Abstract Rheumatoid arthritis an autoimmune infectious disorder, is categorized by inflammation and increased level of pro-inflammatory cytokines which are released by immune cells, macrophages or activation of arachidonic acid metabolism. The expression of these cytokines, oxidative free radicals and the activation of COX-2 enzymes are crucial targets for chronic inflammation. On the basis of established anti-inflammatory efficacy of Nerolidol, the primary study was further appraised to determine its efficacy against Freund’s complete adjuvant (CFA) rheumatoid model. Arthritis was persuaded by inoculation of 0.1mL CFA injection into left hind footpad of rats. Anti-arthritic potential of nerolidol (at 200, 400 and 800mg/kg doses) was assessed by measuring the paw volume, body weight, serum analysis, histopathological and radio-graphics of ankle joints. Expressions of cytokine’s panels like IL-10, IL-4, COX-2, NF- K β, TNF-α, IL-6, PGE-2 and IL-1β were determined by real time qPCR. Antioxidant enzyme analyses was calculated by measuring the SOD, POD and catalase activity from serum and equated with arthritic control group. Nerolidol prevented the body weight loss, stabilized the biochemical and haematological homeostasis and significantly reduced the paw volume. Furthermore, X-ray and histopathological assessment of ankle joints showed an improvement in the joint structure of rats treated with nerolidol. Besides that, over expression of gene pointers like TNF-α, IL-1β, IL-6, NF- K β, PGE-2 and COX-2 in CFA treated control rats were also reversed with nerolidol. This anti-arthritic mechanism was further supported by the increased level of IL-10, IL-4 and serum anti-oxidant activity. The present findings demonstrate that nerolidol reduce the adjuvant arthritis by down-regulating the proinflammatory cytokines and up-regulating the aforementioned anti-inflammatory cytokines and may be used as a therapeutic substance for the management of human rheumatoid arthritis.
BACE1 enzyme has been known a potential target involved in Alzheimer's disease (AD). Present research was focused on the principles of virtually screening, chemical synthesis and protease inhibitory effect of BACE1 enzyme via biaryl guanidine derivatives. In-silico based paradigm (ligand binding interaction within active domain of BACE 1 enzyme i.e., aspartate Asp32 and Asp228) a novel compound was synthesized and subsequently subjected to in-vitro and in-vivo evaluation. 1,3-di(isoquinolin-6-yl) guanidine was synthesized and found potent (IC50 6±0.56 µM) and active to arrest (99 %) β-secretase enzyme (FRET assay). Furthermore, it was found to improve novel object recognition test (RTI =56.55%) and Morris water maze test (32.26±3.45s) significantly (p<0.05). Enhanced pharmacokinetics and related properties (high iLOGP and Log S =-3.98) along with improved permeation to the blood brain barrier (BBB) (zero Lipinski violation) made it feasible to inhibit BACE1 as a novel therapeutic source to treat AD in future.
Synthesis of some novel 1-(3,4,5-trimethoxy)benzoyl-3- arylthiourea derivatives (1a-o) was accomplished in 2 steps. The synthetic route involves the reaction of 1-(3,4,5-trimethoxy)benzoyl chloride with potassium thiocyanate in 1:1 molar ratio in acetone to afford the corresponding isothiocyante followed by treatment with suitably substituted anilines. The structures of the products were established by elemental analyses, IR, ^1H- and ^{13}C-NMR, and mass spectroscopy and for 1b and 1m from single crystal X-ray diffraction data. All of the synthesized compounds (1a-o) were screened for antibacterial activity against gram positive and gram negative bacterial strains and were found to exhibit low activity towards the tested microorganisms, compared to chloramphenicol, the standard drug.
