Synthesis, Pharmacological Evaluation, and Molecular Docking Studies of Novel Ibuprofen Amide Derivatives Containing Substituted 2-Aminothiophenes

Synthesis, pharmacology and preclinical evaluation of 11C-labeled 1,3-dihydro-2H-benzo[d]imidazole-2-ones for imaging γ8-dependent transmembrane AMPA receptor regulatory protein

Numerous phytochemical substances have been used by traditional medicinal systems to treat epileptic conditions. The antiepileptic properties of isolated phytochemicals from various natural medicinal sources are well documented. The underlying mechanisms behind how these isolated elements exhibit their anticonvulsant effects is particularly unknown. The goal of the current investigation is to suggest potential receptors for these phytoconstituents’ binding and predict their mechanisms of action, pharmacokinetic and toxicological properties. Molecular interactions were investigated utilizing in-silico molecular docking research with verified docking techniques to determine their potential binding mechanisms. Phytochemicals with favourable docking scores were further sent for in-silico ADME/T (Absorption Distribution Metabolism Excretion Toxicity) studies, so as to determine their pharmacokinetic and toxicological properties. The hit compound obtained from the study was validated using Molecular Dynamics simulations. Amentoflavone, a biflavone present in Rhus pyroides, emerged as the hit compound. It exhibited good binding affinity with majority of the target proteins, which indicates that it might act through multiple targeted mechanisms. It also exhibits high absorption and clearance rates, with low toxicity. Validation of the hit compound Amentoflavone with GABA B (Gamma Amino Butyric Acid receptor type B) was performed through molecular dynamics studies in order to gain deeper insights into their binding interactions. Amentoflavone was identified as the hit compound upon performing molecular docking, ADME/T and molecular dynamics studies. Additionally, validation of the identified hit molecule by pharmacological evaluation would prove its effectiveness as a potential antiepileptic agent.

BackgroundTraditionally, Grewia optiva is widely used for the treatment of many diseases like dysentery, fever, typhoid, diarrhea, eczema, smallpox, malaria and cough.MethodsShade-dried roots of G. optiva were extracted with methanol. Based on HPLC results, chloroform and ethyl acetate fractions were subjected to silica column isolation and four compounds: glutaric acid (V), 3,5 dihydroxy phenyl acrylic acid (VI), (2,5 dihydroxy phenyl) 3',6',8'-trihydroxyl-4H chromen-4'-one (VII) and hexanedioic acid (VIII) were isolated in pure form. Ellman’s assay was used to determine the anticholinesterase potential of isolated compounds while their antioxidant potential was estimated by DPPH and ABTS scavenging assays.ResultsAmongst the isolated compounds, VI and VII exhibited excellent percent inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) (83.23±1.11, 82.72±2.20 and 82.11±2.11, 82.23±1.21, respectively, at 1000 µg/mL) with IC50 of 76, 90, 78 and 92 µg/mL, respectively. Highest percent radicals scavenging against DPPH and ABTS (87.41±1.20 and 86.13±2.31) with IC50 of 64 and 65 µg/mL, respectively, were observed for compound VII. Molecular docking studies also supported the binding of compound VI and VII with the target enzyme. The para-hydroxyl group of the phenolic moiety is formed hydrogen bonds with the active site water molecule and the side chain carbonyl and hydroxyl residues of enzyme.ConclusionThe isolated compounds inhibited the DPPH and ABTS-free radicals, and AChE and BChE enzymes. It was concluded that these compounds could be used in relieving the oxidative stress and pathological symptoms associated with excessive hydrolysis of acetyl and butyryl choline. The results of the study were supported by docking studies for compounds VI and VII.

Schiff bases are bioactive compounds that have been synthesized by many researchers in recent years. They may also exhibit strong antimicrobial activities against various pathogenic microorganisms in both medicine and veterinary applications. The synthesis of new Schiff base-derived compounds remains of interest due to the increasing problem of antibiotic-resistance in clinical practice. Seven new Schiff base derivatives were synthesized, and their chemical structures were characterized using FT-IR, 1H/13C NMR, and LCMS-MS analyses. The antimicrobial activities of thesyntesized compounds against various pathogenic bacteria, yeasts, and fungi were evaluated using the disk-diffusion method, and their MIC values were also determined. In addition, one representative microorganisms from each class were selected for molecular docking studies. IFD analyses were performed for the 4f and 4g ligands using the dihydrofolate reductase enzyme. Spectroscopic analyses confirmed the structures of the synthesized compounds, revealing the presence of characteristic imine functionalities and validating the integrity of the molecular frameworks. Antimicrobial assays demonstrated that several derivatives exhibited measurable activity, with compounds 4f and 4g showing the most potent effects, displaying MIC values of 32 µg/mL against B. cereus and E. faecalis, respectively. Molecular docking studies further indicated that both 4f and 4g bind efficiently to the DHFR active site. These findings indicate that among the synthesized Schiff base derivatives, compounds 4f and 4g exhibit particularly promising antimicrobial activity, warranting further pharmacological evaluation and medicinal chemistry optimization.

