Design and synthesis of novel dithiazole carboxylic acid Derivatives: In vivo and in silico investigation of their Anti-Inflammatory and analgesic effects.

Inflammation is a complex set of interactions that can occur in tissues as the body's defensive response to infections, trauma, allergens, or toxic compounds. Therefore, in almost all diseases, it can be observed because of primary or secondary reasons. Since it is important to control and even eliminate the symptoms of inflammation in the treatment of many diseases, anti-inflammatory and analgesic drugs are always needed in the clinic. Therefore, the discovery of new anti-inflammatory/analgesic drugs with increased effectiveness and safer side effect profiles is among the popular topics of medicinal chemistry. Therefore, in this study, in order to synthesize and diversify new molecules, we focused on the N,N-dithiazole carboxylic acid core and linked it with the chalcone functional group. The final eleven molecules were analyzed via HRMS, 1H NMR, and 13C NMR. The antinociceptive effects of the test compounds were examined by tail-clip, hot-plate, and formalin methods in mice, while their anti-inflammatory activities were investigated by carrageenan-induced inflammation tests in rats. The motor activities of the experimental animals were evaluated using an activity-meter device. Obtained findings revealed that none of the test compounds (10 mg/kg) were effective in the tail-clip and hot-plate tests. However, compounds 4b, 4c, 4f, 4 h, and 4 k in the serial shortened the paw-licking times of mice in the late phase of the formalin test indicating that these compounds had peripherally-mediated antinociceptive effects. The same compounds, moreover, showed potent anti-inflammatory effects by significantly reducing paw edema of rats in the inflammation tests. To provide an approach to pharmacological findings regarding possible mechanisms of action, the binding modes of the most active compounds were investigated by in silico approaches. The results of molecular docking studies indicated that the anti-inflammatory and analgesic activities of the compounds might be related to the inhibition of both COX-1 and COX-2 isoenzymes. Findings obtained from in silico studies showed that 4 k, which was chosen as a model for its analogs in the series, forms strong bindings to the basic residues (Arg120, Tyr355), side pocket loop area and deep hydrophobic regions of the enzyme. Moreover, results of the molecular dynamics simulation studies revealed that ligand-COX enzyme complexes are quite stable. Obtained results of in vivo and in silico studies are in harmony, and all together point out that compounds 4b, 4c, 4f, 4 h, and 4 k have significant anti-inflammatory and analgesic activities with good ADME profiles. The potential of the derivatives, whose pharmacological activities were revealed for the first time in this study, as anti-inflammatory and analgesic drug candidates, needs to be evaluated through comprehensive clinical studies.

Catecholaminergic and Cholinergic Systems Mediate Beneficial Effect of Vortioxetine on Diabetes-Induced Neuropathic Pain.

The therapeutic potential of vortioxetine on mechanical hyperalgesia/allodynia was investigated in rats with streptozotocin-induced diabetes, and its possible mechanism of action was elucidated in this study. The obtained findings demonstrated that subacute vortioxetine treatment (5 and 10 mg/kg for 2 weeks) increased the reduced paw-withdrawal thresholds of diabetic rats both in the Randall-Selitto and Dynamic plantar tests. Moreover, the falling latencies of animals did not change in the Rota-rod assessments. These results suggest that vortioxetine administration significantly improved diabetes-induced hyperalgesia and allodynia responses in the rats without affecting their motor coordination. The vortioxetine (5 mg/kg)-induced antihyperalgesic and antiallodynic effects were reversed by AMPT, yohimbine, ICI 118,551, sulpiride and atropine pre-treatments, suggesting the involvement of the catecholaminergic system, α2- and ß2-adrenoceptors, D2/3 dopaminergic receptors and cholinergic muscarinic receptors in the exhibited pharmacological activity, respectively. Moreover, the data from the immunohistochemical studies indicated that the inhibition of c-Fos overexpression in dorsal horn neurons also mediates the beneficial effect of this drug. Vortioxetine induced no difference in plasma glucose levels in diabetic rats. If clinical studies confirm these findings, the concomitant beneficial effect of vortioxetine on mood disorders and its neutral activity profile on glycemic control may make it an alternative drug for the treatment of neuropathic pain.

Antidepressant-like effect of tofisopam in mice: A behavioural, molecular docking and MD simulation study.

