Anti-neuropathic and anticonvulsant activities of various substituted triazoles analogues

ISSN: 2410-9649 Asif, M., / Chemistry International 1(4) (2015) 174-183 www.iscientic.org 175 www.bosaljournals/chemint/ [email protected] Dimroth rearrangement. 1,2,3-triazole is considered to be the most useful component, widely used in research purpose as a building block for complex chemical compounds such as pharmaceutical drugs like tazobactam (Kaplancikli et al., 2005; Karakurt et al., 2006; Karthikeyan, 2009; Kharb et al., 2012; Kokil, 2010; Lin et al., 2005; Mohamed et al., 2006; PachutaStec et al., 2009). 1, 2, 4-Triazole is a basic aromatic heterocycle and its derivatives posses a wide variety of pharmacological activity such as antifungal, anticancer, anticonvulsant, antimicrobial, anti-inflammatory, antioxidant, anti-tubercular, anti-malarial, anti-nociceptive (Ali et al., 2015, Asif et al., 2015a-f; Havaldar and Patil, 2008; Ibrahim, 2009; Jadhav et al., 2009; Jordao et al., 2009. Kakefuda et al., 2002; Pandey et al., 2009; Pandey, et al., 2001; Shafiee et al., 2002; Shiradkar et al., 2007; Siddiqui and Arora, 2005). Some of the marketed preparation which contains triazole ring is fluconazole and itraconazole. 1,2,3-Triazole finds use in research as a building block for more complex chemical compounds, such as some antifungal drugs like tazobactam include fluconazole, isavuconazole, itraconazole, voriconazole, pramiconazole, and posaconazole. The triazole plant protection fungicides include epoxiconazole, triadimenol, propiconazole, metconazole, cyproconazole, tebuconazole, flusilazole and paclobutrazol (Agarwal and Singh, 2006; Sussman et al., 2001; Akbarzadeh et al., 2003; Brodie et al., 2009; Sidwell et al., 2005; Mauras et al., 2009; Sheehan et al., 2007). Anticonvulsant activity of triazole derivatives Epilepsy is a kind of disorder of central nervous system, which has affected at least 50 million people all over the world. However, most of the clinical drugs cannot control this disease effectively due to the gradually exposed side effect. In recent years, some attention has been paid to develop triazole compounds as anticonvulsant drugs due to their good activities and low toxicity. Various 3-(4-(substituted phenyl)-1,3-thiazol2-ylamino)-4-(substituted phenyl)-4,5-dihydro-1H-1,2,4triazole-5-thiones (1) has been prepared by clubbing thiazole and triazole moieties for the pharmacophore model for anticonvulsant activity (Siddiqui and Ahsan, 2010). Two compounds (1a and 1b) showed significant anticonvulsant activity in both maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (sc PTZ) screen along with wide safety of margin with protective index (PI), median hypnotic dose (HD 50) and median lethal dose (LD 50) much higher than standard drugs. Novel 8-chloro-6-(2-fluorophenyl)1-(aryl)-4H(1,2,4)triazolo(4,3-a)(1,4) benzo diazepines (2) were prepared by treating 7-chloro-5-(2-fluorophenyl)-1,3dihydro-2H-1,4-benzodiazepine-2-thione with various aromatic acid hydrazides. Compounds were tested for anticonvulsant activity. Four of the tested compounds exhibited excellent activity in comparison with diazepam (Narayana et al, 2006). A series of 4,5-diphenyl-2H-1,2,4-triazol-3(4H)-one (3) were study the effect of cyclization of the semicarbazone moiety of aryl semicarbazones on the anticonvulsant activity. All compounds were evaluated for their anticonvulsant activity in animal models of seizures, viz. MES, scPTZ, subcutaneous strychnine (scSTY), and subcutaneous picrotoxin (scPIC)induced seizure threshold tests. The compounds were also evaluated for neurotoxicity. Eight compounds exhibited anticonvulsant activity in all the animal models of seizure (Shalini et al., 2009). A series of novel 3-{((substituted phenyl)methyl)thio}-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2,4triazoles (4) and several related Schiff’s bases, 3-{((substituted phenyl)-methyl)thio}-4-alkyl/aryl-5-{(((substituted phenyl/5nitro-2-furyl)methylene)amino)-phenyl}-4H-1,2,4-triazoles 5 has been evaluation of their biological properties4. All compounds were evaluated for their anticonvulsant activity by MES, scPTZ and neurotoxicity (NT) screens. A number of triazole derivatives, exhibited protection at the dose of 100 and 300 mg/kg in one or both models employed. Three compounds were subjected to oral MES screening in rats at 30 mg/kg and were observed to protect 50% of the animals employed in the experiment. Analogues of 3-amino-7-(2,6-dichlorobenzyl)-6methyltriazolo(4,3-b)pyridazine 6 containing amide or carboxylic acid function were tested for anticonvulsant activity. The compounds having the imidazole ring substituted with an amide group have been found to be generally more active against maximal electroshock-induced seizures in mice (ED50 = 37.5 mg/kg orally). The maximum activity was generally linked with a 2,6-dichlorobenzyl substitution