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Objectives Migraine, typically occurs on one side of the head, lasts for hours to days. Trigemino-vascular system (TVS) plays a vital role in pain generation, with neurogenic inflammation and oxidative stress playing key roles in its pathophysiology. Methods This study aimed to investigate genistein's potential as anti-inflammatory and anti-oxidant agent in mitigating migraine pain. Genistein (20 and 50 mg/kg) was administered intraperitoneally (IP) to nitroglycerin (NTG; 10 mg/kg)-induced migraine model in rats. Behavioral analysis, antioxidant assay, immunohistochemistry (IHC), histopathological examination, ELISA, and RT-PCR were conducted to evaluate the antimigraine potential of genistein. key findings In-silico analysis showed genestien's ACE values of −4.8 to −9.2 Kcal/mol against selected protein targets. Genistein significantly reversed mechanical and thermal nociception, light phobicity, and head scratching; increased the intensities of GST, GSH, catalase; and down regulated lipid peroxidase (LPO) in cortex and trigeminal nucleus caudalis (TNC). It also reduced Nrf2, NF-kB, and IL6 expression, analyzed through IHC, improved histopathological features, and increased COX-2 and decreased PPAR-γ expressions, while RT-PCR analysis revealed increased PPAR-γ expressions in genistein-treated rats. Conclusion Genistein exhibited potent antioxidant and anti-inflammatory properties in migraine treatment, acting through multifactorial mechanisms by modulating the expression of numerous proteins in the region cortex and TNC. [ABSTRACT FROM AUTHOR]

Backgound: Alzheimer disease (AD) is a disastrous disease characterized by accretion of amyloid-beta plaques, neurofibrillary tangles inducing oxidative stress, loss of neuronal functions and continuous progression of cognitive impairment leading to severe dementia. Material and Methods: The newly synthesized benzimidazole derivative 4-chloro-3-(2-phenyl-1H-benzimidazole-1-sulfonyl) benzoic acid (CB) was evaluated for its anti-Alzheimer activity using in silico, in vivo, in vitro and molecular techniques (ELISA, WB & IHC). Results:In-silico studies revealed that CB has atomic contact energy values of −3.9 to −8.9 kcal/mol against selected targets. In vitro assay showed that CB caused acetylcholinesterase (AChE) and diphenyl-1-picrylhydrazyl inhibition. In-vivo findings revealed improvement in dementia as observed in the morris water maze test and Ymaze test. Amyloid-beta disaggregation, increased level of anti-oxidants, decreased expressions of inflammatory markers and enhanced cellular architecture were found in the cortex and hippocampus of treated rats in the histopathological examination, immunohistochemistry analysis, enzyme-linked immunosorbent assay and western blot analysis. Conclusions: This study revealed that CB possess different binding affinities with the Alzheimer-related targets and it possess anti-Alzheimer activity, mediated via AChE and amyloid-beta inhibition, anti-oxidant and anti-inflammatory pathways. [ABSTRACT FROM AUTHOR]

Benzimidazole is an important pharmacophore for clinically active drugs against inflammation and treatment of pain, however, it is associated with gastrointestinal side effects. Here we synthesized benzimidazole based agents with significant analgesic/anti‐inflammatory potential but with less gastrointestinal adverse effects. In this study, we synthesized novel, orally bioavailable 2‐mercaptobenzimidazole amino acid conjugates (4a–4o) and screened them for analgesic, anti‐inflammatory and gastro‐protective effects. The synthesized 2‐mercaptbenzimidazole derivatives were characterized for their structure using FTIR, 1H NMR and 13C NMR spectroscopic techniques. The 2‐mercaptobenzimidazole amino acid conjugates have found to possess potent analgesic, anti‐inflammatory and gastroprotective activities, particularly with compound 4j and 4k. Most of the compounds exhibited remarkable anti‐ulcer and antisecretory effects. Molecular docking studies were carried out to study the binding affinities and interactions of the synthesized compounds with target proteins COX‐2 (PDB ID: 3LN1) and H+/K+‐ATPase (PDB ID: 5Y0B). Our results support the clinical promise of these newly synthesized 2‐mercaptobezimidazol conjugates as a component of therapeutic strategies for inflammation and analgesia, for which the gastric side effects are always a major limitation. [ABSTRACT FROM AUTHOR]