BACKGROUND: Depression is a disease that affects millions of people worldwide, and the discovery and development of effective and safe antidepressant drugs is one of the important topics of psychopharmacology. OBJECTIVES: In this study, it was aimed to investigate the antidepressant-like activity potential of tofisopam, an anxiolytic drug with 2,3-benzodiazepine structure, and to elucidate the pharmacological mechanisms mediating this effect. METHODS: The antidepressant-like activity of tofisopam was investigated using tail suspension and modified forced swimming tests. Possible interactions of tofisopam with µ- and δ-opioid receptor subtypes were clarified by pharmacological antagonism, molecular docking and molecular dynamics simulation studies. RESULTS: Tofisopam (50 and 100 mg/kg) significantly shortened the immobility time of mice in both the tail suspension and the modified forced swimming tests. The drug, at the same doses, prolonged the duration of swimming and climbing behaviours measured in modified forced swimming tests. A dosage of 25 mg/kg was ineffective. Mechanistic studies showed that the pretreatment with p-chlorophenylalanine methyl ester (serotonin synthesis inhibitor; 4 consecutive days, 100 mg/kg), α-methyl-para-tyrosine methyl ester (catecholamine synthesis inhibitor; 100 mg/kg), naloxonazine (selective µ-opioid receptor blocker, 7 mg/kg) and naltrindole (a selective δ-opioid receptor blocker, 0.99 mg/kg) abolished the anti-immobility effect induced by the 50 mg/kg dose of tofisopam in the tail suspension tests. Our in silico studies supported the behavioural findings that the antidepressant-like effect of tofisopam is mediated by µ- and δ-opioid receptors. CONCLUSION: This study is the first to show that tofisopam has antidepressant-like activity mediated by the serotonergic, catecholaminergic and opioidergic systems.

Synthesis and Antinociceptive Effect of Some Thiazole-Piperazine Derivatives: Involvement of Opioidergic System in the Activity.

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, 1H-NMR, 13C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a-3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a-3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system.

5-HT1A Serotonergic, α-Adrenergic and Opioidergic Receptors Mediate the Analgesic Efficacy of Vortioxetine in Mice.

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30-180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.

Synthesis, characterization, and in vivo pharmacological evaluation of novel mannich bases derived from 1,2,4-triazole containing a naproxen moiety.

A new series of 1,2,4-triazole-5-thione Mannich derivatives containing a naproxen moiety (1a-o) was designed and synthesized to create naproxen analogs, with the aim of developing novel anti-inflammatory/analgesic agents with improved safety profiles. Target compounds were synthesized using classical Mannich reaction (i.e. one-pot three component condensation reaction), by reacting triazole molecule (1), formaldehyde, and diverse secondary amines in ethanol. The synthesized compounds were investigated using FT-IR, 1H NMR, 13C NMR and mass spectroscopies, as well as elemental analysis. Compounds were then evaluated for their potential antinociceptive and anti-inflammatory activities using some validated invivo methods. Data obtained from acetic acid induced-writhing and carrageenan-induced paw edema tests revealed that all compounds induced peripherally-mediated antinociceptive activities, as well as notable anti-inflammatory effects. The results of hot-plate and tail-clip tests indicated that compounds 1a, 1b, 1c, 1d, 1g, and 1j have also centrally-mediated antinociceptive activities in addition to their peripherally-mediated effects. Molecular docking studies were performed to investigate the putative binding modes of the interactions between all compounds and COX-1/COX-2 enzymes using AutoDock Vina software. Docking of the compounds into the COX-2 active site produced binding interactions that are essential for COX-2 inhibitory activity. None of the compounds in the serial, except for 1m and 1j, induced significant gastrointestinal irritation. Overall, the results indicated that triazol Mannich bases bearing a naproxen moiety potentially represent a novel class of antinociceptive and anti-inflammatory agent with an improved gastric safety profile.

Catecholaminergic and opioidergic system mediated effects of reboxetine on diabetic neuropathic pain.