pattern (Küçükgüzel et al., 2004). The 3-Amido-7-(2,6-dichlorobenzyl)-6-methyltriazolo(4,3b)pyridazine was also protective in the PTZ-induced seizures test (ED50 = 91.1 mg/kg orally) and blocked STY-induced tonic extensor seizures (ED50 = 62.9 mg/kg orally). A series of 4-(4alkoxylphenyl)-3-ethyl-4H-1,2,4-triazole derivatives 7 and 8 was synthesized as open-chain analogues of 7-alkoxyl-4,5dihydro(1,2,4)triazolo(4,3-a)quinolines. Their anticonvulsant activities were evaluated by the MES test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). MES test showed that 3-ethyl-4-(4-octyloxyphenyl)-4H1,2,4-triazole was found to be the most potent with ED50 value of 8.3 mg/kg and protective index (PI = TD50/ED50) value of 5.5. The possible mechanism of action, it was tested in PTZ test, isoniazid test, thiosemicarbazide test, 3-mercaptopropionic acid and strychnine test (Moreau et al., 1998; Chen et al., 2007). A series of 7-alkoxyl-4,5-dihydro-(1,2,4)triazolo(4,3a)quinoline derivatives 9 was synthesized using 6-hydroxy-3,4dihydro-1H-quinolin-2-one as a starting material (Xie et al, 2005). Their anticonvulsant activities were evaluated by the MES test and the scPTZ test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). MES and scMet tests show that 7-(4-fluorobenzyloxy)-4,5-dihydro(1,2,4)triazolo(4,3-a)quinoline was found to be the most potent with ED50 value of 11.8 and 6.7 mg/kg respectively. A series of 5-alkoxy-(1,2,4)triazolo(4,3-a)quinoline derivatives 10, 11 were synthesized using 4-hydroxyquinolin-2(1H)-one as the starting material. Their anticonvulsant activities were evaluated by the MES and their neurotoxicities were measured by the rotarod test. The results of these tests demonstrated that 5hexyloxy-(1,2,4)triazolo(4,3-a)quinoline was the most potent anticonvulsant, with median effective dose (ED50) of 19.0 mg/kg and protective index (PI=TD50/ED50) values of 5.8 in the MES test. Compound 5-benzyloxy-(1,2,4)triazolo(4,3a)quinoline, exhibited a little weaker activity than previous ISSN: 2410-9649 Asif, M., / Chemistry International 1(4) (2015) 174-183 www.iscientic.org 176 www.bosaljournals/chemint/ [email protected] compound in controlling the seizure induced by MES test at the dose of 22.8 mg/kg, but it possessed lower neurotoxicity with PI value of 12.0, which was safer than marketed drug carbamazepine. To explain the possible mechanism of anticonvulsant activity, the compounds were tested in PTZ test, isoniazid test, thiosemicarbazide test; 3-mercaptopropionic acid and STY test (Guo et al., 2009). To further investigate anticonvulsant activity of quinoline derivatives, a series of 7alkoxy-4,5-dihydro-(1,2,4)triazolo (4,3-a)quinoline-1(2H)-one derivatives 12 was synthesized starting from 7-hydroxyl-3,4dihydro-2(1H)-quinoline (Jin et al., 2006). In initial (phase I) screening and quantitative (phase II) evaluation, compound 7benzyloxyl-4,5-dihydro-(1,2,4)thiazolo(4,3-a)quinoline-1(2H)one was among the most active and also has the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED50) of 12.3 mg/kg, median toxicity dose (TD50) of 547.5 mg/kg. Thus demonstrating much greater margin of safety compared to prototype drugs. It also showed significant oral activity against MES-induced seizures and low oral neurotoxicity in mice. Thiazolyl-containing triazoles 13a and 13b both showed comparable anticonvulsant activity and higher protective index than the standard drugs phenytoin, ethosuximide and phenobarbital. Compound 13a possessed strong anti-maximal MES activity with effective dose (ED50) of 13.4 mg/kg which was close to phenytoin and carbamazepine and better than phenobarbital and valproate. Compound 13b also displayed a better profile of anticonvulsant activity with lesser neurotoxicity (PI = 18.3). Both of the triazoles showed wide range of safe profile as the hypnotic dose (HD)50/ED50 values of 13a and 13b were found to be 36.27 and 47.16 against MES induced seizures, which were much higher than those showed by phenytoin. Moreover, they also gave a significant safety profile in PTZ induced seizure indicating the compounds as broad anticonvulsant spectrum. Notably, the ED50 and toxic dose (TD50) values demonstrated that both of them exhibited adequate absorption in mice orally with lesser neurotoxic effects (Siddiqui, and Ahsan. 