1,3,5-Pyrazoline Derivatives in CNS Disorders: Synthesis, Biological Evaluation and Structural Insights through Molecular Docking

2020 ◽  
Vol 19 (6) ◽  
pp. 448-465
Author(s):  
Himanshi Sharma ◽  
Pooja A. Chawla ◽  
Rohit Bhatia
Keyword(s):  
In Silico ◽  
Antidepressant Activity ◽  
Tail Suspension Test ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Hydroxyl Group ◽  
Spectral Techniques ◽  
Lipinski’S Rule

Background: Anxiety and oxidative stress are the common disorders prevailing in the modern age. Many new pyrazoline derivatives have been synthesized and patented, but there is still continuous research in progress to explore antidepressant and antioxidant potential of pyrazoline scaffold. Objective: The present work was carried out to synthesize, characterize and evaluate the pharmacological potential of 1,3,5-Pyrazoline derivatives. Methods: Ten new 1,3,5-Pyrazoline derivatives were synthesized and characterized by IR, 1HNMR and mass spectral techniques. The synthesized pyrazoline derivatives were investigated for their in vivo antidepressant activity by Tail Suspension Test (TST) and in vitro antioxidant activity by FRAP and DPPH assay methods. The docking studies and in silico ADME and toxicity characteristics were also evaluated. Results: Among the synthesized analogues, IVh showed the highest antidepressant activity with a significant reduction in the duration of immobility. The compound IVh emerged as the most potent antioxidant compound due to the presence of an electron releasing hydroxyl group. Docking studies of most potent compounds revealed good interaction points with the MAO-A enzyme. The compounds were found to obey Lipinski’s Rule of Five and displayed the least in silico toxicity profile. Conclusion: The synthesized compounds were found to possess great potential in decreasing the duration of immobility in Swiss albino mice and scavenging free radicals. These compounds may serve as new leads for further drug exploration.

Ester Prodrugs of Ketoprofen: Synthesis, In Vitro Stability, In Vivo Biological Evaluation and In Silico Comparative Docking Studies Against COX-1 and COX-2

2016 ◽  
Vol 13 (1) ◽  
pp. 41-57 ◽  
Author(s):  
Musa Ahmed ◽  
Faizul Azam ◽  
Abdul Gbaj ◽  
Abdulmottaleb E. Zetrini ◽  
Amna S. Abodlal ◽  
...  
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Cox 2 ◽  
In Vitro Stability ◽  
Ester Prodrugs ◽  
Cox 1

In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

2018 ◽  
Vol 21 (3) ◽  
pp. 215-221
Author(s):  
Haroon Khan ◽  
Muhammad Zafar ◽  
Helena Den-Haan ◽  
Horacio Perez-Sanchez ◽  
Mohammad Amjad Kamal
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
In Vivo Studies ◽  
In Vitro Assays ◽  
Chronic Obstructive ◽  
Lipoxygenase Inhibitors ◽  
Lipoxygenase Inhibition ◽  
In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

scholarly journals Oleuropein modulates over-proliferation of keratinocytes in mice with imiquimodmediated psoriasis and inhibits differentiation of TH17 cells through the JAK3/STAT3 axis

2020 ◽  
Author(s):  
Quan Shi ◽  
Qi He ◽  
Weiming Chen ◽  
Jianwen Long ◽  
Bo Zhang
Keyword(s):  
T Cells ◽  
In Silico ◽  
Th17 Cells ◽  
Skin Lesions ◽  
Docking Studies ◽  
Inflammatory Disorder ◽  
T Helper 17 ◽  
In Silico Docking

IntroductionOleuropein (OLP) is polyphenol obtained from olive oil; it is proved in Chinese traditional medicine for its use in disorders including autoimmune and inflammatory disorders. Psoriasis (PSR) is an autoimmune and inflammatory disorder triggered by T-helper-17 (Th17) cells.Material and methodsWe developed an imiquimod (IMQ)-mediated PSR model in mice to study the anti-inflammatory role of OLP in psoriasis. The mice were given 50 mg/kg and 100 mg/kg dose of OLP. Histology was done to assess the inflammation of lesions. Western blot analysis was done for JAK3/STAT3 in isolated T cells, expression of RORgt was done by RT-PCR. The In silico molecular docking studies were done for interaction of OLP with target protein STAT3 and JAK3.ResultsTreatment of OLP attenuated proliferation in IMQ-mediated keratinocytes, improved infiltration of CD3+ cells in the skin lesions and in CD4+ and CD8+ T cells and also ameliorated the levels of cytokines. In in vitro studies in isolated T cells, OLP blocked the differentiation of Th17 cells and also the levels of IL-17 and the JAK3/STAT3 pathway. The in silico docking showed that OLP had potential binding affinity with JAK3 and STAT3 which was parallel to in vivo and in vitro findings.ConclusionsOLP ameliorates psoriasis skin lesions by blocking Th17-mediated inflammation. OLP may be an interesting molecule for treating autoimmunity in psoriasis.

