Anti-inflammatory Discovery Research Articles

DEVELOPMENT OF 1H-INDAZOLE DERIVATIVES AS ANTI-INFLAMMATORY AGENTS USING COMPUTATIONAL METHODS

Objective: Due to the rising prevalence of disorders linked to inflammation, there is a greater emphasis on the discovery and development of anti-inflammatory drugs, with a focus on producing new structural compounds. Methods: In this research, molecular docking and Molecular Dynamics (MD) simulation study were carried out to evaluate the 1H-indazole analogs as potent anti-inflammatory agents. Results: The compounds containing difluorophenyl, para-toulene and 4-methoxyphenyl group shows significant binding results (9.11, 8.80 and 8.46 kcal/mol respectively) when docked with Cyclooxygenase-2 (COX-2) enzyme 3NT1. The results of the MD simulation indicated that test compound BDF was relatively stable in the COX-2 enzymes active sites. The compound BDF-3NT1 demonstrated substantial affinities for binding with all of its aimed targets following a dynamic Molecular Mechanics with Generalized Born Surface Area (MM-GBSA) analysis. Conclusion: In accordance to this study, newly developed 1H-indazole compounds have the potential for treating inflammation.

Editorial: Hot topic: anti-inflammatory drug discovery

Editorial: Hot topic: anti-inflammatory drug discovery

Synthesis of 2-Phenoxyacetic Acid Analogs for Evaluation of the Anti-inflammatory Potential and Subsequent <i>In Silico</i> Analysis

Several 2-phenoxyacetic acid derivatives and their isosteres were synthesized in moderate to high yield (57–96%) for searching newer and safer alternatives to these existing anti-inflammatory agents. The compounds were characterized by 1H-NMR, 13C-NMR and HRMS. The synthesized compounds have been subjected to in vitro anti-inflammatory activity using egg albumin denaturation and human red blood cell membrane stabilization methods. The compounds were also evaluated for their anti-inflammatory activity in the mice model. The synthesized compounds were subsequently subjected to docking analysis. The in vitro pharmacokinetic properties were analyzed by applying the pkCSM software and drug-likeness was checked by using Lipinski’s rule. Some synthesized esters and amides, like SM61, SM81, SM82, SM83, SM91 and SM101, were significantly more powerful as anti-inflammatory agents. The efficacies were correlated with their orientations in the binding pocket of the cyclooxygenase enzyme. The encouraging in vitro and in vivo activities, the optimum pharmacokinetic profile, and good drug-likeness indicated that these scaffolds could be considered for future discovery of newer nonsteroidal anti-inflammatory drugs (NSAIDs).

Natural Products from Marine-Derived Fungi with Anti-Inflammatory Activity.

Inflammation is considered as one of the most primary protective innate immunity responses, closely related to the body's defense mechanism for responding to chemical, biological infections, or physical injuries. Furthermore, prolonged inflammation is undesirable, playing an important role in the development of various diseases, such as heart disease, diabetes, Alzheimer's disease, atherosclerosis, rheumatoid arthritis, and even certain cancers. Marine-derived fungi represent promising sources of structurally novel bioactive natural products, and have been a focus of research for the development of anti-inflammatory drugs. This review covers secondary metabolites with anti-inflammatory activities from marine-derived fungi, over the period spanning August 2018 to July 2024. A total of 285 anti-inflammatory metabolites, including 156 novel compounds and 11 with novel skeleton structures, are described. Their structures are categorized into five categories: terpenoids, polyketides, nitrogen-containing compounds, steroids, and other classes. The biological targets, as well as the in vitro and in vivo screening models, were surveyed and statistically summarized. This paper aims to offer valuable insights to researchers in the exploration of natural products and the discovery of anti-inflammatory drugs.

Phenolic Acids Derivatives from Meehania Fargesii with Anti-inflammation Effects.