RATIONALE: Current data indicate that the noradrenergic system plays a critical role in neuropathic pain treatment. Notably, drugs that directly affect this system may have curative potential in neuropathy-associated pain. OBJECTIVES: The aim of this study was to evaluate the potential therapeutic efficacy of reboxetine, a potent and selective noradrenaline reuptake inhibitor, on hyperalgesia and allodynia responses in rats with experimental diabetes. Furthermore, mechanistic studies were performed to elucidate the possible mode of actions. METHODS: Experimental diabetes was induced by a single dose of streptozotocin. Mechanical hyperalgesia, mechanical allodynia, thermal hyperalgesia, and thermal allodynia responses in diabetic rats were evaluated by Randall-Selitto, dynamic plantar, Hargreaves, and warm plate tests, respectively. RESULTS: Reboxetine treatment (8 and 16 mg/kg for 2 weeks) demonstrated an effect comparable to that of the reference drug, pregabalin, improving the hyperalgesic and allodynic responses secondary to diabetes mellitus. Pretreatment with phentolamine, metoprolol, SR 59230A, and atropine did not alter the abovementioned effects of reboxetine; however, the administration of α-methyl-para-tyrosine methyl ester, propranolol, ICI-118,551, SCH-23390, sulpiride, and naltrindole significantly inhibited these effects. Moreover, reboxetine did not induce a significant difference in the rat plasma glucose levels. CONCLUSIONS: Our findings indicate that the antihyperalgesic and antiallodynic effects of reboxetine are mediated by the catecholaminergic system; ß2-adrenoceptors; D1-, D2/D3-dopaminergic receptors; and δ-opioid receptors. The results suggest that this analgesic effect of reboxetine, besides its neutral profile on glycemic control, may be advantageous in the pharmacotherapy of diabetic neuropathy-induced pain.

Antiamnesic effects of tofisopam against scopolamine-induced cognitive impairments in rats.

In this study, we investigated the potential therapeutic effects of tofisopam, a 2,3-benzodiazepine derivative anxiolytic, on cognitive deficits in rats with scopolamine-induced amnesia. Cognitive performance of the rats was investigated by using the Morris water maze and passive avoidance tests. Changes in motor activity were assessed by using the activity cage and Rota-rod tests and then morphological changes in the hippocampus were assessed via immunohistochemical stainings. The results indicated that scopolamine impaired learning and memory parameters in rats. Worsened cognitive performance, neuronal loss, and decreased hippocampal synaptophysin, Ki-67, and glial fibrillary acidic protein density were observed. Tofisopam administration at a dose of 50 mg/kg for seven days improved the impaired cognitive performance, enhanced the attenuated synaptic transmission in the hippocampus, increased proliferation in subgranular zones, and improved the decrease in astrocytes in amnesic rats. These findings point out the anti-amnesic effects of tofisopam with concomitant improvements in the hippocampal synaptogenesis, neurogenesis, and glial plasticity, for the first time. Presented beneficial effects of tofisopam on cognitive dysfunctions may have a notable clinical value considering the fact that one of the most important side effects of 1,4-benzodiazepines, which are classical anxiolytic drugs, is amnesia. However, these preclinical results need to be confirmed with further clinical studies, first.

Beneficial effect of mirtazapine on diabetes-induced hyperalgesia: involvement of TRPV1 and ASIC1 channels in the spinal cord and dorsal root ganglion.

OBJECTIVES: Neuropathic pain reduces the life qualities of patients with Diabetes mellitus. Clinical guidelines recommend relief in diabetic neuropathic pain through the use of some antidepressants, anticonvulsants, opioids as well as capsaicin cream or lidocaine patches. However, since the majority of patients do not or partially respond to current treatments, there is a growing necessity for new drugs increasing the pain relief in patients with diabetes. Therefore, based on the therapeutic potential of antidepressants on neuropathic pain, we investigated the promising antihyperalgesic effect of mirtazapine (MRT) in painful diabetic neuropathy. METHODS: Experimental diabetes was induced in rats by single intraperitoneal injection of 55 mg/kg dose of streptozocin (STZ). After 4 weeks of injection of STZ, MRT was administrated for 14 days at 40 mg/kg dose. Randall-Selitto and Hargreaves tests were applied for paw-withdrawal threshold and paw-withdrawal latency measurement. TRPV1 and ASIC1 expressions measured by Western blot in dorsal root ganglion and spinal cord. RESULTS: Administration of MRT significantly improved both of the decreased paw-withdrawal threshold and shortened the paw-withdrawal latency of diabetic rats, respectively. Besides, increased levels of TRPV1 and ASIC1 channels in dorsal root ganglion and spinal cord of diabetic rats, evaluated by Western blot method, were decreased following the MRT treatment. DISCUSSION: These data show, for the first time, that MRT has beneficial effects against diabetes-induced hyperalgesia, and that suppressive effect of this drug on TRPV1 and ASIC1 levels, which are increased in diabetic rats, may be some of the pharmacological mechanisms underlying the exhibited antihyperalgesic effect of MRT.

