marker tools in revealing genetic diversity and relationships in chickpea and can contribute to efficient identification, conservation, and utilization of germplasm for plant improvement through conventional as well as molecular breeding approaches.

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.

Homocysteine in neurological disease: a marker or a cause?

Hyperhomocysteinemia is increasingly recognized as an independent risk factor for several cerebral, vascular, ocular, and agerelated disorders. Whether it is a cause or a consequence or a mere marker necessitates further clarification. This review focuses on the pathophysiological aspects of homocysteine's involvement in neurodegenerative and neuropsychiatric disorders and complications. The pharmacological agents (antiepileptic drugs, L-DOPA) augment the homocysteine levels, thus, raising concern for physicians. The mechanisms underlying the enhanced homocysteine levels and its related pathophysiological cascades remain poorly understood, inspite of numerous epidemiological and research studies that have been carried out in recent years. This article will review the current understanding of these underlying mechanisms and the research being carried with homocysteine as a core molecule.

Bisphosphonates in phenytoin-induced bone disorder.

Chronic administration of phenytoin (PHT) has been associated with bone loss. Bisphosphonates [alendronate (ALD), ibandronate (IBD) and risedronate (RSD)] are potential candidates to prevent PHT-induced bone disorders, and the present study evaluated their effect on the antiepileptic efficacy of PHT. The PHT-induced depletion in folic acid (FA), vitamin B6 and vitamin B12 results in hyperhomocysteinemia. The elevated circulating homocysteine (hcy) could be a risk indicator for micronutrient-deficiency-related osteoporosis via generation of free radicals. Thus, an attempt was also made to unravel the PHT's and bisphosphonates' effect on hcy. Male mice received PHT (35 mg/kg, p.o.) for 90 days to induce bone loss. ALD, RSD and IBD were administered orally at doses 0.65 mg/kg, 0.33 mg/kg, and 0.17 mg/kg respectively, for prevention and 1.3mg/kg, 0.65 mg/kg, and 0.33 mg/kg respectively, for treatment of PHT-induced bone loss. The bone loss was confirmed by bone mineral density (BMD) analysis and bone turnover markers. Serum levels of hcy and FA were estimated along with hydrogen peroxide levels and total antioxidant capacity in order to assess the antioxidant profile of bisphosphonates. The induction of bone loss by PHT was marked by lowered BMD and altered bone turnovers. ALD and RSD administration to PHT treated groups significantly reverted the bony adverse effects. No such effects were observed with IBD. In the bisphosphonates treated groups, hcy levels were statistically at par with the control group. PHT at 35 mg/kg, p.o. could compromise bone mass and thus, could be a model of bone demineralization in mice. The ALD, IBD and RSD have no pharmacodynamic interaction when administered along with PHT at the experimental level. Thus, their usage in the management of PHT-induced bone disease could be worthwhile if clinically approved.

3-arylidene-5-(4-isobutylphenyl)-2(3H)-furanones: a new series of anti-inflammatory and analgesic compounds having antimicrobial activity.

An ideal anti-inflammatory drug should have the desired effect in minimum dose with minimum side effects. Antimicrobial actions associated with such agents will be an added advantage as they broaden the spectrum of the compounds. Promising anti-inflammatory and antimicrobial activity together with low ulcerogenic properties of some 2(3H)-furanones, synthesized in our previous study, prompted us to investigate the effect of the isobutyl group on their pharmacological profile. Since compounds 3, 9, 13, and 14 have both anti-inflammatory and analgesic effects in addition to low ulcerogenic incidence, they were selected for investigation of their inhibitory effects on various cyclo-oxygenase enzymes. It was found that they were more selective toward COX-2 enzymes. An MIC of 6.25 microg/mL was recorded for compounds 3, 13, and 14 against S. aureus, E. coli, R. oryza, and P. citrum. The study supports the development of furanone derivatives as potential anti-inflammatory agents with antimicrobial activity.

Evaluation of tumor necrosis factor-α (TNF-α) levels in plasma and their correlation with periodontal status in obese and non-obese subjects.

BACKGROUND: Obesity is emerging as a significant health problem worldwide and is a risk factor for various systemic diseases. Periodontal disease is a multifactorial inflammatory disease. Recent evidence points to a link between obesity and periodontal disease, and a role for tumor necrosis factor-α (TNF-α) has been suggested. MATERIALS AND METHOD: FORTY NONDIABETIC SUBJECTS WERE DIVIDED INTO TWO GROUPS: group A (non-obese) included subjects with body mass index (BMI) of 18.5 to 27 kg/m2, and group B (obese) included subjects with BMI>27 kg/m2. The BMI, TNF-α levels in plasma and Periodontal Disease Index (PDI) scores were assessed, compared and correlated. RESULTS: Significantly higher PDI scores and TNF-α levels were found in the obese group as compared to those in the non-obese group. Also, a significant and positive correlation was seen between BMI and TNF-α, TNF-α and PDI as well as BMI and PDI. CONCLUSION: Increase in the levels of tumor necrosis factor-a in plasma and an increase in the severity of periodontal disease may be seen in subjects with a higher body mass index (BMI). This indicates that obesity may be detrimental to the periodontal health of individuals.

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.

Insights into liaison between antiepileptic drugs and bone.

The adverse effect on bone caused by chronic anticonvulsant therapy causes multiple abnormalities in calcium and bone metabolism, varying from bone turnover, without significant loss of cortical or trabecular bone, to osteopenia/osteoporosis and to osteomalacic disorder. The studies conducted to date have documented anticonvulsant bone disease as a state of increased bone remodeling. With the newer antiepileptic drugs (AEDs) gaining importance and starting to replace conventional medicines, it may be appropriate to compare them with the conventional AEDs and to examine their impact on multiple aspects of bone health. This review focuses on the status of the bony effects of AEDs.