Utilizing systematic plant chemistry separation techniques, two previously unreported phenolic acids (1-2) and eighteen (3-20) phenolic acids were isolated from 70% ethanol extract of Meehania fargesii var. radicans (Vaniot) C.Y.Wu. The structures of the unreported compounds were determined using spectroscopic methods, including 1D and 2D NMR, ECD, and HR-ESI-MS. The activity of all isolated phenolic acids was evaluated for their ability to inhibit nitric oxide (NO) production in RAW264.7 cells activated by lipopolysaccharide (LPS). Among the isolated compounds, compounds 1 and 19 exhibited significant inhibitory activity against NO production in RAW264.7 cells, with higher concentrations being more active than the indomethacin, without displaying cytotoxicity. This study provides a basis for the application and development of M. fargesii and the discovery of natural anti-inflammatory drugs.

Anti-inflammatory Principles of the Plant Family Amaryllidaceae.

There is considerable interest in the utilisation of plants against inflammation. Over 50 species of the plant family Amaryllidaceae are known for such usage in traditional medicine. This review was undertaken to identify the chemical principles responsible for these anti-inflammatory effects. It describes the findings from in vitro, in vivo and in silico studies, as well as the probes made on the mechanisms of action. The literature search returned over 600 hits, of which around 130 were chosen for their relevance to the text. Over 140 compounds have thus far been screened for anti-inflammatory effects. These were mostly isoquinoline alkaloids but also included other classes of secondary metabolites such as chromones, flavonoids and triterpenoids. In vitro studies were carried out in mononuclear cells such as lymphocytes, monocytes, neutrophils and macrophages, against which no serious side effects were observed. The constituents were also effective against inflammation induced by physical and chemical stimuli in a variety of murine test subjects. Chief among the compounds were the isoquinoline alkaloids lycorine and narciclasine, which displayed potent effects against pain, swelling, asthma and arthritis, amongst others. From a mechanistic perspective, several of the compounds were shown to mediate in inflammatory pathways, notably via the modulation of both pro-inflammatory (such as NF-κB, TNF-α and IL-1) and anti-inflammatory (such as IL-10 and TGF-β) factors. Useful insights also emerged from active-site docking studies of some of the compounds. The Amaryllidaceae affords a rich and diverse platform for the discovery of potential anti-inflammatory drugs.

Development of Anti-Inflammatory Drug from Crataeva Nurvala: In Silico and In Vitro Approach

ABSTRACT Background: Crataeva nurvala, a medicinal plant with potential therapeutic properties, offers a promising avenue for the development of novel anti-inflammatory drugs. This study adopted a combined in silico and in vitro approach to investigate the anti-inflammatory potential of compounds derived from Crataeva nurvala. Materials and Methods: In the in silico phase, virtual screening and molecular docking analyses were conducted to identify bioactive compounds from Crataeva nurvala that could interact with key inflammatory targets. Subsequently, selected compounds were synthesized and subjected to in vitro experimentation. Cellular models were employed to assess the anti-inflammatory effects of Crataeva nurvala-derived compounds, focusing on the modulation of pro-inflammatory cytokine levels and the underlying signaling pathways. Results: Virtual screening and molecular docking led to the identification of several bioactive compounds with favorable interactions with inflammatory targets. In the in vitro experiments, treatment with Crataeva nurvala-derived compounds resulted in a significant reduction in pro-inflammatory cytokine production. Moreover, the compounds exhibited the ability to modulate inflammatory signaling pathways, further substantiating their anti-inflammatory potential. Conclusions: This study not only contributes to the development of effective anti-inflammatory drugs but also underscores the value of harnessing natural sources such as Crataeva nurvala for therapeutic interventions in inflammatory disorders. The dual-phase strategy presented here provides a robust framework for anti-inflammatory drug discovery and validation.

CXCR4/CXCL12 axis: "old" pathway as "novel" target for anti-inflammatory drug discovery.