Mirtazapine suppresses sterile inflammation through NLRP3-inflammasome in diabetic rat kidney.

AIM: The aim of this study was to investigate the effects of mirtazapine, which is anti-oxidative and antidepressant agent, on the kidney damage caused by diabetes mellitus. MATERIALS AND METHODS: The rats were randomly divided into three groups (n = 7 animals in each group). The group I rats served as control and they received 0.1 mol/L of citric acid buffer (pH = 4.5) as vehicle. The rats in the group II (DM group) and III (DM + Mirtazapine-treated group) were treated intraperitoneally with a single dose of 55 mg/kg streptozotocin dissolved in 0.1 mol/L of citric acid buffer. Group III rats were also received 20 mg/kg/day of mirtazapine for 2 weeks. At the end of the experiment, the rats were sacrificed. Then, the kidneys were excised and prepared for microscopical examination. caspase-1 and NLRP3 proteins were examined using immunohistochemistry and western blotting. The TUNEL assay for apoptosis and ELISA assay for IL-1ß were performed. RESULTS: Histological examination showed that mirtazapine administration has an ameliorative effect on DM-induced kidney damage. Immunohistochemical and western blot analyses showed that NLRP3 and caspase-1 expressions were increased in the DM group according to the control group and the mirtazapine administration decreased these expressions. The intraglomerular and tubular TUNEL-positive cells were numerous in the DM group compared to the mirtazapine-treated group. The level of IL-1ß was highest in the DM group, and decreased significantly in the mirtazapine-treated group. CONCLUSION: In this study, 20 mg/kg/day mirtazapine administration for 2 weeks reduced NLRP3 and caspase-1 expressions and IL-1ß level in the diabetic rat kidneys. These results suggesting that mirtazapine may be useful in the treatment of DM and other metabolic diseases. Advanced molecular studies are needed to elucidate the exact effects of mirtazapine on NLRP3 inflammasome.

Synthesis of Novel Benzazole Derivatives and Evaluation of Their Antidepressant-Like Activities with Possible Underlying Mechanisms.

Novel benzazole derivative compounds 4a⁻4h were obtained by the reaction of corresponding 2-(benzazol-2-ylthio)acetohydrazide and appropriate 4-substituted benzaldehydes. The chemical structures of the synthesized compounds were elucidated by FT-IR, ¹H-NMR, 13C-NMR and LCMS spectroscopic methods. Antidepressant-like effects of the compounds were evaluated by tail suspension test (TST) and modified forced swimming tests (MFST). Moreover, locomotor activities of the animals were assessed by an activity cage apparatus. In the series, compounds 4a, 4b, 4e and 4f (at 50 mg/kg) significantly decreased the immobility time of mice in both of the TST and MFST. The same compounds prolonged the swimming time of animals in MFST without any change in the climbing duration. These data indicated that compounds 4a, 4b, 4e and 4f possess significant antidepressant-like activities. Moreover, pre-treatments with p-chloro-phenylalanine methyl ester (an inhibitor of serotonin synthesis), NAN-190 (a 5-HT1A antagonist), ketanserin (a 5-HT2A/2C antagonist), and ondansetron (a 5-HT3 antagonist) reversed the exhibited pharmacological effects. Results of the mechanistic studies suggested the involvement of serotonergic system and contributions of 5-HT1A, 5-HT2A/2C and 5-HT3 receptors to the antidepressant-like effects of compounds 4a, 4b, 4e and 4f. Furthermore, unchanged locomotor activity of mice following the administrations of these four derivatives confirmed that the presented antidepressant-like effects are specific.

The Effect of Agomelatine Treatment on Diabetes-Induced Cognitive Impairments in Rats: Concomitant Alterations in the Hippocampal Neuron Numbers.