2010). Benzo(d)oxazolyl-derived triazole 14 showed an ED50 of 29.5 mg/kg, a TD50 of 285 mg/kg, in the anti-MES potency test, which was greater than the reference drug carbamazepine (Wei et al., 2009). Oxadiazolyl-substituted triazole 15 and its analogues exhibited considerable activity in both PTZ and MES models. Compound 15 was protective in the PTZ model in rats with an oral ED50 of 25.5 mg/kg and in the MES model in rats with an oral ED50 of 14.6 mg/kg. Neurotoxicity was observed with an ED50 of 335 mg/kg. The research also manifested that these triazoles acted as selective γ-aminobutyricacid (GABA) potentiating compounds with no interaction to the benzodiazepine binding site (Lankau et al., 2007). The results indicated that compound 15 was potential to be developed as selective GABA potentiating drugs. A series of phenyl-substituted triazoles were showed that compound 16a was the most potent one with ED50 value of 8.3 mg/kg and PI (TD50/ED50) value of 5.5, whereas compound 16b exhibited better PI value of 9.3, which was much greater than PI value of the prototype drug phenytoin (Chen et al., 2007). The anticonvulsant evaluation of indolylsubstituted triazoles indicated that compound 17a was more potent than carbamazepine after 4 h in the MES model and compounds 17b-d displayed lower neurotoxicity than phenytoin (Siddiqui, et al, 2008). Pyridyl-containing triazole 18 showed good anticonvulsant activity with total recovery time and time for hind limb extension recovery less than the standard drug phenytoin (Kshirsagar et al, 2009). Anti-neuropathic activity of triazole derivatives Triazole compounds as anti-neuropathic agents were developed early. Some triazole antidepressant drugs like trazodone (19), etoperidone (20) and nefazodone (21) as well as hypnotic/sedative drugs alprazolam (22) and estazolam (23) are prevalently used in clinic. Triazole derivatives have been demonstrated to possess good biological activities against some neuropathic-relative diseases such as Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, dementia, anxiety, depression and so on. Several literatures reported that many triazoles had potential activities for treating AD (Fischer et al., 2011). Triazolylthiophene derivatives 24a and 24b were good inhibitors of cdk5/p25 with the IC50 values of 32 and 0.035μmol/l (Shiradkar, et al, 2011), thus they had potential as possible treatments for AD. Another purinebased fluoroaryltriazole 25 was also found to bind to the ATP binding site of cdk5/p25 with comparable binding energies (Nair, et al, 2011). Berberine is a major constituent of many natural drugs, which possesses various biological activities (Fang et al., 2010). Triazole-containing berberine derivatives 26a and 26b were inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Compound 26a with a diisopropylamino moiety substituted on the triazole ring, displayed the best inhibitory activity (IC50 = 0.044 μmol/L) against AChE. Meanwhile, the butyl derivative 26b showed good inhibitory activity with IC50 value of 0.201μmol/l against AChE and gave the highest potency of abnormal aggregation of β-amyloid (Aβ) aggregation inhibition (77.9%). Molecular modeling simulations showed that the triazole moieties actually contributed to the inhibitory activities through interacting with the catalytic sites of AChE (Shi et al., 2011), which manifested that the triazole ring is beneficial for their biological activity. These compounds are potential candidates for treating AD. Aβ Peptides into toxic aggregates have been identified as a key event in AD. Inhibition of this process has thus emerged as a major therapeutic track against AD (Ouberai, et al, 2009). The prepared series of 1,4-diphenyltriazoles as probes targeting β-Amyloid aggregates in AD showed excellent binding affinities to Aβ aggregates (Ki = 0.004-0.03 μmol/L). Compounds 27a and 27b exhibited very good in vivo properties-high initial uptake and fast washout in normal mice (Qu et al., 2007). Taken together, these diphenyltriazole probes demonstrate promising in vitro and in vivo characteristics and they may provide a convenient platform for development of new imaging agents targeting amyloid plaques in the brain Very recently, a great many of tacrine-derived triazole compounds have been attracting much attention as AChE inhibitors (Bourne et al., 2010). ISSN: 2410-9649 Asif, M., / Chemistry International 1(4) (2015) 174-183 www.iscientic.org 177 www.bosaljournals/chemint/ [email protected] The series of compound 28, the most potent noncovalent AChE inhibitors known, are in pre-clinical trials (Krasinski et al., 2005). Parkinson’s disease (PD) is a neurodegenerative disorder, more and more people are infected in the world. There are currently no drugs to treat neurodegeneration in PD, and all existing medications only treat symptoms, lose efficacy over time, and produce untoward side effects. The first highly selective, orally bioavailable c-jun-N-terminal kinase (JNK) inhibitor 29 for protection of dopaminergic neurons in vitro and in vivo. At 0.3μmol/l, this compound showed statistically significant protection of primary dopaminergic neurons, had pharmacokinetic properties in rodents consistent with twice daily dosing, and was orally efficacious at 30 mg/kg in a mouse model of PD (Chambers et al., 2011). Collectively, these results suggested that this triazole JNK inhibitor could be a promising therapeutic neuroprotective agent in the treatment of PD. S N R NH N H N S