S-substituted Derivatives Research Articles

In silico Design, Synthesis and Biological Evaluation of Novel Thieno[3,2-d]pyrimidine Derivatives for Cancer Therapy - A Preliminary Study on the Inhibitory Potential towards ATR Kinase Domain and PIKK Family.

Continuing our studies in the field of new heterocyclic compounds with biological interest, herein we report the synthesis and anticancer activity of new N- and S-substituted derivatives of tetracyclic pyrido[3',2' : 4,5]thieno[3,2-d]pyrimidines. In this regard, starting from the thieno[2,3-b]pyridine-2-carboxylates, the corresponding 8(9)-aminopyrido[3',2' : 4,5]thieno[3,2-d]pyrimidin-7(8)-ones, as well as chloro derivatives were obtained. Based on the latter, amino, hydrazino and S-alkyl derivatives of pyrido[3',2' : 4,5]thieno[3,2-d]pyrimidines were synthesized subsequently. The current study focuses on identifying the potential of thieno[3,2-d]pyrimidine derivatives primarily towards ATR kinase inhibition, through computational predictions, followed by synthesis and cancer cell viability studies, along with an aim to develop the core as PIKK inhibitors for cancer therapy.

Synthesis and antimicrobial activity of s-substituted derivatives of 1,2,4-triazol-3-thiol

The aim of the work. 1,2,4-triazole derivatives possess a wide range of pharmacological activity, so they are used for the development of drugs and active pharmaceutical ingredients. Due to the reactivity of 1,2,4-triazoles there are many options for their further structural modification on different reaction centers. Therefore, the aim of the work was to obtain new S-substituted derivatives of 1,2,4-triazole-3-thiols, study physicochemical parameters of the substances synthesized, evaluate the antimicrobial activity of new S-derivatives of the 4-R1-5-((3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)thio)methyl)-4H-1,2,4-triazole-3-thiol series, and study some regularities of the “structure – biological activity” relationship for the synthesized compounds as well.
 Materials and methods. The subject of the study was new S-substituted 1,2,4-triazoles containing 2-oxopropan-1-yl and 2-aryl-2-oxoethan-1-yl substituents. The antimicrobial activity was studied by double serial dilutions on test cultures of Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), and Candida albicans (ATCC 885-653).
 The results of the biological screening showed that at a concentration of 125 g/mL, all synthesized substances showed activity (MIC – in the range of 31.25 - 62.5 μg/mL, MBCK - in the range of 62.5–125 μg/mL) against strains of Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans. Variation of substituents on the sulfur atom did not lead to a significant change in antimicrobial and antifungal activities among derivatives of 4-R1-5-((3-(pyridin-4-yl)-1H-1,2,4-triazole-5-yl) thio)methyl)-4H-1,2,4-triazole-3-thiols.
 Conclusions. Biological screening data indicate the prospects for the search for new antimicrobial substances among the abovementioned derivatives of 1,2,4-triazoles. The most active compounds were 1-((4-ethyl-5-((3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)thio)methyl)-4H-1,2,4-triazol-3-yl)thio)propan-2-one and 1-(4-methoxyphenyl)-2-(4-ethyl-5-(((3-(pyridin-4-yl)-1H)-1,2,4-triazol-5-yl)thio)methyl)-4H-1,2,4-triazol-3-yl)thio)ethanone, which showed the most pronounced antimicrobial activity against the Pseudomonas aeruginosa strain (MIC – 31.25 μg/mL, MBcK - 62.5 μg/mL)

Theoretical and experimental comparison of the reactivity of the sulfanyl-closo-decaborate and sulfanyl-closo-dodecaborate anions and their mono-S-substituted derivatives

In this work, we have extended the method proposed by Gabel for the preparation of mono- and di-S,S-substituted derivatives of sulfanyl-closo-dodecaborate anion [B12H11SH]2− to derivatives of the closo-decaborate anion. The method is based on the β-elimination of the propionitrile group of sulfonium derivatives [BnHn-1S(R)CH2CH2CN]− in the presence of bases with the formation of the corresponding mono-S-substituted derivatives and acrylonitrile. We also calculated the Fukui functions for the nucleophilic attack of the S-atom in the [B10H9SH]2− and [B12H11SH]2− anions and their mono-S-substituted derivatives using the Hirshfeld approach. As a result, the calculated value of nucleophilicity in the [B10H9SH]2− anion was found to be 5–10 times lower than in other compounds, which completely agrees with the experimental data.