Researches that are related to the central nervous system complications of diabetes have indicated higher incidence of cognitive disorders in patients. Since the variety of nootropic drugs used in clinics is limited and none of them consistently improves the outcomes, new and effective drug alternatives are needed for the treatment of diabetes-induced cognitive disorders. Based on the nootropic potential of agomelatine, the promising efficacy of this drug on cognitive impairments of diabetic rats was investigated in the current study. Experimental diabetes model was induced by streptozotocin. After development of diabetes-related cognitive impairments in rats, agomelatine (40 and 80 mg/kg) was administrated orally for two weeks. Cognitive performance was assessed by Morris water-maze and passive avoidance tests. Then, the total numbers of neurons in both dentate gyrus and Cornu Ammonis (CA) 1⁻3 subfields of the hippocampus were estimated by the optical fractionator method. Agomelatine treatment induced notable enhancement in the learning and memory performance of diabetic rats. Moreover, it reversed the neuronal loss in the hippocampal subregions of diabetic animals. Obtained results suggest that agomelatine has a significant potential for the treatment of diabetes-induced cognitive impairments. However, therapeutic efficacy of this drug in diabetic patients suffering from cognitive dysfunctions needs to be confirmed by further clinical trials.

Antihyperalgesic Activity of Atomoxetine on Diabetes-Induced Neuropathic Pain: Contribution of Noradrenergic and Dopaminergic Systems.

Atomoxetine is a selective noradrenaline reuptake inhibitor drug. Based on the knowledge that agents increasing monoamine levels in the central nervous system have therapeutic potential for neuropathic pain, it is planned to investigate the possible efficacy of atomoxetine on diabetes-induced hyperalgesia, in this study. Randall-Selitto (mechanical noxious stimuli) and Hargreaves (thermal noxious stimuli) tests were used to evaluate nociceptive perception of rats. Obtained data indicated that streptozotocin-induced diabetes causes significant decreases in the paw withdrawal threshold and paw withdrawal latency values of the animals, respectively. However, atomoxetine administered at 3 mg/kg/day for 7 and 14 days improved these diabetes-induced hyperalgesia responses. Furthermore, antihyperalgesic activity was antagonized with α-methyl-para-tyrosine methyl ester, phentolamine, propranolol, and sulpiride pre-treatments. The same effect was not reversed, however, by SCH 23390. These findings demonstrated, for the first time, that atomoxetine possesses significant antihyperalgesic activity on diabetes-induced neuropathic pain and this effect seems to be mediated by α- and ß-adrenergic and D2/D3 dopaminergic receptors. Results of this present study seem to offer a new indication for an old drug; atomoxetine, but these preclinical data should first be confirmed with further well-designed clinical trials.

Synthesis of Some Novel Thiadiazole Derivative Compounds and Screening Their Antidepressant-Like Activities.

Novel thiadiazole derivatives were synthesized through the reaction of acetylated 2-aminothiadiazole and piperazine derivatives. The chemical structures of the compounds were clarified by Infrared Spectroscopy (IR), ¹H Nuclear Magnetic Resonance Spectroscopy (¹H-NMR), 13C Nuclear Magnetic Resonance Spectroscopy (13C-NMR) and Electronspray Ionisation Mass Spectroscopy (ESI-MS) spectroscopic methods. Antidepressant-like activities were evaluated by the tail-suspension (TST) and modified forced swimming (MFST) methods. Besides, possible influence of the test compounds on motor activities of the animals were examined by activity cage tests. In the TST, administration of the compounds 2c, 2d, 2e, 2f, 2g and 2h significantly decreased the immobility time of mice regarding the control values. Further, in the MFST, the same compounds reduced the total number of immobility behaviors while increasing swimming performance. However, no change was observed in the total number of climbing behaviors. These data suggested that compounds 2c, 2d, 2e, 2f, 2g and 2h possess notable antidepressant-like activities. Reference drug fluoxetine (10 mg/kg) was also exhibited its antidepressant activity, as expected. No significant difference was seen between the locomotor activity values of the test groups signifying that observed antidepressant-like activities are specific. Theoretical calculation of absorption, distribution, metabolism, excretion (ADME) properties for the obtained compounds were performed and obtained data supported the antidepressant-like potential of these novel thiadiazole derivatives.

A benzothiazole/piperazine derivative with acetylcholinesterase inhibitory activity: Improvement in streptozotocin-induced cognitive deficits in rats.

