Gowhar Ali

The present study involves the synthesis, toxicity assessment and investigation of anti-nociceptive potential of two adamantane amino thiazole derivatives (AATD), including [N-((1s, 3s)-adamantan-1-yl)-4-(4-bromophenyl)thiazol-2-amine] (AATD1) and [2-(2-(((1s, 3s)-adamantan-1-yl)amino)thiazol-4-yl)-5-bromophenol] (AATD2). These derivatives were obtained through a multistep synthesis by reacting amantadine with benzoyl chloride. The amantadine substituted thiourea obtained on subsequent hydrolysis was cyclized with alpha bromo acetophenone. In this regard we aimed to synthesize novel compounds utilizing adamantane and thiazole rings, both being medicinally valuable moieties, in the hope of obtaining safe and potent analgesic agents. In acute toxicity study, the synthesized compounds were administered to the BALB/c mice (up to 800 mg/kg dose). No signs of any toxicity or mortality were observed at the tested doses. The sub-acute toxicity screening involved the intraperitoneal administration of 15, 30 mg/kg doses of compounds to BALB/c mice for 28 days followed by isolation of liver and kidneys for histopathological evaluation. Moreover, blood specimens were collected for determining biochemical parameters including LFTs and RFTs. The test compounds were further evaluated for their potential anti-nociceptive properties at 15 mg/kg and 30 mg/kg doses using phasic thermal nociceptive paradigms including tail immersion, hotplate tests and chemically induced tonic visceral nociceptive test like acetic acid induced writhing assay. The histological screening demonstrated no significant alterations, except mild sinusoidal dilatation, lymphocyte infiltration and inflammatory changes in the liver tissues. Slight tubular dilatations in the kidneys were observed at 30 mg/kg doses. Biochemical investigations correlated with the histological findings, indicating no significant elevation in the ALP, AST, ALT, BUN and serum creatinine. The synthesized compounds demonstrated considerable anti-nociceptive effects indicated by an increase in the latency time in tail immersion, hotplate tests. A decline in the number of writings was observed in acetic acid induced writhing test. The anti-nociceptive effect of compounds was impeded by opioid receptor antagonist, naloxone (1 mg/kg), and GABA receptor antagonist, pentylenetetrazole (15 mg/kg) which suggest the possible involvement of opioid and GABA receptors. Our findings suggest that our synthesized compounds are considerably safe and exhibit promising analgesic effects possibly mediated via opioidergic and GABAergic anti-nociceptive mechanisms.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, marked by cognitive impairment. Currently, the available treatment provides only symptomatic relief and there is a great need to design and formulate new drugs to stabilize AD. In the search for a new anti-Alzheimer’s drug, 3,5-bis(2-hydroxyethyl)-1,3,5-thiadiazinane-2-thione (THTT), a tetrahydro-2H-1,3,5-thiadiazine-2-thione derivative, was investigated against a scopolamine-induced Alzheimer’s model. The selected test compound was administered intraperitoneally in three doses (15 mg/kg, 30 mg/kg, and 45 mg/kg). The test compound exhibited an IC50 value of 69.41 µg/mL, indicating its ability to inhibit the acetylcholinesterase enzyme. An antioxidant DPPH assay revealed that the IC50 value of the test compound was 97.75 µg/mL, which shows that the test compound possesses antioxidant activity. The results of behavior tests including the Y-maze and elevated plus maze (EPM) show that the test compound improved short-term memory and spatial memory, respectively. Furthermore, in the Morris water maze (MWM) and light/dark model, the test compound shows improvements in learning and memory. Moreover, the results of histological studies show that the test compound can protect the brain against the harmful effects of scopolamine. Overall, the findings of our investigation suggest that our chosen test compound has disease-modifying and neuroprotective activities against the scopolamine-induced Alzheimer’s model. The test compound may be beneficial, subject to further elaborate investigation for anti-amyloid disease-modifying properties in AD.