scholarly journals Antidepressant Potential of Lotus corniculatus L. subsp. corniculatus: An Ethnobotany Based Approach

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1299
Author(s):  
Fatma Tuğçe Gürağaç Dereli ◽  
Haroon Khan ◽  
Eduardo Sobarzo-Sánchez ◽  
Esra Küpeli Akkol
Keyword(s):  
Antidepressant Activity ◽  
Tail Suspension Test ◽  
Lotus Corniculatus ◽  
Antidepressant Effect ◽  
In Vivo Test ◽  
Aerial Parts ◽  
Test Models ◽  
Bioassay Guided Fractionation

As a Turkish traditional medicinal plant, aerial parts of Lotus corniculatus L. subsp. corniculatus (Fabaceae) are used as a painkiller, antihemoroidal, diuretic and sedative. In this study, the antidepressant potential of the plant has been attempted to clarify. Extracts with water, n-Hexane, ethyl acetate, and methanol were prepared respectively from the aerial parts. Antidepressant activity of the extracts were researched by using three different in vivo test models namely a tail suspension test, antagonism of tetrabenazine-induced hypothermia, ptosis, and suppression of locomotor activity and forced swimming test on male BALB/c mice and in vitro monoamine oxidase (MAO)-A and B inhibition assays. The results were evaluated through comparing with control and reference groups, and then active compounds of the active extract have been determined. Bioassay-guided fractionation of active fraction led to the isolation of three compounds and structures of the compounds were elucidated by spectroscopic methods. The data of this study demonstrate that the MeOH extract of the aerial parts of the plant showed remarkable in vivo antidepressant effect and the isolated compounds medicarpin-3-O-glucoside, gossypetin-3-O-glucoside and naringenin-7-O-glucoside (prunin) from the active sub-fractions could be responsible for the activity. Further mechanistic and toxicity studies are planned to develop new antidepressant-acting drugs.

scholarly journals Crambescin C1 Acts as A Possible Substrate of iNOS and eNOS Increasing Nitric Oxide Production and Inducing In Vivo Hypotensive Effect

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan A. Rubiolo ◽  
Emilio Lence ◽  
Concepción González-Bello ◽  
María Roel ◽  
José Gil-Longo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Active Site ◽  
In Silico ◽  
Hypotensive Effect ◽  
Docking Studies ◽  
No Production ◽  
Guanidine Alkaloids ◽  
Endogenous Substrate

Crambescins are guanidine alkaloids from the sponge Crambe crambe. Crambescin C1 (CC) induces metallothionein genes and nitric oxide (NO) is one of the triggers. We studied and compared the in vitro, in vivo, and in silico effects of some crambescine A and C analogs. HepG2 gene expression was analyzed using microarrays. Vasodilation was studied in rat aortic rings. In vivo hypotensive effect was directly measured in anesthetized rats. The targets of crambescines were studied in silico. CC and homo-crambescine C1 (HCC), but not crambescine A1 (CA), induced metallothioneins transcripts. CC increased NO production in HepG2 cells. In isolated rat aortic rings, CC and HCC induced an endothelium-dependent relaxation related to eNOS activation and an endothelium-independent relaxation related to iNOS activation, hence both compounds increase NO and reduce vascular tone. In silico analysis also points to eNOS and iNOS as targets of Crambescin C1 and source of NO increment. CC effect is mediated through crambescin binding to the active site of eNOS and iNOS. CC docking studies in iNOS and eNOS active site revealed hydrogen bonding of the hydroxylated chain with residues Glu377 and Glu361, involved in the substrate recognition, and explains its higher binding affinity than CA. The later interaction and the extra polar contacts with its pyrimidine moiety, absent in the endogenous substrate, explain its role as exogenous substrate of NOSs and NO production. Our results suggest that CC serve as a basis to develop new useful drugs when bioavailability of NO is perturbed.