Background: Hyperlipidemia is a worth-mentioning risk factor in quickly expanding cardiovascular diseases, including myocardial infarction and, furthermore, in stroke. Methods: The present work describes the synthesis of phenolic derivatives 4a–e and 6a–c with the aim of developing antihyperlipidemic agents. The structures of the synthesized compounds were confirmed by spectroscopic data. The in silico docking studies were performed against human 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase enzyme (PDB ID: 1HWK), and it was observed that compounds 4a and 6a exhibited maximum binding affinity with target protein having binding energies −8.3 and −7.9 kcal, respectively. Results: Compound 4a interacts with amino acids Val805 with distance 1.89 Å and Met656, Thr558, and Glu559 with bonding distances 2.96, 2.70, and 2.20 Å, respectively. The in vivo antihyperlipidemic activity results revealed that compound 4a indicated minimum weight increment, ie, 20% compared with 35% weight increment with standard drug atorvastatin during 6 weeks of treatment. Moreover, increment in high-density lipoprotein cholesterol and decrease in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were more prominent in case of 4a compared to atorvastatin with P <0.05. The synthesized compounds were nontoxic and well tolerated because none of the mice were found to suffer from any kind of morbidity and death during 6 weeks of dosing. Conclusion: Based on our pharmacological evaluation, we may propose that compound 4a may act as a lead structure for the design and development of more potent antihyperlipidemic drugs. Keywords: phenolic derivatives, synthesis, antihyperlipidemic, in silico docking, HMG CoA reductase, atorvastatin
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Chili (Capsicum annuum L.) is the utmost significant cash crop of Pakistan. Annually, about 50 % chili yield is reduced by chili anthracnose disease caused by Colletotrichum capsici. The current study was conducted to explore the antifungal potential of plant extracts in comparison with commercial fungicides against C. capsici. Morphologically recognized strains of C. capsici were subjected to pathogenicity assay where strain CC-2 showed a highly virulent response. Results from in-vitro studies showed that Ginger (15% concentration) inhibited fungal mycelial growth and spore germination and results were comparable to Nativo and Antracol at 1000 ppm. From the protective and curative trials, among plant extracts, Ginger at 15 % showed maximum crop protective activity (84 %) and maximum curative activity (70 %). Consequently, among fungicides, Antracol at 1000 ppm showed highest crop protective activity (92 %) and maximum curative efficacy (96 %). The results of pot experiments showed that among the plant extracts, Ginger significantly inhibited C. capsici and increased plant growth while among fungicides, Antracol was found to be more effective than Nativo. PCA explored the correlation between growth parameters of chili plants treated with plant extracts and fungicides. Biochemical profiling and phytochemical characterization indicated the presence of tannins, phenols, terpenoids, flavonoids, alkaloids, reducing sugars and anthraquinones in ginger and chicory extracts. Ginger showed the highest DPPH scavenging activity (64.9 ± 1.85) as compared to chicory (54.6 ± 2.8). GC-MS analysis of plant extracts revealed the presence of various bioactive compounds including Ethanol, Acetone, 2-Butanone, Trichloromethane, 2-Butanone, 4-(4-hydroxy-3-methoxyphenyl)-, Gingerol, 1, 2-Benzenedicarboxylic acid, diisooctyl ester, Hexane, Glycerin, Sucrose, Hexadecanoic acid, methyl ester, 9-Octadecenoic acid (Z)-, methyl ester, 1,2-Benzenedicarboxylic acid, mono (2-ethylhexyl) ester, n-Hexadecanoic acid, cis-Vaccenic acid, 1-Monolinoleoylglycerol trimethylsilyl ether, and 9,12,15-Octadecatrienoic acid, 2-[(trimethylsilyl)oxy]-1-[[(trimethylsilyl)oxy] methyl]ethyl ester, (Z,Z,Z). FTIR analysis showed 12, 8 and 13 peak values respectively indicating the presence of important functional groups. NMR analysis showed 4 and 7 peak values of ginger and chicory extracts indicating the structures of functional groups. There is a need to test the disease suppressive potential of plant extracts under field conditions to manage other fatal plant pathogens.
To discover promising therapeutic agents, novel diaryl pyrimidine linked acyl thiourea derivatives (6a–j) were designed and synthesized via straightforward and multistep synthesis.
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