The current study was designed to evaluate the 2-hydroxybenzohydrazide (HBH) as a drug having efficacy against pyrexia, inflammation, and nociception. Besides, the therapeutic effects of HBH on oxidative stress and C-reactive proteins were also evaluated. The pharmacological studies on HBH (20–60 mg/kg) were conducted using nociception, inflammation, and pyrexia standard models. Naloxone antagonism was performed to assess the possible involvement of opioidergic mechanisms. The antioxidant study was conducted on ABTS and DPPH assays using gallic acid as a standard. Moreover, the binding capability of HBH with enzymes cyclooxygenase-I/II (COX-I/II) was determined using molecular modeling analysis. The findings indicated that the HBH dose-dependently inhibited pain, inflammation, and pyrexia. The HBH has significant anti-nociceptive and anti-inflammatory activities at 60 mg/kg (^***p < 0.001), similar to the lower doses of diclofenac sodium (50 mg/kg) and tramadol (30 mg/kg). The HBH at 60 mg/kg reduced pyrexia as paracetamol (150 mg/kg). The HBH at 20–60 mg/kg doses declined the plasma C-reactive protein concentration. The mechanistic studies showed that the anti-nociceptive effect of HBH was antagonized by naloxone, indicating that the opioidergic mechanisms are involved. Furthermore, computational studies showed that the HBH exhibited an affinity for COX-I/II target receptors. The HBH significantly inhibited ABTS and DPPH radicals (IC₅₀ = 33.81 and 26.74 μg/ml). These results proposed that the HBH has significant antipyretic, anti-inflammatory, and anti-nociceptive activities involving opioidergic mechanism.

Indazolones possess interesting pharmacological activities. The search for indazole and indazolone-containing nuclei as drugs is an important research area of medicinal chemistry. The current work aims to evaluate a novel indazolone derivative against in vivo and in silico targets of pain, neuropathy, and inflammation. An indazolone derivative (ID) was synthesized and characterized using advanced spectroscopic techniques. Well-established animal models of abdominal constriction, hot plate, tail immersion, carrageenan paw edema, and Brewer’s yeast-induced pyrexia were employed for evaluating the potential of the ID at different doses (20–60 mg kg–1). Nonselective GABA antagonists, opioid antagonist naloxone (NLX) and pentylenetetrazole (PTZ), were employed to assess the potential role of GABAergic and opioidergic processes. The antineuropathic potential of the drug was evaluated using a vincristine-induced neuropathic pain model. In silico studies were performed to assess any possible interactions of the ID with pain target sites like cyclooxygenases (COX-I/II), GABAA, and opioid receptors. This study revealed that the selected ID (doses of 20–60 mg kg–1) efficiently hampered chemically and thermally induced nociceptive responses, producing significant anti-inflammatory and antipyretic effects. These effects produced by the ID were dose-dependent (i.e., 20–60 mg kg–1 and p range of 0.001–0.01) and significant in comparison to standards (p < 0.001). Antagonistic studies with NLX (1.0 mg kg–1) and PTZ (15.0 mg kg–1) revealed the involvement of the opioidergic mechanism rather than the GABAergic mechanism. The ID showed promising anti-static allodynia effects as well. In silico studies revealed preferential binding interactions of the ID with cyclooxygenases (COX-I/II), GABAA, and opioid receptors. According to the results of the current investigation, the ID may serve in the future as a therapeutic agent for the treatment of pyrexia, chemotherapy-induced neuropathic pain, and nociceptive inflammatory pain.

Background and Objective: Gabapentin is a commonly prescribed antiepileptic agent for seizures, which is also used for pain and addiction management. Due to growing evidence of its abuse liability, there has been an incentive to synthesise potentially useful gabapentin derivatives devoid of adverse effects. A gabapentin adduct with a fluoxetine moiety, GBP1F, was assessed for any sedative, cognitive, anxiolytic, or antidepressant-like actions in murine behavioral models. Materials and Methods: Selected groups of mice were used for each behavioral paradigm, and the effect of GBP1F (5, 10, and 15 mg/kg) was assessed using spontaneous locomotor activity, the tail suspension test, elevated plus maze test, and the Y maze test models. Immediately following behavioral experiments, postmortem striatal and hippocampal tissues were evaluated for the effect of GBP1F on concentrations of dopamine, DOPAC, HVA, serotonin, 5-HIAA, vitamin C, and noradrenaline using high performance liquid chromatography with electrochemical detection. Results: GBP1F induced a mild suppression of locomotor activity, ameliorated anxiety and depression-like behavior, did not alter cognitive behavior, and raised serotonin and 5-HIAA concentrations in the hippocampus and striatum. GBP1F also positively enhanced dopamine and vitamin C tissue levels in the striatum. Thus, GBP1F represents a compound with anxiolytic- and antidepressant-like effects though further studies are warranted at the molecular level to focus on the precise mechanism(s) of action.