Background: Carveol is a natural drug product present in the essential oils of orange peel, dill, and caraway seeds. The seed oil of Carum Carvi has been reported to be antioxidant, anti-inflammatory, anti-hyperlipidemic, antidiabetic, and hepatoprotective. Methods: The antidiabetic potential of carveol was investigated by employing in-vitro, in-vivo , and in-silico approaches. Moreover, alpha-amylase inhibitory assay and an alloxan-induced diabetes model were used for in-vitro and in-vivo analysis, respectively. Results: Carveol showed its maximum energy values (≥ -7 Kcal/mol) against sodium-glucose co-transporter, aldose reductase, and sucrose-isomaltase intestinal, whereas it exhibited intermediate energy values (≥ -6 Kcal/mol) against C-alpha glucosidase, glycogen synthase kinases-3β, fructose-1,6-bisphosphatase, phosphoenolpyruvate carboxykinase, and other targets according to in-silico analysis. Similarly, carveol showed lower energy values (≥ 6.4 Kcal/mol) against phosphoenolpyruvate carboxykinase and glycogen synthase kinase-3β. The in-vitro assay demonstrated that carveol inhibits alpha-amylase activity concentration-dependently. Carveol attenuated the in-vivo alloxan-induced (1055.8 µMol/Kg) blood glucose level in a dose- and time-dependent manner (days 1, 3, 6, 9, and 12), compared to the diabetic control group, and further, these results are comparable with the metformin positive control group. Carveol at 394.1 µMol/Kg improved oral glucose tolerance overload in rats compared to the hyperglycemic diabetic control group. Moreover, carveol also attenuated the glycosylated hemoglobin level along with mediating anti-hyperlipidemic and hepatoprotective effects in alloxan-induced diabetic animals. Conclusions: This study reveals that carveol exhibited binding affinity against different targets involved in diabetes and has antidiabetic, anti-hyperlipidemic, and hepatoprotective actions. [ABSTRACT FROM AUTHOR]

Objective(s): This study was designed to investigate various gastrointestinal effects of Manilkara zapota (Sapodilla), exploring its anti-diarrheal, anti-secretary, anti-spasmodic, anti-ulcer and antimotility potential. Materials and Methods: Antidiarrheal and anti-secretary activities were investigated using castor oil induced diarrhea and castor oil induced fluid accumulation. Isolated rabbit jejunum tissues (antispasmodic) were employed for in vitro experiments. Antiulcer, antimotility and molecular docking were performed using ethanol-HCl induced ulcer assay, charcoal meal transit time and Auto Doc Vina. Results: Mz.Cr exhibited protection against castor oil-induced diarrhea (P<0.05 vs. saline group) and dose-dependently inhibited intestinal fluid secretions (P<0.001 vs. castor oil group). Mz.Cr caused relaxation of spontaneous and K+ (80 Mm)-induced contractions with EC50 values of 0.11mg/ml (0.08-0.1, n=4) and 0.16 mg/ml (0.09-0.2, n=4) respectively (*P<0.05**P<0.01 ***P<0.001). It showed protective effect against gastric ulcers induced by ethanol-HCl (P<0.001 vs. saline group). Mz.Cr reduced distance travelled by charcoal meal (P<0.001 vs. saline group). Plant constituents: caffeoylquinic acid and methyl 4-O-galloylchlorogenate showed high binding affinities (E-value=-6.5 Kcal/mol) against histaminergic H2 receptors, H+/K+ ATPase pump and voltage gated L-type calcium channels, while possesses moderate affinities (E-value=8 Kcal/mol) against histaminergic H1, muscarinic M1, M3 and mu-opioid, whereas lower affinities (E-value=9.5 Kcal/mol) vs. calmodulin, adrenergic a1, phosphodiesterase enzyme and dopaminergic D2 receptors. Lupeol-3-acetate and ß-amyrin-3-(3'-dimethyl) butyrate observed weak affinities. Conclusion: In present study, M. zapota is reported to exhibits anti-diarrheal, anti-secretory, antispasmodic, anti-motility, anti-ulcer effects and computational binding affinities against gastrointestinal targets. [ABSTRACT FROM AUTHOR]