A series of 3-{2-[1-acetyl-5-(substitutedphenyl)-4,5-dihydropyrazol-3-yl]hydrazinylidene}-1,3-dihydro-2H-indol-2-ones 24-43 was synthesized using an appropriate synthetic route and evaluated experimentally by the maximal electroshock test. These compounds were evaluated for antidepressant and antianxiety activities. The most active compound, 3-{2-[1-acetyl-5-(4-chlorophenyl)-4,5-dihydropyrazol-3-yl]hydrazinylidene}-1,3-dihydro-2H-indol-2-one 25, exhibited an ED50 of 13.19 mmol/kg, a TD50 of 43.49 mmol/kg, and a high protective index of 3.29, compared with the standard drug diazepam. To get insights into the intermolecular interactions, molecular docking studies were performed at the active site of the GABAA receptor and the MAO-A enzyme. Molecular docking studies are also in agreement with the pharmacological evaluation with potent compounds, exhibiting docking scores of -1.5180 and 0.7458 for the GABAA receptor and MAO-A, respectively. The 3D-QSAR analysis was carried out by Vlife MDS engine 4.3.1, and a statistically reliable model with good predictive power (r2 = 0.7523, q2 = 0.3773) was achieved. The 3D-QSAR plots gave insights into the structure-activity relationship of these compounds, which may aid in the design of potent benzopyrrole derivatives as anticonvulsant agents. So, our research can make a great impact on those medicinal chemists who work on the development of anticonvulsant agents.

Triazolothiadizepinylquinolines as potential MetAP-2 and NMT inhibitors: Microwave-assisted synthesis, pharmacological evaluation and molecular docking studies

The novel 1,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine framework, a structurally rigidified variant of the 1-phenylbenzazepine template, was synthesized via direct arylation as a key reaction. Evaluation of the binding affinities of the rigidified compounds across a battery of serotonin, dopamine, and adrenergic receptors indicates that this scaffold unexpectedly has minimal affinity for D1 and other dopamine receptors and is selective for the 5-HT6 receptor. The affinity of these systems at the 5-HT6 receptor is significantly influenced by electronic and hydrophobic interactions as well as the enhanced rigidity of the ligands. Molecular docking studies indicate that the reduced D1 receptor affinity of the rigidified compounds may be due in part to weaker H-bonding interactions between the oxygenated moieties on the compounds and specific receptor residues. Key receptor-ligand H-bonding interactions, salt bridges, and π-π interactions appear to be responsible for the 5-HT6 receptor affinity of the compounds. Compounds 10 (6,7-dimethoxy-2,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine) and 12 (6,7-dimethoxy-2-methyl-2,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine) have been identified as structurally novel, high affinity (Ki =5nM), selective 5-HT6 receptor ligands.

In vitro and in silico Screening of Bioactive Compounds from Jasminum subtriplinerve Blume as α-glucosidase Inhibitor

This study presents the synthesis of indolizine derivatives 4a–f employing a green chemistry protocol, designed to mitigate the environmental drawbacks of traditional synthetic routes while enhancing efficiency and sustainability in indolizine preparation. Reaction progress was tracked via thin‐layer chromatography, with products isolated by column chromatography. The structures of all purified compounds were verified using elemental analysis and spectroscopic methods, including FT‐IR, 1 H NMR, 13 C NMR, and LC‐MS. Molecular docking studies were conducted using Schrödinger Maestro in Standard Precision mode against four tuberculosis targets (4R9R, 7WVZ, 1ZVW, 6J2V) and three cancer‐associated targets (3D3P, 6Z4B, 5EW3). The compounds exhibited robust hydrogen bonding interactions and favorable docking scores against Mycobacterium tuberculosis and multiple cancer targets. Notably, compound 4e emerges as a promising candidate for further pharmacological evaluation as a potential multi‐target anti‐TB agent, while 4d shows promise against various anticancer targets. Furthermore, these compounds were evaluated for in vitro antifungal and antibacterial activities, with 4a , 4b , 4c , 4d , and 4f demonstrating superior efficacy against bacteria and fungi.

The synthesis of a new series of long‐chain arylpiperazine as serotoninergic ligands (FG 1‐18) is described. The combination of structural elements including heterocyclic nucleus, propyl chain, and 4,5‐dihydrothiazol‐2‐ylphenylpiperazines leads to the preparation of different derivatives tested for their affinity toward 5‐HT1A, 5‐HT2A, and 5‐HT2C receptors. The compounds with better affinity and selectivity binding profiles toward 5‐HT1A and 5‐HT2C (FG‐1, FG‐4, FG‐5, FG‐6, FG‐7, FG‐8, and FG‐18) are selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies are performed. The results of pharmacological studies show that compounds FG‐1, FG‐5, FG‐8, and FG‐6 exert antidepressant‐like effects, and FG‐1, FG‐18, FG‐6, and FG‐7 reveal also significant anxiolytic properties. Among the developed derivatives, the most promising compounds seem to be FG‐1, which exhibit antidepressant, anxiolytic, and anticonvulsant properties, FG‐7 and FG‐18 that show features as anxiolytic combine to a pro‐cognitive property and notable affinity and selectivity for 5‐HT2C receptor, respectively.