Inflammation is the body's defense response to exogenous or endogenous stimuli, involving complex regulatory mechanisms. Discovering anti-inflammatory drugs with both effectiveness and long-term use safety is still the direction of researchers' efforts. The inflammatory pathway was initially identified to be involved in tumor metastasis and HIV infection. However, research in recent years has proved that the CXC chemokine receptor type 4 (CXCR4)/CXC motif chemokine ligand 12 (CXCL12) axis plays a critical role in the upstream of the inflammatory pathway due to its chemotaxis to inflammatory cells. Blocking the chemotaxis of inflammatory cells by CXCL12 at the inflammatory site may block and alleviate the inflammatory response. Therefore, developing CXCR4 antagonists has become a novel strategy for anti-inflammatory therapy. This review aimed to systematically summarize and analyze the mechanisms of action of the CXCR4/CXCL12 axis in more than 20 inflammatory diseases, highlighting its crucial role in inflammation. Additionally, the anti-inflammatory activities of CXCR4 antagonists were discussed. The findings might help generate new perspectives for developing anti-inflammatory drugs targeting the CXCR4/CXCL12 axis.

Anti-inflammatory activity of a new lactone isolated from the leaves of Ardisia crenata Sims.

One new lactone (1) named Ardisicreolide C, together with three saponin compounds, Ardisiacrispin B (2), Ardisicrenoside A (3), Ardisiacrispin A (4) were isolated and identified from the leaves of Ardisia crenata Sims. The structures of 1-4 were elucidated by 1D, 2D-NMR and HR-MS spectra and together with the published data. In view of structures with lactone moieties showed good anti-inflammatory activity, the anti-inflammatory effects of Ardisicreolide C on LPS-induced RAW264.7 cells were evaluated by enzyme linked immunosorbent assay (ELISA) method. As a result, Ardisicreolide C could reduce release of nitric oxide (NO), tumour necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 4 (IL-4) and interleukin 10 (IL-10) of the cell supernatant to exert anti-inflammatory activity. This indicates that the leaves as non-medicinal parts of Ardisia crenata Sims contain compounds with good anti-inflammatory activity, which provides a new direction for the discovery of anti-inflammatory drugs.

Maydistacins A-G, Terpestacin-type Sesterterpenoids with Anti-inflammatory Activity from the Phytopathogenic Fungus Bipolaris maydis.

Seven undescribed terpestacin-type sesterterpenoids, maydistacins A-G (1-7), along with two known congeners (8 and 9), were isolated from the phytopathogenic fungus Bipolaris maydis collected from the leaves of Hypericum longistylum. The structures of 1-7 were elucidated based on extensive spectroscopic analysis, chemical methods, NMR calculations with DP4+ probability analysis, and comparison of experimental and calculated electronic circular dichroism (ECD) calculations. In vitro anti-inflammatory effects of these compounds were tested in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Compound 1 exhibited inhibition of the production of nitric oxide in LPS-induced macrophages, with an IC50 value of 19 ± 2 μM. A dexamethasone control displayed an IC50 value of 6.7 ± 0.6 μM. Compound 1 is the first terpestacin-type sesterterpenoid reported to display anti-inflammatory activity and may provide a novel chemical scaffold for the discovery of new anti-inflammatory drugs.

Design and synthesis of pyrazole derivatives against neutrophilic inflammation

Neutrophils are the most abundant immune cells. However, neutrophil dysregulation leads to acute and chronic inflammation and is involved in various diseases. The aim of this study was to develop anti-inflammatory agents in human neutrophils. A drug screening was conducted on in-house compounds with the potential to inhibit the respiratory burst, which involves the generation of superoxide anions in human neutrophils. Bioisosteric replacement was then applied to design more active derivatives. The most potent inhibitors of superoxide anion generation activity were compounds 58 and 59, which had IC50 values of 13.30 and 9.06 nM, respectively. The inhibitory effects of 58 and 59 were reversed by H89, a PKA inhibitor. PDE selective screening indicated that the best inhibitory effects were PDE4B1 and PDE4D2, and the inhibitory activities were 83% and 85%, respectively, at a 10 μM concentration of 59. The final molecular simulation experiment highlighted the slightly different binding poses of 58 and 59 in the PDE4 active site. An in vivo pharmacokinetic study revealed that the half-life of 59 was approximately 79 min when using intravenous bolus administration. This work introduced a new class structure of PDE4 inhibitors resulting in potent neutrophil inactivation activity, with the aim of contributing to new anti-inflammatory drug discovery.