Novel bioactive compounds as synthetic analogs of the potent herbal medicines can be optimized as potential drug candidates for various neurologic disorders. This study was performed to investigate the newly synthesized dibenzylidene ketone derivatives: (2E,6E)‐2,6‐dibenzylidene cyclohexanone (A1K1) and (1E,4E)‐5‐(2,3‐dichlorophenyl)‐1‐(4‐methoxyphenyl)‐2‐methylpenta‐1,4‐diene‐3‐one (A2K2) and evaluate its potential anti‐Alzheimer's and anti‐depressant properties. Both the derivatives are chemically characterized by using HNMR and CNMR techniques. Auto Dock Vina program was used to investigate ligand‐protein affinity. Forced swim test, tail suspension test, open field test, Y‐maze test, and Morris water maze test (MWM) models were employed to evaluate anti‐depressant and anti‐Alzheimer's activity of dibenzylidene ketone derivatives in mice. Both A1K1 and A2K2 showed high binding affinities against various proteins involved in depression and Alzheimer's mechanisms like monoamine oxidase B, acetylcholinesterase, norepinephrine transporter 2, serotonin transporter, dopamine receptor, serotonin receptor modulator, and beta‐amyloid targets. A1K1 and A2K2 dose‐dependently (0.1–1 mg/kg) decreased immobility time, while increased swimming and climbing time of mice in forced swim test (FST). A1K1 and A2K2 decreased animal immobility time in TST. In the open field test, both A1K1 and A2K2 increased the number of ambulations and rearings. A1K1 and A2K2 dose‐dependently (0.5–1.0 mg/kg) increased spontaneous alternation behavior (%) and the number of entries of mice in Y‐maze test. In the MWM test, A1K1 and A2K2 decreased escape latency time. Overall, both in‐silico and in‐vivo investigations of A1K1 and A2K2, report their therapeutic potential for antidepressant and anti‐Alzheimer properties. Hence, these compounds possess potent neuroprotective properties and may be further evaluated for their therapeutic potential in various neurological disorders. [ABSTRACT FROM AUTHOR]

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Abstract: In this study different derivatives of ferrocene‐incorporated acyl ureas and homoleptic cadmium carboxylates were investigated for potential anticonvulsant, anxiolytic and sedative properties, using in‐silico and in‐vivo techniques. The molecular docking studies reveled that ferrocene compounds derivative 1‐(4‐bromobenzoyl)‐3‐(4‐ferrocenylphenyl) urea (PB1) and cadmium compounds derivative bis (diphenylacetato) cadmium (II) (DPAA) exhibit binding affinities against various neurotherapeutic molecular targets involved in epilepsy, anxiety, and sedation. Both PB1 and DPAA showed high binding affinities against protein targets like mammalian shaker voltage dependent potassium channel beta subunit complex, calcium release‐activated calcium channel, sodium channel 2A inactivation gate, human sodium/hydrogen exchanger regulatory factor, and gamma amino butyric acid A receptor associated protein. PB1 (2–10 mg/kg) and DPAA (1–5 mg/kg) delayed onset time of pentylenetetrazole‐induced myoclonic jerks and tonic‐clonic seizures in mice while decreased duration of tonic‐clonic seizures, determining the anticonvulsant effect of these compounds. PB1 and DPAA (0.5–1 mg/kg) exhibited anxiolytic effect by increasing time spent and number of animals entries into open arms, while decreasing time spent in dark compartment. Furthermore, PB1 (0.5–1 mg/kg) and DPAA (0.1–1 mg/kg) reduced onset time of sleep and increased duration time of sleep in mice, showing sedative effect. Taken together, our results indicate that aforementioned derivatives of ferrocene and cadmium are potent neurotherapeutic agents possessing anticonvulsant, anxiolytic and sedative properties. [ABSTRACT FROM AUTHOR]

