molecules Article
Synthesis and Biological Evaluation of Novel Benzothiazole Derivatives as Potential Anticonvulsant Agents Da-Chuan Liu, Hong-Jian Zhang, Chun-Mei Jin * and Zhe-Shan Quan * Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, China;
[email protected] (D.-C.L.);
[email protected] (H.-J.Z.) * Correspondence:
[email protected] (C.-M.J.);
[email protected] (Z.-S.Q.); Tel./Fax: +86-433-243-6017 (C.-M.J.); +86-433-243-6020 (Z.-S.Q.) Academic Editors: Shufeng Zhou and Wei-Zhu Zhong Received: 6 January 2016 ; Accepted: 25 January 2016 ; Published: 29 February 2016
Abstract: New benztriazoles with a mercapto-triazole and other heterocycle substituents were synthesized and evaluated for their anticonvulsant activity and neurotoxicity by using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ), and rotarod neurotoxicity (TOX) tests. Among the compounds studied, compound 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-((3-fluorobenzyl) oxy)benzo[d]thiazol-2-yl)acetamide (5i) and 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-((4-fluorobenzyl)oxy) benzo[d] thiazol-2-yl)acetmide (5j) were the most potent, with an ED50 value of 50.8 mg/kg and 54.8 mg/kg in the MES test and 76.0 mg/kg and 52.8 mg/kg in the scPTZ seizures test, respectively. They also showed lower neurotoxicity and, therefore a higher protective index. In particular, compound 5j showed high protective index (PI) values of 8.96 in the MES test and 9.30 in the scPTZ test, which were better than those of the standard drugs used as positive controls in this study. Keywords: synthesis; benzothiazole; mercapto-triazole; anticonvulsant; maximal electroshock; neurotoxicity; pentylenetetrazole
1. Introduction February ninth, 2015 was the first International Epilepsy Day, and it helped more people raise awareness and understanding about epilepsy. Such efforts are urgently needed, because with more than 50 million people presenting with epilepsy worldwide, epilepsy is the most common, chronic, serious neurological disease. In 2013, 119,000 deaths worldwide were attributable to epilepsy. Currently, 40% of patients in high-income countries and more than 70% of patients in developing countries do not get the treatment they need, because of the high expense or low availability of the appropriate drugs [1–3]. Therefore, there is a pressing need to develop more effective antiepileptic drugs (AEDs) endowed with an improved safety profile. On the basis of a number of related materials, azoles and their derivatives have gained much attention in recent years due to their potential biological applications linked to their anticonvulsant [4], anti-inflammatory [5], anti-fungal [6], antiviral [7], and anticancer [8] activities. Among them, heterocyclic compounds with the 3-mercapto-1,2,4-triazole substructure exhibit a wide spectrum of biological activities [9,10]. Similarly, we also demonstrated that the benzothiazole nucleus is a unique scaffold for further molecular exploration to synthesize novel compounds. A literature survey revealed that benzothiazole analogs are associated with diverse pharmacological effects [11–14], including anticonvulsant activity [15,16]. For this reason, and in continuation to our efforts directed toward the synthesis of new heterocyclic compounds with
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Molecules 2016, 21, 164 2 of 13 anticonvulsant biological activities, in this study, we combined both biological components (3-mercapto-1,2,4-triazole and benzothiazole) with an amide, which has anticonvulsant bioactivities which has anticonvulsant bioactivities in some AEDs (such as carbamazepine and riluzole, also see in some AEDs (such as carbamazepine and riluzole, also see references [17,18]), to obtain a series of references [17,18]), to obtain a series of 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-alkoxybenzo[d]thiazol-2-yl) 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-alkoxybenzo[d]thiazol-2-yl)acetamide. To compare the compound acetamide. To compare the compound activities with those of other azoles, the mercapto-triazole in activities with those of other azoles, the mercapto-triazole in compound 5 was replaced with other compound 5 was replaced with other heterocycles such as imidazole, triazole, tetrazole, and 3-aminoheterocycles such imidazole, triazole, tetrazole, 3-amino-1,2,4-triazole, to obtain compounds 1,2,4-triazole, to as obtain compounds 6, 7, 8, and 9and (Figure 1). Their anticonvulsant activities were 6, 7, 8, and 9 (Figure 1). Their anticonvulsant activities were evaluated using the maximal electroshock evaluated using the maximal electroshock (MES) test and their neurotoxicity (TOX) was evaluated (MES) their neurotoxicity (TOX) was evaluated with the rotarod test in mice. withtest the and rotarod test in mice.