BACKGROUND: Acetylcholinesterase (AChE) inhibitors are frequently prescribed to mitigate the cognitive decline in Alzheimer's disease. Thus, we investigated the possible efficacy of the AChE inhibitor 2-[(6-Nitro-2-benzothiazolyl)amino]-2-oxoethyl4-[2-(N,N-dimethylamino)ethyl] piperazine-1 carbodithioate (BPCT) in a streptozotocin (STZ)-induced Alzheimer's disease model (SADM). METHODS: First, we analyzed the molecular interaction of BPCT with AChE via a docking study. Then, the cognitive effects of BPCT (10 and 20mg/kg) were evaluated in intracerebroventricular STZ- and vehicle-administered rats with the elevated plus maze (EPM), Morris water maze (MWM), and active avoidance (AA) tests. Locomotor activity was also assessed. RESULTS: Docking analysis indicated significant binding of BPCT to the AChE active site. In behavioral tests, STZ administration impaired cognitive performance in SADM rats versus control rats. Treatment with donepezil or BPCT significantly decreased the prolonged 2nd retention transfer latency and 2nd retention latency time values of the SADM group in the EPM and MWM tests, respectively. Further, prolonged latency times were decreased and reduced frequency of avoidance events were increased in the AA test. Locomotor activity between groups was not different. CONCLUSION: BPCT appears to function as a central AChE inhibitor, and its improvement of deficits in SADM rats suggests that it has therapeutic potential in Alzheimer's disease.

Antidepressant-like effect of gallic acid in mice: Dual involvement of serotonergic and catecholaminergic systems.

AIMS: This study was planned to examine the antidepressant potency of gallic acid (30 and 60mg/kg), a phenolic acid widely distributed in nature, together with its possible underlying monoaminergic mechanisms. MAIN METHODS: Antidepressant-like activity was assessed using the tail suspension (TST) and the modified forced swimming tests (MFST). Locomotor activity was evaluated in an activity cage. KEY FINDINGS: Administration of gallic acid at 60mg/kg reduced the immobility duration of mice in both the TST and MFST without any changes in the locomotor activity. The anti-immobility effect observed in the TST was abolished with pre-treatment of p-chlorophenylalanine methyl ester (an inhibitor of serotonin synthesis; 100mg/kg i.p. administered for 4-consecutive days), ketanserin (a 5-HT2A/2C antagonist; 1mg/kg i.p.), ondansetron (a 5-HT3 antagonist; 0.3mg/kg i.p.), α-methyl-para-tyrosine methyl ester (an inhibitor of catecholamine synthesis; 100mg/kg i.p.), phentolamine (non-selective alpha-adrenoceptor antagonist; 5mg/kg i.p.), SCH 23390 (a dopamine D1 antagonist; 0.05mg/kg s.c.), and sulpiride (a dopamine D2/D3 antagonist; 50mg/kg i.p.). However, NAN 190 (a 5-HT1A antagonist; 0.5mg/kg i.p.) and propranolol (a non-selective ß-adrenoceptor antagonist; 5mg/kg i.p.) pre-treatments were ineffective at reversing the antidepressant-like effects of gallic acid. SIGNIFICANCE: The results of the present study indicate that gallic acid seems to have a dual mechanism of action by increasing not only serotonin but also catecholamine levels in synaptic clefts of the central nervous system. Further alpha adrenergic, 5-HT2A/2C and 5-HT3 serotonergic, and D1, D2, and D3 dopaminergic receptors also seem to be involved in this antidepressant-like activity.

Synthesis and Antidepressant Activity Profile of Some Novel Benzothiazole Derivatives.

Within the scope of our new antidepressant drug development efforts, in this study, we synthesized eight novel benzothiazole derivatives 3a-3h. The chemical structures of the synthesized compounds were elucidated by spectroscopic methods. Test compounds were administered orally at a dose of 40 mg/kg to mice 24, 5 and 1 h before performing tail suspension, modified forced swimming, and activity cage tests. The obtained results showed that compounds 3c, 3d, 3f-3h reduced the immobility time of mice as assessed in the tail suspension test. Moreover, in the modified forced swimming tests, the same compounds significantly decreased the immobility, but increased the swimming frequencies of mice, without any alteration in the climbing frequencies. These results, similar to the results induced by the reference drug fluoxetine (20 mg/kg, po), indicated the antidepressant-like activities of the compounds 3c, 3d, 3f-3h. Owing to the fact that test compounds did not induce any significant alteration in the total number of spontaneous locomotor activities, the antidepressant-like effects of these derivatives seemed to be specific. In order to predict ADME parameters of the synthesized compounds 3a-3h, some physicochemical parameters were calculated. The ADME prediction study revealed that all synthesized compounds may possess good pharmacokinetic profiles.