We investigated possible anti-diabetic effect of ferrocene-based acyl ureas: 4-ferrocenyl aniline (PFA), 1-(4-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DPC1), 1-(3-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DMC1), 1-(2-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DOC1) and homoleptic cadmium carboxylates: bis (diphenylacetato) cadmium (II) (DPAA), bis (4-chlorophenylacetato) cadmium (II) (CPAA), using in silico and in vivo techniques. PFA, DPC1, DMC1, DOC1, DPAA and CPAA exhibited high binding affinities (ACE ≥ -350 Kcal/mol) against targets: aldose reductase, peroxisome proliferator-activated receptor γ, 11β-hydroxysteroid dehydrogenase-1, C-alpha glucosidase and glucokinase, while showed moderate affinities (ACE ≥ -250 Kcal/mol) against N-alpha glucosidase, dipeptidyl peptidase-IV, phosphorylated-Akt, glycogen synthase kinase-3β, fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase, whereas revealed lower affinities (ACE < -250 Kcal/mol) vs. alpha amylase, protein tyrosine phosphatases 1B, glycogen phosphorylase and phosphatidylinositol 3 kinase. In alloxan (300 mg/Kg)-induced diabetic mice, DPAA and DPC1 (1-10 mg/Kg) at day 1, 5, 10, 15, and 20th decreased blood glucose levels, compared to diabetic control group and improved the treated animals body weight. DPAA (10 mg/Kg) and DPC1 (5 mg/Kg) in time-dependent manner (30-120min.) enhanced tolerance of oral glucose overload in mice. DPAA and DPCI dose-dependently at 1, 5, and 10 mg/Kg decreased glycosylated hemoglobin levels in diabetic animals, as caused by metformin. These results indicate that aforementioned derivatives of ferrocene and cadmium possess anti-diabetic potential. [ABSTRACT FROM AUTHOR]

Diabetes is a complex endocrine and metabolic disorder. Continentalic acid is a natural drug product found in roots of Aralia continentalis (family Araliaceae), which used in traditional medicine for treatment of rheumatic arthritis, lumbag, lameness, inflammation, gastritis, nephritis and diabetes mellitus. This study is aim to investigate the continentalic acid anti-diabetic potential. In-silico, in-vitro , in-vivo and molecular techniques were used to investigate various effects of continentalic acid by Auto Doc Vina, α-amylase and α-glucosidase inhibitory assay and alloxan-induced diabetes rats model. In-silico results revealed that continentalic acid exhibits binding energy values of − 5 to − 9.3 Kcal/mol against selected targets. In-vitro assay showed that continentalic acid caused α-amylase and α-glucosidase enzymes inhibition. In-vivo finding exhibits that continentalic acid (50 mg/kg) decreased blood glucose level, body weight, oral glucose tolerance overload, glycosylated hemoglobin, triglycerides, total cholesterol, low density lipoprotein, aspartate transaminase, aspartate aminotransferase, alkaline phosphate, total bilirubin and increased high density lipoprotein (P < 0.05, P < 0.01, P < 0.001 vs. diabetic control group). In animals pancreas and liver tissues, continentalic acid enhanced glutathione-s-transferase, reduced glutathione, catalase and decreased lipid hydroperoxide level, improved cellular architecture in histopathological examination and decrease expression of inflammatory markers: cyclooxygenase 2, tumor necrosis factor alpha, phosphorylated-nuclear factor kappa B, prostaglandins E 2 , interleukin-18 and increased heme oxygenase-1, as evidenced in immunohistochemistry and enzyme-linked immunosorbent assay molecular investigations. This study shows that continentalic acid exhibited binding affinities against the different targets and anti-diabetic action, mediated possibly through α-amylase and α-glucosidase inhibition, anti-hyperlipidemic, hepatoprotection, antioxidant and anti-inflammatory pathways. [Display omitted] • This study revealed that continentalic acid exhibited binding energy values of −5 to −9.3 Kcal/mol against selected targets. • In-vitro studies, continentalic acid caused α-amylase and α-glucosidase inhibition which are helpful in management of DM. • In-vivo studies confirmed that continentalic acid has reduced glucose levels and HbA1C count but improved glucose tolerance. • Continentalic acid also possess the anti-hyperlipidemic, hepatoprotective, antioxidant and anti-inflammatory actions. • Hence, this study demonstrating that continentalic acid has a therapeutic potential in diabetes management. [ABSTRACT FROM AUTHOR]