Figure of azoles azolescombined combinedwith withamide. amide. Figure1.1.Benzothiazole Benzothiazole and and kinds kinds of
Resultsand andDiscussion Discussion 2. 2.Results Chemistry 2.1.2.1. Chemistry the targetcompounds compoundswere weresynthesized synthesized according according to 3a–m were AllAll the target to Scheme Scheme1.1.Compounds Compounds 3a–m were prepared according to previous studies in our laboratory [19]. Compounds 3a–m were treated with prepared according to previous studies in our laboratory [19]. Compounds 3a–m were treated with chloroacetylchloride chloride at at room in in acetone to yield derivatives 4a–m [20,21]. Finally, when chloroacetyl roomtemperature temperature acetone to yield derivatives 4a–m [20,21]. Finally, derivatives 4a–m werewere allowed to react with different azoles, such asas1H-1,2,4-triazole-3-thiol, when derivatives 4a–m allowed to react with different azoles, such 1H-1,2,4-triazole-3-thiol, imidazole, triazole, tetrazole, and 3-amino-1,2,4-triazole in refluxing dimethylformamide (DMF)ininthe imidazole, triazole, tetrazole, and 3-amino-1,2,4-triazole in refluxing dimethylformamide (DMF) the presence of NaOH [22–25], the 2-chlorine atom was substituted by these heterocycles, producing thethe presence of NaOH [22–25], the 2-chlorine atom was substituted by these heterocycles, producing corresponding compounds: 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-alkoxybenzo[d]thiazol-2-yl)acetamide corresponding compounds: 2-((1H-1,2,4-triazol-3-yl)thio)-N-(6-alkoxybenzo[d]thiazol-2-yl)acetamide (5a–m), N-(6-alkoxybenzo[d]thiazol-2-yl)-2-(1H-imidazol-1-yl)acetamide (6a–b), N-(6-alkoxybenzo[d] (5a–m), N-(6-alkoxybenzo[d]thiazol-2-yl)-2-(1H-imidazol-1-yl)acetamide (6a–b), N-(6-alkoxybenzo[d] thiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide (7a–b), N-(6-alkoxybenzo[d]thiazol-2-yl) -2-(1H-tetrazol-1thiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)acetamide (7a–b), N-(6-alkoxybenzo[d]thiazol-2-yl)-2-(1H-tetrazol-1-yl) yl)acetamide (8a–b), and 2-(3-amino-1H-1,2,4-triazol-1-yl)-N-(6-alkoxybenzo[d] thiazol-2-yl)acetamide acetamide (8a–b), and 2-(3-amino-1H-1,2,4-triazol-1-yl)-N-(6-alkoxybenzo[d] thiazol-2-yl) acetamide (9a–b). The structures of the targeted compounds were characterized using spectral methods, and all (9a–b). The structures of the targeted compounds were characterized using spectral methods, and all spectral data corroborated the assumed structures. spectral data corroborated the assumed structures.
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Scheme 1. 1. Synthetic route of target compounds. Reagents and conditions: (a) HBr (48(a) wt HBr % in H 2O,wt 99.99% Scheme Synthetic route of target compounds. Reagents and conditions: (48 % in 2 Cl, CH 3 COCH 3 , K 2 CO 3 , reflux, 18–24 h; (c) ClCOCH 2Cl,h; metals basis), reflux, 18 h; (b) RBr/RPHCH H2 O, 99.99% metals basis), reflux, 18 h; (b) RBr/RPHCH2 Cl, CH3 COCH3 , K2 CO3 , reflux, 18–24 acetone, room temperature, 9–10 h; (d–h) DMF, NaOH, room temperature, 8–12 h. (c) ClCOCH 2 Cl, acetone, room temperature, 9–10 h; (d–h) DMF, NaOH, room temperature, 8–12 h.