A series of compounds was synthesized and characterized to explore new antimicrobial agents. These compounds were evaluated by using the agar cup plate method. The most active compound exhibited a zone of inhibition 18±0.09 mm and 19±0.09 mm against E. Coli and S. aureus, respectively. To gain insights into the intermolecular interactions, molecular docking studies were performed at the active site of the glucosamine fructose 6 phosphate synthase (GlcN 6 p) enzyme (PDB Id: 1XFF). The results of the molecular docking studies are in agreement with the pharmacological evaluation with potent compounds, exhibiting docking scores of -11.2. However, deformability, B-factor and covariance computations showed a result that the most active compound favored molecular connections with the protein. Therefore, our research is important for the development of antimicrobial agents.

The manuscript describes design and synthesis of novel oxadiazolyl-2-oxoindolinylidene propane hydrazides as amide tethered hybrids of indole and oxadiazole and their evaluation for anti-inflammatory and analgesic activity. The compounds were synthesized following five step reaction to yield fifteen derivatives as 3-(5-substituted-1,3,4-oxadiazol-2-yl)-N'-[2-oxo-1,2-dihydro-3H-indol-3-ylidene]propane hydrazides. The final derivatives 3-[5-(4-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-dihydro-3H-indol-3-ylidene]propane hydrazide and 3-[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]-N'-[2-oxo-1,2-dihydro-3H-indol-3-ylidene]propane hydrazide were found to be highly promising molecules with severity index of 0.35 and 0.56, respectively, which is promising for an analgesic compound. The hydroxy and methyl substitution on phenyl ring system provided with active anti-inflammatory compounds having increase in reaction time of 84.11 and 83.17%, respectively compared to standard drug at 85.84%. Molecular docking studies exhibit comparable interaction with synthesized derivatives and standard drug having a dock score of -4.44 by the K-nearest neighbour genetic algorithm method.

The pro-inflammatory response triggered by influenza viruses can contribute to viral pneumonia, even death. The effect and mechanism of BaBaoWuDanYaoMo (BB) against influenza virus remains obscure. To predict its therapeutic targets via network pharmacology and verify the therapeutic effect and the mechanism of BB against influenza virus in vitro and in vivo. The potential active and underlying mechanism of BB in the treatment of influenza virus was predicted through network pharmacological strategies and Molecular Docking. The protective and anti-inflammatory effects of BB were determined by cytopathic effect (CPE), quantitative real-time PCR, mitochondrial membrane potentials and Western blotting assay in vitro. BALB/c mice were intranasally infected with A/PR/8/34 (H1N1) (PR8) and orally administrated BB (500 mg/kg, 250 mg/kg and 125 mg/kg) or oseltamivir daily. The normal group was orally administrated PBS for 5 days. Lung indexes, histological changes and cytokines were determined on the 6th day. BB could effectively inhibit A/Puerto Rico/8/1934 (H1N1), A/GZ/GIRD07/09 (H1N1), A/HK/Y280/97 (H9N2) and A/Aichi/68 (H3N2) with IC50 values of 116.5 ± 2.2, 59.86 ± 8.33, 102.87 ± 6.66 and 66.43 ± 6.785μg/mL, respectively. It could inhibit PR8-induced apoptosis and inhibit the expression of apoptosis markers (cleaved PARP). BB inhibited the mRNA expression of MCP-1/CCL-2, IL-6, CXCL-8/IL-8, TNF-α and CXCL-10/IP-10, and downregulated the protein expression of phosphorylated AKT/p38 and TLR3 in vitro. BB (500 and 250 mg/kg) could improve pulmonary histopathological changes, decrease the lung index and suppress the mRNA expression of CXCL1/KC, TNF-α, CXCL9/MIG and IL-1β in vivo. BB has a protective effect on PR8-induced acute lung injury (ALI) probably via inhibition of apoptosis process and interfering with TLR3, p38 MAPK and PI3K-AKT signaling pathways. This study provided a potential treatment for influenza from BB, and network pharmacology provided a strategy to explore active components and mechanism of TCMs against influenza virus infection.

Synthesis, pharmacological evaluation and molecular docking studies of pyrimidinedione based DPP-4 inhibitors as antidiabetic agents

Fusidic acid is a natural product antibiotic used clinically, primarily against staphylococcal infections. It has also exhibited antimycobacterial activity against Mycobacterium species, including Mycobacterium tuberculosis (Mtb). Novel C-21 fusidic acid amides were synthesized and evaluated for antimycobacterial activity in a drug repositioning approach for tuberculosis. The synthesized compounds exhibited good potency in MB7H9/CAS medium albeit showing low to no activity in MB7H9/ADC medium. The fusidic acid ethanamides were, generally, the most potent of the analogues evaluated for antimycobacterial activity (MIC90 < 10 μM) in the MB7H9/CAS medium. The lack of activity in the MB7H9/ADC medium was supported by strong binding interactions in the fusidic acid binding site of the human serum albumin (HSA) protein. The most potent antimycobacterial analogue was the N-(4-sulfamoylbenzyl)fusidic acid amide (1.26) with an MIC90 value of 2.71 μM.