Synthesis of Perchlorinated Sulfonium Derivatives of closo-Decaborate Anion [2-B10Cl9SR2]- (R = i-C3H7, n-C3H7, n-C4H9, n-C8H17, n-C12H25, n-C18H37, CH2Ph, and cyclo-S(CH2)4).

A method for obtaining perchlorinated di-S,S-substituted derivatives of the closo-decaborate anion with various alkyl groups has been developed: [B10Cl9SR2]- (R= i-C3H7, n-C3H7, n-C4H9, n-C8H17, n-C12H25, n-C18H37, CH2Ph, and cyclo-S(CH2)4). The method is based on the preparation of the sulfonium-substituted anion [B10H9SR2]- by alkylation of the anion [B10H9SH]2- with bromoalkanes (i-C3H7Br, n-C3H7Br, n-C4H9Br, n-C8H17Br, n-C12H25Br, n-C18H37Br, PhCH2Br, and BrCH2(CH2)2CH2Br) followed by the cluster chlorination with sulfuryl chloride SO2Cl2 in acetonitrile. The process proceeds until the hydrogen atoms in the boron cluster are completely replaced with chlorine and completes within 60 h. It has been found that the melting point of salts ((C4H9)4N)[B10Cl9SR2] (R= i-C3H7, n-C3H7, n-C4H9, n-C8H17, n-C12H25, and n-C18H37) strongly depends on the length of the hydrocarbon chain of the substituent R.

SYNTHESIS AND SOME TRANSFORMATIONS OF HETEROCYCLIC SUBSTITUTED DERIVATIVES OF THIOGLYCOLICACID

The methods have been developed for the preparation of diheterocyclic systems of a new structure, such as pyrazolo- and 1,3,4-oxadiazolo-1,2,4-triazoles, based on S-substituted thioglycolic acid derivatives.

Synthesis of Novel Bi-Heterocycles as Valuable Anti-Diabetic Agents: 2-({5-((2-Amino-1,3-Thiazol-4-yl)methyl)-1,3,4-Oxadiazol-2-yl}sulfanyl)-N-(Substituted)acetamides

The synthesis of a new series of S-substituted acetamides derivatives of 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol were synthesized and evaluated for enzyme inhibition study along with cytotoxic behavior. Ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate was converted to corresponding acid hydrazide by hydrazine hydrate in ethanol. The reflux of acid hydrazide with carbon disulfide resulted to 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol. Different electrophiles were synthesized by the reaction of respective anilines (one in each reaction) and 2-bromoacetylbromide in an aqueous medium. The targeted bi-heterocyclic compounds were synthesized by stirring nucleophilic 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol with different acetamides electrophiles (one after another), in DMF using LiH as base and activator. The proposed structures of newly synthesized compounds were deduced by spectroscopic techniques such as 1H NMR, 13C NMR, EI MS and elemental analysis. These novel bi-heterocycles were tested for their anti-diabetic potential via the in vitro inhibition of $$\alpha $$ -glucosidase enzyme. The in silico study of these molecules was also coherent with their enzyme inhibition data. Furthermore, these molecules were analyzed for their cytotoxic behavior against brine shrimps. It was inferred from the results that most of them exhibited very potent inhibitory potential against the studied enzyme and can be utilized as valuable anti-diabetic agent.

Interactions of binuclear copper(II) complexes with S-substituted thiosalicylate derivatives with some relevant biomolecules

Interactions of copper(II) complexes which contain S-alkyl derivatives of thiosalicylic acid (alkyl = methyl, ethyl, propyl and butyl; aryl = benzyl), marked as 1–5, with guanosine-5′-monophosphate (5′-GMP) and calf thymus DNA (CT-DNA) were studied. Kinetics of substitution reactions of 1–5 with 5′-GMP and CT-DNA were investigated under pseudo-first-order conditions at 310 K and pH = 7.2 in 25 mM Hepes buffer using stopped-flow method. All complexes have high affinity toward studied bio-molecules. Additionally, interactions with CT-DNA were followed by absorption spectroscopy and fluorescence quenching measurements. The results indicate that complexes bind to DNA exhibiting high binding constants (Kb = 104 M−1). During the examination of competitive reactions with ethidium bromide (EB), results showed that complexes can replace EB-bound DNA. In addition, a new crystal structure of the binuclear Cu(II) complex with S-substituted thiosalicylate derivative has been reported. In the present series of Cu(II) complexes the crystal structure is the first example of a complex comprising an S-aryl derivative of thiosalicylate ligand. Through comparative study of structural properties of six molecules from four crystal structures we examined the structural variations, potentially important for biological activity of these complexes.

Repositioning Salirasib as a new antimalarial agent.