2.2.Pharmacology Pharmacologyand andStructure-Activity Structure-Activity Relationship Relationship 2.2. The anticonvulsant anticonvulsant activity thio)-N-(6The activity evaluation evaluationofofcompounds compounds2-((1H-1,2,4-triazol-3-yl) 2-((1H-1,2,4-triazol-3-yl) thio)-N alkoxybenzo[d]thiazol-2-yl)acetamide (5a–m) were determined using the MES test, which -(6-alkoxybenzo[d]thiazol-2-yl)acetamide (5a–m) were determined using the MES test, whichisisaa mechanism-independent animal seizure model that enables the identification of compounds mechanism-independent animal seizure model that enables the identification of compounds preventing preventing seizure spread [26]. It should be noted that the MES model remains the most useful tool seizure spread [26]. It should be noted that the MES model remains the most useful tool for the for the identification of new anticonvulsants, despite significant advances in epilepsy research in the identification of new anticonvulsants, despite significant advances in epilepsy research in the past past several years [27]. The MES seizure model was used for preliminary (phase I) screening of several years [27]. The MES seizure model was used for preliminary (phase I) screening of compounds compounds 5a–m. They were administered to mice intraperitoneally (i.p.) at the fixed dose of 100 mg/kg 5a–m. They were administered to mice intraperitoneally (i.p.) at the fixed dose of 100 mg/kg and the and the anticonvulsant protection was observed at two post-treatment times: 0.5 and 4 h. The method anticonvulsant protection was observed at two post-treatment times: 0.5 and 4 h. The method applied applied here allowed the determination of the number of animals (in a group consisting of three here allowed the determination of the number of animals (in a group consisting of three mice) protected mice) protected against electrically-induced seizures as well as the estimation of the time course of against electrically-induced seizures as well as the estimation of the time course of anticonvulsant anticonvulsant activity, including quick-acting (0.5 h) or long-acting properties (4 h). The results are activity, including quick-acting (0.5 h) or long-acting properties (4 h). The results are presented in presented in Table 1. The preliminary pharmacological screening revealed that five compounds (5b, 5c, Table 1. The preliminary pharmacological screening revealed that five compounds (5b, 5c, 5g, 5i, 5g, 5i, and 5j) showed 100% anticonvulsant protection in the 0.5 h period and some of them (5c, 5i, and 5j) showed 100% anticonvulsant protection in the 0.5 h period and some of them (5c, 5i, and 5j) and 5j) still had a little activity in the 4 h period. One compound, 5h, showed 67% anticonvulsant still had a little activity in the 4 h period. One compound, 5h, showed 67% anticonvulsant protection protection in the 0.5 h period, but no activity in the 4 h period. None of the compounds presented inneurotoxicity the 0.5 h period, no of activity in the Based 4 h period. ofpreliminary the compounds at thebut dose 100 mg/kg. on theNone above data,presented six active neurotoxicity compounds atwere the dose of 100 mg/kg. Based on the above preliminary data, six active compounds were screened screened at the dose of 30 mg/kg in mice (i.p.) at the two post-treatment times (0.5 h and 4 h). atAs the dose of 30 mg/kg in mice (i.p.) at the two post-treatment times (0.5 h and 4 h). As shown shown in Table 2, only two compounds, 5i and 5j, showed about 33% anticonvulsant protectionin Table 2, only two 5j, showed 33% anticonvulsant protection activity in the activity in the 0.5compounds, h period but 5i noand activity in the 4about h period. 0.5 h period but no activity in the 4 h period. The following structure-activity relationships (SAR) were obtained, while analyzing the The following structure-activity relationships (SAR) were the obtained, while analyzing the preliminary screening of the synthesized compounds. Among six alkyl chain-substituted preliminary screening of the synthesized compounds. Among the six alkyl chain-substituted derivatives, 5b and 5c showed better activities, and 5c still presented some activities in the 4 h period. derivatives, 5b and 5c showed better the activities, and 5c still presented activitiesCompound in the 4 h However, with the increase in length, activities of the compounds didsome not increase. period. However, with the increase in length, the activities of the compounds did not increase. 