Pharmacological and Toxicological Screening of Novel Benzimidazole-Morpholine Derivatives as Dual-Acting Inhibitors.

The aim of this study was to investigate acetylcholinesterase (AChE), monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme inhibitory, and antimicrobial activities of a new series of 2-(4-substituted phenyl)-1-[2-(morpholin-4-yl)ethyl]-1H-benzimidazole derivatives, for their possible use as multi-action therapeutic agents. Target compounds (n = 15) were synthesized under microwave irradiation conditions in two steps, and their structures were elucidated by FT-IR, ¹H-NMR, 13C-NMR and high resolution mass spectroscopic analyses. Pharmacological screening studies revealed that two of the compounds (2b and 2j) have inhibitory potential on both COX-1 and COX-2 enzymes. In addition, cytotoxic and genotoxic properties of the compounds 2b, 2j and 2m were investigated via the well-known MTT and Ames tests, which revealed that the mentioned compounds are non-cytotoxic and non-genotoxic. As a concise conclusion, two novel compounds were characterized as potential candidates for treatment of frequently encountered inflammatory diseases.

MAO enzymes inhibitory activity of new benzimidazole derivatives including hydrazone and propargyl side chains.

In the present work, 15 new N'-(arylidene)-4-(1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-yl)benzohydrazide (4a-4o) were designed and synthesized. The structures of the synthesized compounds were elucidated using FT-IR, 1H-NMR, 13C-NMR, and HRMS spectral data. The inhibitory activity of the compounds 4a-4o against hMAO-A and hMAO-B enzymes was evaluated by using in vitro Amlex Red® reagent based fluorometric method. Due to lots of high-cost kits including this assay, we determined the ingredients of the kits from the data sheets of several suppliers, and adjusted a protocol by working with various concentrations and volumes of these ingredients. As a result, a fast and sensitive assay was applied as in the commercially available MAO kits with lower costs and clearer ingredients than those of the kits. The enzyme inhibition assay revealed that synthesized compounds have selective inhibition potency against hMAO-B. The compound 4e and 4f displayed IC50 values of 0.075 µM and 0.136 µM against hMAO-B, respectively. The reference drugs selegiline (IC50 = 0.040 µM) and rasagiline (IC50 = 0.066 µM) also displayed a significant inhibition against hMAO-B. The enzyme kinetic study was performed in order to observe the effect of the most active compound 4e on substrate-enzyme relationship and non-competitive inhibition of hMAO-B was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 4e was found as non-cytotoxic and non-genotixic. Theoretical calculation of ADME properties suggested that compound 4e may have a good pharmacokinetic profile. The docking study of compound 4e revealed that there is a strong interaction between the active sites of hMAO-B and analyzed compound.

Design, synthesis, and AChE inhibitory activity of new benzothiazole-piperazines.

In the current study, 14 new benzothiazole-piperazine compounds were designed to meet the structural requirements of acetylcholine esterase (AChE) inhibitors. The target compounds were synthesised in three steps. Structures of the newly synthesised compounds (7-20) were confirmed using IR, 1H NMR, 13C NMR, and HRMS methods. The inhibitory potential of the compounds on AChE (E.C.3.1.1.7, from electric eel) was then investigated. Among the compounds, 19 and 20 showed very good activity on AChE enzyme. Kinetics studies were performed to observe the effects of the most active compounds on the substrate-enzyme relationship. Cytotoxicity studies, genotoxicity studies, and theoretical calculation of pharmacokinetics properties were also carried out. The compounds 19 and 20 were found to be nontoxic in both of the toxicity assays. A good pharmacokinetics profile was predicted for the synthesised compounds. Molecular docking studies were performed for the most active compounds, 19 and 20, and interaction modes with enzyme active sites were determined. Docking studies indicated a strong interaction between the active sites of AChE enzyme and the analysed compounds.