In this study dibenzylidene ketone derivatives (2E,5E)-2-(4-methoxybenzylidene)-5-(4-nitrobenzylidene) cyclopentanone (AK-1a) and (1E,4E)-4-(4-nitrobenzylidene)-1-(4-nitrophenyl) oct-1-en-3-one (AK-2a) were newly synthesized, inspired from curcuminoids natural origin. Novel scheme was used for synthesis of AK-1a and AK-2a. The synthesized compounds were characterized by spectroscopic techniques. AK-1a and AK-2a showed high computational affinities (E-value > − 9.0 kcal/mol) against cyclooxygenase-1, cyclooxygenase-2, proteinase-activated receptor 1 and vitamin K epoxide reductase. AK-1a and AK-2a showed moderate docking affinities (E-value > − 8.0 kcal/mol) against mu receptor, kappa receptor, delta receptor, human capsaicin receptor, glycoprotein IIb/IIIa, prostacyclin receptor I2, antithrombin-III, factor-II and factor-X. AK-1a and AK-2a showed lower affinities (E-value > − 7.0 kcal/mol) against purinoceptor-3, glycoprotein-VI and purinergic receptor P2Y12. In analgesic activity, AK-1a and AK-2a decreased numbers of acetic acid-induced writhes (P < 0.001 vs. saline group) in mice. AK-1a and AK-2a significantly prolonged the latency time of mice (P < 0.05, P < 0.01 and P < 0.001 vs. saline group) in hotplate assay. AK-1a and AK-2a inhibited arachidonic acid and adenosine diphosphate induced platelet aggregation with IC50 values of 65.2, 37.7, 750.4 and 422 µM respectively. At 30, 100, 300 and 1000 µM concentrations, AK-1a and AK-2a increased plasma recalcification time (P < 0.001 and P < 0.001 vs. saline group) respectively. At 100, 300 and 1000 µg/kg doses, AK-1a and AK-2a effectively prolonged bleeding time (P < 0.001 and P < 0.01 vs. saline group) respectively. Thus in-silico, in-vitro and in-vivo investigation of AK-1a and AK-2a reports their analgesic, antiplatelet and anticoagulant actions. [ABSTRACT FROM AUTHOR]

In the present study, a series of new hydrazone and sulfonamide derivatives of 1,2,4-triazole were synthesized. Initially three 4-substituted-5-(2-pyridyl)-1,2,4-triazole-3-thiones ZE-1(a–c) were treated with ethyl chloroacetate to get the corresponding thioesters ZE-2(a–c), which were reacted with hydrazine hydrate to the respective hydrazides ZE-3(a–c). The synthesized hydrazides were condensed with different aldehydes and p-toluene sulfonylchloride to furnish the target hydrazone derivatives ZE-4(a–c) and sulfonamide derivatives ZE-5(a–c) respectively. All the synthesized compounds were characterized by FTIR, 1HNMR, 13CNMR and elemental analysis data. Furthermore, the new hydrazone and sulfonamide derivatives ZE-4(b–c) and ZE-5(a–b) were evaluated for their antiplatelet and anticoagulant activities. ZE-4b, ZE-4c, ZE-5a and ZE-5b inhibited arachidonic acid, adenosine diphosphate and collagen-induced platelets aggregation with IC50 values of 40.1, 785 and 10.01 (ZE-4b), 55.3, 850.4 and 10 (ZE-4c), 121.6, 956.8 and 30.1 (ZE-5a), 99.9, 519 and 29.97 (ZE-5b) respectively. Test compounds increased plasma recalcification time (PRT) and bleeding time (BT) with ZE-4c being found most effective, which at 30, 100, 300 and 1000 µM increased PRT to 84.2 ± 1.88, 142 ± 3.51, 205.6 ± 5.37 and 300.2 ± 3.48 s and prolonged BT to 90.5 ± 3.12, 112.25 ± 2.66, 145.75 ± 1.60 s (P < 0.001 vs. saline group) respectively. In silico docking approach was also applied to screen these compounds for their efficacy against selected drug targets of platelet aggregation and blood coagulation. Thus in silico, in vitro and in vivo investigations of ZE-4b, ZE-4c, ZE-5a and ZE-5b prove their antiplatelet and anticoagulant potential and can be used as lead molecules for further development. [ABSTRACT FROM AUTHOR]