5g, substituted with a benzyl group at the 6-position of the benzothiazole core, showed moderate Compound 5g, substituted with a benzyl group at the 6-position of the benzothiazole core, showed activity at 100 mg/kg. Thus, the F, Cl, and CF3 groups were subsequently added onto the benzyloxy moderate activity at 100positions, mg/kg. Thus, thecompounds F, Cl, and CF were subsequently added onto the group of 5g at different yielding 5h–m. Substituent position on the phenyl ring 3 groups benzyloxy groupanticonvulsant of 5g at different positions, compounds 5h–m.asSubstituent on the also influenced activity in the yielding 6-fluorobenzyl derivatives m-F = p-F > position o-F. However, phenyl ring also influenced anticonvulsant activityatin the 6-fluorobenzyl m-Fsubstituted = p-F > o-F. the 6-chlorobenzyl derivatives showed no activity the dose of 100 mg/kg.derivatives Compoundas5m, However, the 6-chlorobenzyl no activity theshowed dose ofno 100 mg/kg.regardless Compound 5m, with a trifluoromethyl at the derivatives 3-position ofshowed the benzyl group, at also activity, of the period (0.5 h or 4 h) at the dose of 100 mg/kg. Based on the above-mentioned results, six compounds
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substituted with a trifluoromethyl at the 3-position of the benzyl group, also showed no activity, regardless of the period (0.5 h or 4 h) at the dose of 100 mg/kg. Based on the above-mentioned results, Molecules 2016, 21, 164 of 13 six compounds (5b, 5c, 5g, 5h, 5i, and 5j) were selected from all the compounds for the next4 step and were (5b, tested at a dose of 30 mg/kg. As shown in Table 2, at the dose of 30 mg/kg, only m-F and p-F 5c, 5g, 5h, 5i, and 5j) were selected from all the compounds for the next step and were tested at substituted compounds presented some anticonvulsant activities in the 0.5 h period. a dose of 30 mg/kg. As shown in Table 2, at the dose of 30 mg/kg, only m-F and p-F substituted compounds presented some anticonvulsant activities in the 0.5 h period. Table 1. Anticonvulsant activities screening (maximal electroshock test) and neurotoxicity screening in mice Table at the 1.dose of 100 mg/kg. Anticonvulsant activities screening (maximal electroshock test) and neurotoxicity screening in mice at the dose of 100 mg/kg.
O RO
S
N NH
N
S
NH
N 5a-m
Comp. Comp. 5a 5b 5a 5b5c 5c5d 5d5e 5e5f 5f5g 5g5h 5h 5i 5i 5j 5j 5k 5k 5l5l 5m 5m
R R -CH3 3H7 n-C -CH 3 n-C n-C43H H97 n-C n-C54HH119 n-C H1311 n-C65H n-C H1513 n-C76H n-C H 7 155 -CH2C6H -CH C H5 2 6 -CH2C6H4 (o-F) -CH2 C6 H4 (o-F) -CH2C6H4 (m-F) -CH2 C6 H4 (m-F) -CH2C6H4 (p-F) -CH2 C6 H4 (p-F) -CH -CH22CC66HH4 4(o-Cl) (o-Cl) -CH -CH22CC66HH4 4(m-Cl) (m-Cl) -CH22C C66H H44(m-CF (m-CF3)3 )
MES (100 mg/kg) a Toxicity (100 mg/kg) MES (100 mg/kg) a Toxicity (100 mg/kg) 0.5 h 4h 0.5 h 4h 0.5b h 4h 0.5 h 1/3 0/3 0/3 0/34 h b 3/3 0/3 0/3 0/3 0/3 0/3 0/3 1/3 3/3 1/3 0/3 0/30/3 3/3 0/3 0/3 0/3 0/3 0/3 0/30/3 3/3 1/3 0/3 0/3 0/3 0/3 1/3 0/3 0/3 0/30/3 1/3 0/3 0/3 1/3 0/3 0/3 0/30/3 1/3 0/3 0/3 3/3 0/3 0/3 0/30/3 3/3 0/3 0/3 2/3 0/3 0/3 0/30/3 2/3 0/3 0/3 0/3 3/3 1/3 0/3 0/3 3/3 1/3 0/3 0/3 3/3 1/3 0/3 0/3 3/3 1/3 0/3 0/3 0/3 0/3 0/3 0/30/3 0/3 0/3 0/3 0/3 0/3 0/3 0/30/3 0/3 0/3 0/3 0/3 0/3 0/3 0/30/3 0/3 0/3 0/3
a Maximal electroshock (MES): doses of 100 mg/kg were administrated intraperitoneally in mice. Maximal electroshock (MES): doses of 100 mg/kg were administrated intraperitoneally in mice. The animals b n1/n2: theb animals The animals at were at h two times: and 4 h after administration; n1/n2: the animals were examined twoexamined times: 0.5 and 4 h 0.5 afterh administration; protected/the animals tested. animals tested. protected/the
a
2. Anticonvulsant activitiesscreening: screening: MES MES test dose of 30 TableTable 2. Anticonvulsant activities testininmice miceatatthe the dose of mg/kg. 30 mg/kg.