In Vitro Analyses of the Multifocal Effects of Natural Alkaloids Berberine, Matrine, and Tabersonine against the O'nyong-nyong Arthritogenic Alphavirus Infection and Inflammation.

O'nyong-nyong virus (ONNV) is a member of the reemerging arthritogenic alphaviruses that cause chronic debilitating polyarthralgia and/or polyarthritis via their tropism for the musculoskeletal system. Thus, the discovery of dual antiviral and anti-inflammatory drugs is a great challenge in this field. We investigated the effects of the common plant-derived alkaloids berberine (isoquinoline), matrine (quinolizidine), and tabersonine (indole) at a non-toxic concentration (10 μM) on a human fibroblast cell line (HS633T) infected by ONNV (MOI 1). Using qRT-PCR analyses, we measured the RNA levels of the gene coding for the viral proteins and for the host cell immune factors. These alkaloids demonstrated multifocal effects by the inhibition of viral replication, as well as the regulation of the type-I interferon antiviral signaling pathway and the inflammatory mediators and pathways. Berberine and tabersonine proved to be the more valuable compounds. The results supported the proposal that these common alkaloids may be useful scaffolds for drug discovery against arthritogenic alphavirus infection.

From the Bush to the Brain: Preclinical Stages of Ethnobotanical Anti-Inflammatory and Neuroprotective Drug Discovery—An Australian Example

The Australian rainforest is a rich source of medicinal plants that have evolved in the face of dramatic environmental challenges over a million years due to its prolonged geographical isolation from other continents. The rainforest consists of an inherent richness of plant secondary metabolites that are the most intense in the rainforest. The search for more potent and more bioavailable compounds from other plant sources is ongoing, and our short review will outline the pathways from the discovery of bioactive plants to the structural identification of active compounds, testing for potency, and then neuroprotection in a triculture system, and finally, the validation in an appropriate neuro-inflammatory mouse model, using some examples from our current research. We will focus on neuroinflammation as a potential treatment target for neurodegenerative diseases including multiple sclerosis (MS), Parkinson’s (PD), and Alzheimer’s disease (AD) for these plant-derived, anti-inflammatory molecules and highlight cytokine suppressive anti-inflammatory drugs (CSAIDs) as a better alternative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) to treat neuroinflammatory disorders.

Pyrazole appended hetero-hybrids: Bioisosteric design, synthesis, in silico and in vitro antibacterial and anti-inflammatory evaluations

In the present investigation, we adopted bioisosteric based design and synthesis of pyrazole appended "New Molecular Hybrids" to develop antibacterial agents that are efficient against multidrug resistant bacteria. Structure of the compounds were well characterized with the aid of spectroscopic and analytical techniques and, the selected derivatives were further confirmed through the single crystal X-ray analysis. Following an in-silico evaluation of the compounds' effectiveness through docking studies and ADMET calculations, we conducted an in vitro antibacterial assessment and found that 6c was the most effective, having an MIC of 5 µg/mL against P. aeruginosa and M. smegmatis, which was superior to standard drug ampicillin (15.6 and 6.25 µg/mL, respectively). SAR studies of compound 6c on protein 1kzn indicate that it has a binding energy of -8.64 kcal mol−1 via various noncovalent interactions. The anti-inflammatory potential screening revealed that, 6b was the most potent with an IC50 of 9.3 µg/mL, which is moderately active in comparison to standard aspirin (5.03 µg/mL). Thus, based on SAR studies, ADMET calculations, and in vitro studies, the new hybrids appear to be promising hits for the antibacterial and anti-inflammatory drug discovery endeavours.