New Benzodioxole-based Pyrazoline Derivatives: Synthesis and Anticandidal, In silico ADME, Molecular Docking Studies

2018 ◽  
Vol 16 (1) ◽  
pp. 82-92 ◽  
Author(s):  
Ahmet Özdemir ◽  
Belgin Sever ◽  
Mehlika Dilek Altıntop
Keyword(s):  
In Silico ◽  
Fungal Infections ◽  
Computational Study ◽  
Docking Studies ◽  
In Vivo Studies ◽  
Heme Group ◽  
In Silico Studies ◽  
Nih 3T3

Background: Azoles are commonly used in the treatment and prevention of fungal infections. They suppress fungal growth by acting on the heme group of lanosterol 14α-demethylase enzyme (CYP51), thus blocking the biosynthesis of ergosterol. </P><P> Objectives: Due to the importance of pyrazolines in the field of antifungal drug design, we aimed to design and synthesize new pyrazoline-based anticandidal agents. Methods: New pyrazoline derivatives were synthesized via the reaction of 1-(chloroacetyl)-3-(2- thienyl)-5-(1,3-benzodioxol-5-yl)-2-pyrazoline with aryl thiols. These compounds were evaluated for their in vitro antifungal effects on Candida species. Docking studies were performed to predict the affinity of the most effective anticandidal agents to substrate binding site of CYP51. Furthermore, MTT assay was performed to determine the cytotoxic effects of the compounds on NIH/3T3 mouse embryonic fibroblast cell line. A computational study for the prediction of ADME properties of all compounds was also carried out. Results: Compounds 5, 8, 10 and 12 were found as the most potent anticandidal agents against Candida albicans and Candida glabrata in this series with the same MIC values of ketoconazole and they also exhibited low toxicity against NIH/3T3 cells. Docking results indicated that all these compounds showed good binding affinity into the active site of CYP51. In particular, chloro substituted compounds 8 and 12 bind to CYP51 through direct coordination with the heme group. According to in silico studies, compound 8 only violated one parameter of Lipinski’s rule of five, making it a potential orally bioavailable agent. Conclusion: Compound 8 was defined as a promising candidate for further in vitro and in vivo studies.

scholarly journals Design, Sustainable Synthesis, Characterization, Antimicrobial Evaluation and in silico ADMET Prediction of New Functionalized Imidazolium Based Ionic Liquids

2020 ◽  
Vol 32 (8) ◽  
pp. 1972-1980
Author(s):  
Anas R. Al Johani ◽  
Saud M. Almutairi ◽  
Wael S. El-Sayed ◽  
Pramod K. Sahu ◽  
Praveen K. Sahu ◽  
...  
Keyword(s):  
Ionic Liquids ◽  
In Silico ◽  
Phenyl Group ◽  
Antimicrobial Activities ◽  
Spectral Techniques ◽  
In Silico Admet ◽  
Antimicrobial Evaluation ◽  
Ft Ir

A series of sixteen new ionic liquids (ILs) bearing imidazolium moiety were designed and synthesized under sustainable and green conditions which were confirmed by analytical and spectral techniques using 1H- & 13C-NMR, FT-IR, mass and elemental analysis. A panel of clinically isolated strains was used for in vitro inhibitory antimicrobial activities screening of synthesized ionic liquids. The results of antimicrobial assay showed that some of synthesized ionic liquids showed moderate to good activity. Among these ILs, ionic liquids 3, 4 and 5 (bearing alkyl chain with a phenyl group) significantly inhibited cell growth of strains. In this regard, these ionic liquids considered as promising antibacterial agents when compared with standard antibiotics. By encouraging in vitro antimicrobial screening, in silico ADMET evaluation has been performed and found excellent pharmacokinetic, bioavailability and toxicity profiles. Synthesized ionic liquids has found to be safe and non-toxic according to calculated in vivo computed LD50 values (2.49-2.80 mg/kg) for rat acute toxicity.

Synthesis and studies of thiazolidinedione–isatin hybrids as α-glucosidase inhibitors for management of diabetes

2021 ◽  
Vol 13 (5) ◽  
pp. 457-485
Author(s):  
Ramandeep Kaur ◽  
Rajnish Kumar ◽  
Nilambra Dogra ◽  
Ashok Kumar ◽  
Ashok Kumar Yadav ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Free Energy ◽  
Biological Evaluation ◽  
Free Energy Calculations ◽  
Standard Drug ◽  
Glucosidase Inhibitors ◽  
Cytotoxicity Studies ◽  
Cytotoxicity Assessment

Aim: Keeping in view the side effects associated with clinically used α-glucosidase inhibitors, novel thiazolidinedione–isatin hybrids were synthesized and evaluated by in vitro, in vivo and in silico procedures. Materials & methods: Biological evaluation, cytotoxicity assessment, molecular docking, binding free energy calculations and molecular dynamics studies were performed for hybrids. Results: The most potent inhibitor A-10 (IC50 = 24.73 ± 0.93 μM) was competitive in manner and observed as non-cytotoxic. A-10 possessed higher efficacy than the standard drug (acarbose) during in vivo biological testing. Conclusion: The enzyme inhibitory potential and safety profile of synthetic molecules was recognized after in vitro, in vivo, in silico and cytotoxicity studies. Further structural optimization of A-10 can offer potential hit molecules suitable for future investigations.

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