a
a
Comp. Comp. 5b 5b5c 5c5g 5g5h 5h 5i 5i 5j 5j
R R n-C3H7 n-C n-C43H H97 -CH 2 C 6H n-C4 H 95 -CH C46(o-F) H5 -CH 2C62H -CH22CC6H (o-F) 6H -CH 44 (m-F) -CH C H (m-F) 2 6 4 -CH2C6H4 (p-F) -CH2 C6 H4 (p-F)
MES (30 mg/kg) a MES (30 mg/kg) a 0.5 h 4h 0.5 h 0/3 0/34 h 0/3 0/3 0/3 0/3 0/3 0/3 0/3 1/3 1/3 1/3 1/3
0/30/3 0/30/3 0/30/3 0/30/3 0/30/3 0/3
Maximal electroshock (MES): doses of 30 mg/kg were administrated intraperitoneally in mice. Maximal electroshock (MES): doses of 30 mg/kg were administrated intraperitoneally in mice.
According to the bioisosterism, the mercapto-triazole ring of compounds 5i and 5j was replaced with other heterocycles, such as imidazole, triazole, tetrazole, andof3-amino-1,2,4-triazole. According to the bioisosterism, the mercapto-triazole ring compounds 5i andCompounds 5j was replaced 6, 7, 8, and 9 were designed and synthesized. Their anticonvulsant activities were evaluated at the with other heterocycles, such as imidazole, triazole, tetrazole, and 3-amino-1,2,4-triazole. Compounds dose of 100 mg/kg, and screening results are shown in Table 3. The compounds, substituted withat the 6, 7, 8, and 9 were designed and synthesized. Their anticonvulsant activities were evaluated other heterocycles, hardly showed any anticonvulsant activities in the 0.5 h or 4 h period. Thus, we dose of 100 mg/kg, and screening results are shown in Table 3. The compounds, substituted with concluded that when the mercapto-triazole ring in compounds 5a–m was replaced by other heterocycles other(i.e., heterocycles, hardly showed any anticonvulsant activities in the 0.5 h or 4 h period. Thus, imidazole, triazole, tetrazole, and 3-amino-1,2,4-triazole), the resultant compounds, 6a–b, 7a–b, we concluded that when mercapto-triazole in compounds 5a–m was replaced 8a–b, and 9a–b, hardlythe presented any activitiesring compared with the compounds containingby theother heterocycles (i.e., imidazole, triazole, tetrazole, and 3-amino-1,2,4-triazole), the resultant compounds, mercapto-triazole ring.
6a–b, 7a–b, 8a–b, and 9a–b, hardly presented any activities compared with the compounds containing the mercapto-triazole ring.
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Table 3. Anticonvulsant activities of compounds 6, 7, 8, and 9 in MES test.
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Table 3. Anticonvulsant activities of compounds 6, 7, 8, and 9 in MES test.
Comp.
R
6a
-CH2C6H4 (m-F) C66H44 (p-F) -CH22C -CH (m-F) -CH22C C66H H44(m-F) (p-F) -CH -CH C H (m-F) 2 6 4 -CH2C6H4 (p-F) -CH C H (p-F) -CH22C66H44(m-F) -CH2 C6 H4 (m-F) -CH -CH22C C66H H44 (p-F) (p-F) -CH 2 C 6 H -CH2 C6 H44 (m-F) (m-F) -CH22C66H H44 (p-F) (p-F)
Comp.
