Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 24, Issue 3, 2025

Obesity is one of the main health problems worldwide and is associated with type 2 diabetes mellitus. In this context, butenolides and sulfonamides are known for their anti-obesity effects.

The present study aimed to synthesize a novel molecule containing the moieties hydroxybutenolide and sulfonamide [3-chloro-4-(p-chlorophenylsulfonylamino)-5-hydroxyfuran-2(5H)-one] (FS) and evaluate its metabolic effects in an obese mice model with metabolic syndrome.

4 groups of mice were divided into standard diet (ST), standard diet with added hydroxybutenolide (ST+FS), high-fat diet (HF), and high-fat diet with added hydroxybutenolide (HF+FS). Over 30 days, FS was administered by gavage at a dose of 70 mg/kg/day. Body weight, food consumption, glycemic tests, total serum cholesterol, high-density lipoprotein cholesterol, triacylglycerol, histological analyses, and gene expression by RT-PCR for the adipose tissue genes SIRT1, SIRT3, SIRT5, and NFKβ, were evaluated.

A decrease in body weight was observed after FS administration (ST+FS: -7.81±4.39 and HF+FS: -11.77±9.59), reducing glucose and fasting blood glucose in the treated group. Adipose tissue mass (ST+FS: 0.017 ±0.011; HF+FS: 0.062±0.017), white epididymal adipose tissue volume, triglycerides, as well as the adipocyte area, were lower for the HF+FS group. SIRT1 and SIRT3 expressions were higher in groups that received hydroxybutenolide.

Treatment with FS 3-chloro-4-(p-chlorophenylsulfonylamino)-5-hydroxyfuran-2(5H)-one improved metabolic profile and increased the SIRT1 expression.

The presence of insufficient insulin signaling in type 2 diabetes arises due to either insulin resistance or impaired insulin secretion, ultimately leading to elevated blood glucose levels, a condition known as hyperglycemia. Diabetes poses a pervasive worldwide challenge, with its prevalence steadily surging in both developed and developing nations. A promising avenue for improving the management of diabetes type 2 involves the exploration of glucokinase activators as an innovative therapeutic target. Notably, a recent breakthrough in this area has been the market approval granted by the Japanese FDA for the use of the innovative GKA, Dorzagliatin, in the treatment of diabetes type 2.

To augment the management of diabetes type 2 and mitigate the undesirable side effects linked to prolonged use of conventional medications, this research endeavor sought to create innovative glucokinase activators.

The ZINC database yielded a collection of 56 compounds, each showcasing a 40% structural similarity to 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid. These compounds, all featuring the distinctive indole core, were meticulously selected for further investigation. Structural illustrations were crafted using ChemBioDraw Ultra, and 1.5.6 AutoDock Vina was for molecular docking. The Swiss ADME algorithm facilitated online log P predictions, while the software PKCSM was utilized to forecast the toxicity profiles of the leading compounds. DFT analysis was done to ensure the stability of compounds by using Gaussian 16 quantum chemistry software and Mulliken charge distributions used to optimize molecular geometries.

Among all the compounds, RS33 and RS37 exhibited the highest affinities for GK receptors, with the docking scores of -8.93 and -8.44 kcal/mol, respectively. These compounds follow Lipinski’s Rule, indicating promising absorption and excretion profiles through the gastrointestinal tract. Compared to standard drugs Dorzagliatin (GKA) and MRK (co-crystallized ligand), both RS33 and RS37 demonstrate no AMES toxicity, skin sensitization, and hepatotoxicity. RS43 is the most stable compound as it has high ΔE, η, and χ in DFT analysis.

The novel-designed lead molecules demonstrate an enhanced pharmacokinetic profile, superior binding affinity, and minimal toxicity, based on computational study. These attributes make them promising candidates for further optimization as glucokinase activators.

Eleutherine bulbosa (Miller) Urb, popularly known as “marupazinho”, is frequently used in traditional medicine for treating various diseases, including hypertension, ulcers, constipation, and intestinal infection. However, there is little scientific knowledge available regarding the pharmacological effects of this species. Thus in vivo and in silico phytochemical studies are required to establish whether this plant has these effects. Further tests were necessary to evaluate the pharmacological activity of the compounds found in this plant, and demonstrate results related to the anti-inflammatory process, which will serve as the basis for future research in this area.

Therefore, our study aimed to determine the acute toxicity levels of the hexanoic fraction of the ethanolic extract of Eleutherine bulbosa (referred to as ExtHF) using adult zebrafish, with the determination of the LD50, behavioral and histopathological evaluations, as well as the anti-inflammatory potential of ExtHF, at different doses, in abdominal edema induced by carrageenan. The acute toxicity study and histopathological analysis in zebrafish showed that ExtHF has a high toxic potential, with an LD50 of 346.74 mg/kg. However, ExtHF showed an anti-inflammatory effect by inhibiting abdominal edema at all doses tested.

The inhibition rate of 66.2% and 62.4%, respectively, was observed with the 2.5 mg/kg dose, respectively, indicating that ExtHF is safe in terms of acute toxicity based on behavioral changes, mortality rate, and histopathological examination. Therefore, ExtHF has an acceptable level of safety for acute toxicity, defined by the analysis of behavioral changes, mortality, and histopathology, showing a significant anti-inflammatory effect in zebrafish at all doses, showing that ExtHF was very efficient in preventing the formation of edema, in addition, it was also revealed that ExtHF has a great effect in reversing the edema which is already installed.

Molecular docking studies revealed that the eleutherol molecule isolated from E. bulbosa has a dual inhibition profile against cyclooxygenase-1 and 2.

Chronic inflammatory diseases are rising, driving the search for effective natural treatments. Mentha pulegium L. and Pimpinella anisum L. (anise) exhibit notable anti-inflammatory properties individually, but their combined effects are less studied. This research evaluates the in vitro synergistic anti-inflammatory activities of their hydroalcoholic extracts. Phytochemical analysis confirmed the presence of flavonoids, tannins, and polyphenols in both extracts. Individually, they demonstrated significant activity (78.5% and 72.3%, respectively, at 10 g/L) compared to Diclofenac (62.3%). Their combination achieved 88.6% inhibition at the same concentration. These findings highlight their potential as natural anti-inflammatory agents.

The rise in chronic inflammatory diseases has increased interest in natural anti-inflammatory treatments. Mentha pulegium L. and Pimpinella anisum L. are well-known for their anti-inflammatory potential, attributed to their bioactive compounds like flavonoids and polyphenols. While the individual effects of these plants are established, their combined use is underexplored. This study evaluates the in vitro synergistic anti-inflammatory activity of hydroalcoholic extracts from these plants, aiming to offer an effective natural therapeutic alternative.

Hydroalcoholic extracts were prepared by maceration of both plants. Anti-inflammatory activity was assessed using the protein denaturation method with Diclofenac as a standard.

Phytochemical analysis identified flavonoids, alkaloids, tannins, glycosides, and polyphenols in Mentha pulegium, with an absence of saponins. Pimpinella anisum contained flavonoids, tannins, heterosides, and polyphenols. The extracts exhibited strong anti-inflammatory activity individually (78.5% and 72.3%, respectively, at 10 g/L) and even higher inhibition (88.6%) when combined, surpassing Diclofenac (62.3%).

The combination of Mentha pulegium and Pimpinella anisum extracts significantly enhanced anti-inflammatory activity compared to individual extracts, underscoring their potential as natural therapeutic alternatives to conventional treatments.