Oxidative stress and inflammation play crucial roles in macro/microvascular complications. Phenolic compounds and their derivatives show promise as therapeutic agents for diseases like cancer, metabolic disorders, and cardiovascular diseases. With their antioxidant and anti-inflammatory properties, these compounds hold potential for mitigating vascular complications and improving overall health. This study aimed to assess the therapeutic potential of five 2-methoxy phenol derivatives (T2, T5, T6, T7, and T8) as antioxidants, anti-inflammatory agents, and vasorelaxants using in vitro, in silico, and in vivo approaches. Among all, T2 exhibited substantial antioxidant potential against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radicals with IC 50 (27.97 µg/mL), nitric oxide (NO) radicals (IC 50 = 34.36 µg/mL), hydroxyl (OH) radicals (IC 50 = 34.83 µg/mL) and Iron chelation (IC 50 = 24.32 µg/mL). Molecular docking analysis confirms that all derivatives, particularly T2, exhibit favorable binding energies with the target proteins, ACE (−7.7 Kcal/mol), ECE-1 (−7.9 Kcal/mol), and COX-1 (−7.8 Kcal/mol). All of the compounds demonstrated satisfactory physicochemical and pharmacokinetic characteristics, and showed minimal to no toxicity during in silico, in vitro , and in vivo assessments. In isolated aortic rings from Sprague Dawley rats, pre-contracted with high K+ (80 mM), T2 induced vasorelaxation in dose dependent manner and shifted calcium response curves to the right as compared to verapamil. T2 also showed substantial platelet aggregation inhibition in a dose dependent manner with IC 50 21.29 µM. All derivatives except T7 exhibited significant conservation of endogenous antioxidants i.e. catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and reduced glutathione (GSH) and significantly suppressed serum levels of inflammatory markers i.e. nitric oxide (NO), peroxides (TBARS), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). The study concludes that T2 has significant antioxidant potential and vasorelaxant effects with adequate pharmacokinetics, making it a promising lead compound for further molecular investigation in cardiovascular disorders. [Display omitted] • The study encompasses the synthesis of derivatives of methoxy phenol and contain a 2-methoxyphenoxy ring. • The study evaluated five 2-methoxy phenol derivatives as antioxidants, anti-inflammatory agents, and cardioprotective using in-vitro , in-silico, and in-vivo approaches. • T2 exhibited substantial antioxidant potential and favorable binding energies with target proteins ACE, ECE-1, and COX-1. • T2 induced vasorelaxation in dose-dependent manner and showed substantial platelet aggregation inhibition. [ABSTRACT FROM AUTHOR]

The rational design of small molecules that mimic key residues at the interface of interacting proteins can be a successful approach to target certain biological signaling cascades causing pathophysiological outcome. The A-Kinase Anchoring Protein, i.e. AKAP-Lbc, catalyses nucleotide exchange on RhoA and is involved in cardiac repolarization. The oncogenic AKAP-Lbc induces the RhoA GTPase hyperactivity and aberrantly amplifies the signaling pathway leading to hypertrophic cardiomyocytes. We took advantage of the AKAP-Lbc – RhoA complex crystal structure to design in silico small molecules predicted to inhibit the associated pathological signaling cascade. We adopted the strategies of pharmacophore building, virtual screening and molecular docking to identify the small molecules capable to target AKAP-Lbc and RhoA interactions. The pharmacophore model based virtual screening unveils two lead compounds from the TIMBAL database of small molecules modulating the targeted protein-protein interactions. The molecular docking analysis revealed the lead compounds’ potentialities to establish the essential chemical interactions with the key interactive residues of the complex. These features provided a road map for designing additional potent chemical derivatives and fragments of the original lead compounds to perturb the AKAP-Lbc and RhoA interactions. Experimental validations may elucidate the therapeutic potential of these lead chemical scaffolds to deal with aberrant AKAP-Lbc signaling based cardiac hypertrophy. [ABSTRACT FROM AUTHOR]