6b 6a 6b 7a 7a 7b 7b 8a 8a 8b 8b 9a 9a 9b 9b
R
MES (100 mg/kg) MES (100 mg/kg) 0.5 h 4h 0.5 4h 0/3h 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 1/3 1/3 1/3 1/3 0/3 0/3 0/3 0/3
Toxicity (100 mg/kg) Toxicity (100 mg/kg) 0.5 h 4h 0.5 4h 0/3 h 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3 0/3
On the basis of the preliminary screening results, compounds 5i and 5j were subjected to the next
Onphase the basis of the preliminary screening results, compounds 5i and 5j were subjected to the next phase of trials regarding the quantification of their anticonvulsant activity (indicated by ED50 MES)
of trialsinregarding the quantification of their anticonvulsant activity (indicated by ED50 MES) in mice. mice. The MES and and subcutaneous (scPTZ) models the represent The MES subcutaneous pentylenetetrazole pentylenetetrazole (scPTZ) seizureseizure models represent two mostthe two widely used animal seizure models in the search for new AEDs. The scPTZ test employs chemicallymost widely used animal seizure models in the search for new AEDs. The scPTZ test employs induced myoclonic seizures and allows and the identification agents raising the This seizure chemically-induced myoclonic seizures allows theofidentification of seizure agentsthreshold. raising the test is related to human generalized absence seizures [28]. Thus, the quantitative analysis of compounds threshold. This test is related to human generalized absence seizures [28]. Thus, the quantitative 5i and 5j, the most potent compounds in the MES test, was studied in the scPTZ test to obtain ED50 PTZ. analysisThe of quantitative compounds 5i and 5j,data the(indicated most potent compounds in5ithe was from studied neurotoxicity by TD50 ) of compounds andMES 5j wastest, obtained the in the scPTZ test to obtain ED PTZ. The quantitative neurotoxicity data (indicated by TD ) of compounds rotarod test. 50 50 Theobtained results of the quantitative tests test. are reported in Table 4, along with the data from carbamazepine 5i and 5j was from the rotarod andresults phenytoin positive drug control groups. quantitative i.p. data4,in along mice confirmed the safe The of as the quantitative tests are The reported in Table with the data from and potent anticonvulsant activity of 5i and 5j. As shown in Table 4, both compounds showed a weaker carbamazepine and phenytoin as positive drug control groups. The quantitative i.p. data in mice anticonvulsant activity than the control drug carbamazepine (the ED50 MES was 11.8 mg/kg) in the confirmed the safe and potent anticonvulsant activity of 5i and 5j. As shown in Table 4, both MES seizure model. However, they showed a stronger anticonvulsant activity than valproic acid (the compounds showed a weaker activity the carbamazepine (the ED50 ED50 MES was 216.9 mg/kg)anticonvulsant and better activities in thethan scPTZ testcontrol than alldrug the drugs used as positive MES was 11.8 mg/kg) in the MES seizure model. However, they showed a stronger anticonvulsant controls in this study. Especially, compound 5j showed higher safety with lower neurotoxicity than 5i, resulting in higher PI values in mg/kg) the MES test 9.30 activities in the scPTZ activity compound than valproic acid (the ED50 MES was(8.96 216.9 andand better intest). the scPTZ test than all the drugs usedTable as positive controls in this study. Especially, compound 5j showed higher safety 4. Quantitative Pharmacological Parameters ED50, TD50, and PI Values in Mice. with lower neurotoxicity than compound 5i, resulting in higher PI values (8.96 ind the MES test and PI Comp. ED50 a MES (mg/kg) ED50 scPTZ b (mg/kg) TD50 c (mg/kg) 9.30 in the scPTZ test). MES scPTZ 5i
50.8 (37.0–69.8) e
76.0 (65.9–87.7)
353.5 (309.3–404.1)
6.96
4.65
11.8 (8.5–16.4) 216.9 (207.5–226.3)
>100 239.4 (209.2–274.1)
76.1 (55.8–103.7) 372.9 (356.0–389.8) c
6.45 1.72
100 239.4 (209.2–274.1)
491.0 (429.5–561.2) 76.1 (55.8–103.7) 372.9 (356.0–389.8)
8.96 6.45 1.72
9.30