Machine and Deep Learning in Anti-Inflammatory Drug Discovery

Machine and Deep Learning in Anti-Inflammatory Drug Discovery

Machine and Deep Learning in Anti-Inflammatory Drug Discovery

Machine and Deep Learning in Anti-Inflammatory Drug Discovery

Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization.

The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). In silico analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors. Enzymatic and cellular assays revealed the indoline derivative 43 as a notable 5-LOX inhibitor, guiding the design of new analogues. These compounds underwent extensive in vitro investigation revealing dual 5-LOX/sEH inhibitors, with 73 showing the most promising activity (IC50s of 0.41 ± 0.01 and 0.43 ± 0.10 μM for 5-LOX and sEH, respectively). When challenged in vivo in zymosan-induced peritonitis and experimental asthma in mice, compound 73 showed remarkable anti-inflammatory efficacy. These results pave the way for the rational design of 5-LOX/sEH dual inhibitors and for further investigation of their potential use as anti-inflammatory agents.

Multiple Logistic Regression Modeling of Compound Class as Active or Inactive Against COX-2 and Prediction on Designed Coxib Derivatives and Similar Compounds

The development of next generation non-steroidal anti-inflammatory drugs (NSAIDs) is one active area of research as inflammatory diseases continue to afflict over 1.5 billion people worldwide. The publicly available and computationally accessible chemical and biological data provide a wellspring of information for any research pursuit that could expedite the discovery of new anti-inflammatory drugs. Computational statistics is a handy tool in establishing quantitative relationship between the anti-inflammatory activity and the key molecular features that determine the compound’s medicinal property. In this work, Multiple Logistic Regression (MLogR) was employed to develop a mathematical model of the inhibitory activity of a compound on cyclooxygenase-2 (COX-2), an enzyme that facilitates the production of inflammatory prostanoids. The best model with hit ratio of 94% and 91% on the train and test set, respectively, was used to predict the classification (i.e. active or inactive) of newly designed coxib Derivatives and Similars obtained through similarity search. The predicted actives were further screened based on their quantitative estimate of druglikeness (QED), synthetic accessibility, and ADMETox properties. The selected top 15 hits have superior confidence as actives, are highly druglike and easy to synthesize, and generally possess outstanding drug profile.

Vitex trifolia as Cyclooxygenase-2 Inhibitors in Anti-Inflammatory Drug Discovery

Vitex trifolia as Cyclooxygenase-2 Inhibitors in Anti-Inflammatory Drug Discovery

Vitex trifolia as Cyclooxygenase-2 Inhibitors in Anti-Inflammatory Drug Discovery

Inflammation is involved in several stages of diseases such as cardiovascular diseases, asthma, diabetes, neurodegenerative diseases, or cancer. Cyclooxygenase-2 (COX-2) is an important enzyme that catalyzes the production of prostaglandins from arachidonic acid and has an important role in various inflammatory-related pathologies. The selective suppression of COX-2 over COX-1 is thought to be a useful approach for treating inflammation. Vitex trifolia is traditionally used for various inflammatory ailments, thus giving scope for anti-inflammatory studies. Since the action of Ethanol extract of Vitex trifolia (EEVT) on COX-2 has not been previously described. In this study, we further investigated the effect of Cyclooxygenase-2 inhibitory effects spectrophotometrically in ELISA readers and evaluated anti-inflammatory activity in the carrageenan-induced rat paw edema model. The edema volume was measured using a plethysmometer. The results showed that the EEVt (200, 400, and 800 mg/kg BW) had significant anti-inflammatory activity and the EEVt demonstrated a COX-2 Inhibitory effect. The percentage of COX-2 inhibition was 8,04%, 20,74%, 21,92%, and the percentage of inhibition of paw edema was 39,56%, 45,60%, and 40,56%, respectively. These findings suggest that Vitex trifolia leaves extracts to possess promising and remarkable anti-inflammatory activity, which is directed against the enzymatic activity of COX-2.