Discovery of new non-acidic lonazolac analogues with COX-2 selectivity as potent anti-inflammatory agents

Background: The pyrazolines give the reactions of aliphatic derivatives, resembling unsaturated compounds in their behavior towards permanganate and nascent hydrogen. This nucleus has been associated with various biological activities including inflammatory. Thiazolinone is a heterocyclic compound that contains both sulfur and nitrogen atom with a carbonyl group in their structure.Thiazolinone and their derivatives have attracted continuing interest because of their various biological activities, such as anti-inflammatory, antimicrobial, anti-proliferative, antiviral, anticonvulsant etc. The aim of the research was to club pyrazoline nucleus with thiazolinone in order to have significantanti-inflammatory activity. The synthesized compounds were chemically characterized for the establishment of their chemical structures and to evaluate as anti-inflammatory agent. Method: In the present work, eight derivatives of substituted pyrazoline (PT1-PT8) were synthesized by a three step reaction.The compounds were subjected to spectral analysis by Infrared, Mass and Nuclear magnetic resonance spectroscopy and elemental analysis data. All the synthesized were evaluated for their in vivo anti-inflammatory activity. The synthesized derivatives were evaluated for their affinity towards target COX-1 and COX-2, using indomethacin as the reference compound molecular docking visualization through AutoDock Vina. Results: Compounds PT-1, PT-3, PT-4 and PT-8 exhibited significant anti-inflammatory activity at 3rd hour being 50.7%, 54.3%, 52.3% and 57% respectively closer to that of the standard drug indomethacin (61.9%).From selected anti-inflammatory targets, the synthesized derivatives exhibited better interaction with COX-1 and COX-2 receptor, where indomethacin showed docking score of -6.5 kJ/mol, compound PT-1 exhibited highest docking score of -9.1 kJ/mol for COX-1 and compound PT-8 having docking score of 9.4 kJ/mol for COX-2. Conclusion: It was concluded that synthesized derivatives have more interaction with COX-2 receptors in comparison to the COX-1 receptors because the docking score with COX-2 receptors were very good. It is concluded that the synthesized derivatives (PT-1 to PT-8) are potent COX-2 inhibitors.

Download Full-text

Evaluation of Anticonvulsant Activity of Dual COX-2/5-LOX Inhibitor Darbufelon and Its Novel Analogues

Scientia Pharmaceutica ◽

10.3390/scipharm89020022 ◽

2021 ◽

Vol 89 (2) ◽

pp. 22

Author(s):

Mariia Mishchenko ◽

Sergiy Shtrygol’ ◽

Andrii Lozynskyi ◽

Semen Khomyak ◽

Volodymyr Novikov ◽

...

Keyword(s):

Drug Design ◽

Anticonvulsant Activity ◽

Inflammatory Activity ◽

Significant Protection ◽

Protection Level ◽

Inflammatory Drugs ◽

Cox 2 ◽

Anti Inflammatory ◽

Target Agent

Neuroinflammation is an integral part of epilepsy pathogenesis and other convulsive conditions, and non-steroidal anti-inflammatory drugs (NSAIDs) present a potent tool for the contemporary search and design of novel anticonvulsants. In the present paper, evaluation of the anticonvulsant activity of the potential NSAID dual COX-2/5-LOX inhibitor darbufelone methanesulfonate using an scPTZ model in mice in dose 100 mg/kg is reported. Darbufelone possesses anticonvulsant properties in the scPTZ model and presents interest for in-depth studies as a possible anticonvulsant multi-target agent with anti-inflammatory activity. The series of 4-thiazolidinone derivatives have been synthesized following the analogue-based drug design and hybrid-pharmacophore approach using a darbufelone matrix. The synthesized derivatives showed a significant protection level for animals in the scPTZ model and are promising compounds for the design of potential anticonvulsants with satisfactory drug-like parameters.

Download Full-text

An Overview of Novel Bioactive Compounds with Potent Anti-Inflammatory Activity via Dual COX-2 and 5-LOX Enzyme Inhibition

Current Bioactive Compounds ◽

10.2174/1573407218666211230151139 ◽

2021 ◽

Vol 18 ◽

Author(s):

Roopal Mittal ◽

Shailesh Sharma ◽

Ajay Singh Kushwah

Keyword(s):

Bioactive Compounds ◽

Enzyme Inhibitors ◽

World Health Organisation ◽

The Body ◽

Inflammatory Activity ◽

World Health ◽

Quality Data ◽

The World ◽

Cox 2 ◽

Anti Inflammatory

Background: Inflammation is the earliest body defence mechanism in which the immune system recognises and counters the antigens and aids in healing the disease. The World Health Organisation suggests that inflammation is one of the greatest causes of death in the world. Inflammation could be acute or chronic due to the release of inflammatory mediators i.e. prostaglandins, leukotrienes due to mitogens, antigens or cytokines found in the body. Methods: Bibliographic database using pub med cites for peer-reviewed research articles with titles containing dual COX-2 and 5-LOX enzyme inhibitors, heterocyclic moieties, with AND Boolean operator's terms since last ten years of literature work. The quality papers containing the natural or synthetic lead compounds were extracted; the detailed study and conceptual framework attracted its attention. Results: Out of 127 research and review articles evaluated, 54 articles were cited to provide high quality data regarding pharmacoactive molecules having anti-inflammatory activity via dual COX-2/5-LOX inhibition. In addition, highlighting their in silico and experimental wet laboratory studies in increasing order over the past decade with the best illustration of dual enzyme inhibitory activity. Conclusion: This review gathered details of isolated bioactive compounds such as pyrazole, coumaperine, indoles, phenanthrene derivatives that have been significantly reported for anti-inflammatory activities.

Download Full-text

IN SILICO DESIGN AND MOLECULAR DOCKING STUDIES OF SOME 1, 2-BENZISOXAZOLE DERIVATIVES FOR THEIR ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY

International Journal of Current Pharmaceutical Research ◽

10.22159/ijcpr.2017.v9i3.18886 ◽

2017 ◽

Vol 9 (3) ◽

pp. 133

Author(s):

Sarath Sasi Kumar ◽

Anjali T

Keyword(s):

Molecular Docking ◽

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Analgesic Activity ◽

In Silico ◽

Docking Studies ◽

Inflammatory Activity ◽

Nicotinic Acetylcholine ◽

Cox 2 ◽

Anti Inflammatory

Objective: In silico design and molecular docking of 1,2-benzisoxazole derivatives for their analgesic and anti-inflammatory activity using computational methods.Methods: In silico molecular properties of 1,2-benzisoxazole derivatives were predicted using various software’s such as Chemsketch, Molinspiration, PASS and Schrodinger to select compounds having optimum drug-likeness, molecular descriptors resembling those of standard drugs and not violating the ‘Lipinski rule of 5’. Molecular docking was performed on active site of nicotinic acetylcholine receptor (PDB: 2KSR) for analgesic activity and COX-2 (PDB: 6COX) for anti-inflammatory activity using Schrodinger under maestro molecular modelling environment.Results: From the results of molecular docking studies of 1,2-benzisoxazole derivatives, all the compounds showed good binding interactions with Nicotinic acetylcholine receptor and COX-2. Compounds 4a and 4c showed highest binding scores (-7.46 and-7.21 respectively) with nicotinic acetylcholine receptor and exhibited maximum analgesic activity. Compound 4a showed highest binding score (-7.8) with COX-2 and exhibited maximum anti-inflammatory activity.Conclusion: All the derivatives of 1,2-benzisoxazole showed good analgesic and anti-inflammatory activity as predicted using molecular docking on respective receptors.

Download Full-text