Malaria is a serious tropical disease that kills thousands of people every year, mainly in Africa, due to Plasmodium falciparum infections. Salirasib is a promising cancer drug candidate that interferes with the post-translational modification of Ras. This S-farnesyl thiosalicylate inhibits isoprenylcysteine carboxyl methyltransferase (ICMT), a validated target for cancer drug development. There is a high homology between the human and the parasite enzyme isoforms, in addition to being a druggable target. Looking to repurpose its structure as an antimalarial drug, a collection of S-substituted derivatives of thiosalicylic acid were prepared by introducing 1,2,3-triazole as a diversity entry point or by direct alkylation of the thiol. We further investigated the in vitro toxicity of FTS analogues to Plasmodium falciparum in the asexual stages and in Vero cells. An antiplasmodial activity assay was performed using a simple, high-sensitivity methodology based on nanoluciferase (NLuc)-transfected P. falciparum parasites. The results showed that some of the analogs were active at low micromolar concentration, including Salirasib. The most potent member of the series has S-farnesyl and the 1,2,3-triazole moiety substituted with phytyl. However, the compound substituted with methyl-naphthyl shows promising physicochemical and activity values. The low cytotoxicity in eukaryotic cells of the most active analogs provided good therapeutic indices, being starting-point candidates for future antimalarial drug development.

New Heterocyclic Compounds from 1,2,4-triazoles Class with Potential Cytotoxic Activity

Acylhydrazinecarbothioamides (2a,b) were synthesized by addition of 2-(5H-dibenzo[a,d][7]annulen-5-yl)acetohydrazide to different isothiocyanates. The new 1,2,4-triazol-3-thioles (3a,b) were synthesized by cyclization of new 2- acylhydrazinecarbothioamides (3a,b) in basic media. Alkylation of 1,2,4-triazole-3-thiols (3a-c) with ethyl bromide gave only S-substituted derivatives (4a-c). The structures of the synthesized compounds have been established on spectral data (IR, 1H-NMR and 13C-NMR spectroscopy) and elemental analysis. The cytotoxic effect of new compounds was evaluated using two alternative models on plant and invertebrate organisms.

Synthesis and Antitumor Properties of New 1,2,4-Triazoles and 1,3,4-Thiadiazoles

New S-substituted derivatives were synthesized via alkylation of mercapto-substituted 1,2,4-triazoles and 1,3,4-thiadiazoles by various aliphatic and aromatic halides. Aminomethylation of 5-thio-1,2,4-triazoles formed the corresponding Mannich bases. The antitumor properties of the synthesized compounds against sarcoma 37 and EAC grafted tumor models and their influence on DNA methylation were studied

Синтез и противоопухолевые свойства новых производных 1,2,4-триазола и 1,3,4-тиадиазола

Реакцией алкилирования меркаптозамещенных 1,2,4-триазолов и 1,3,4-тиадиазолов различными алифатическими и ароматическими галогенидами синтезированы новые S-замещенные производные последних. Осуществлено аминометилирование 5-тио-1,2,4-триазолов с образованием соответствующих оснований Манниха. Изучены противоопухолевые свойства синтезированных соединений на моделях перевиваемых опухолей саркома 37 и АКЭ, а также их влияние на процессы метилирования ДНК.

Preliminary structure-activity relationship studies on some novel s-substituted aliphatic analogues of 5-{1-[(4- chlorophenyl) sulfonyl]-3-piperidinyl}-1, 3, 4-oxadiazol-2-yl sulfide

Purpose : To study the structure-activity relationships of synthetic multifunctional sulfides through evaluation of lipoxygenase and anti-bacterial activities. Methods : S-substituted derivatives of the parent compound 5-(1-(4- chlorophenylsulfonyl) piperidin-3- yl)-1, 3, 4-oxadiazole-2-thiol were synthesized through reaction with different saturated and unsaturated alkyl halides in DMF medium, with NaH catalyst. Spectral characterization of each derivative was carried out with respect to IR, 1H - NMR, 13C - NMR and EI - MS. The lipoxygenase inhibitory and antibacterial activities of the derivatives were determined using standard procedures . Results : Compound 5e exhibited higher lipoxygenase inhibitory potential than the standard (Baicalein®), with % inhibition of 94.71 ± 0.45 and IC50 of 20.72 ± 0.34 μmoles/L. Compound 5b showed significant antibacterial potential against all the bacterial strains with % inhibition ranging from 62.04 ± 2.78, 69.49 ± 0.41, 63.38 ± 1.97 and 59.70 ± 3.70 to 78.32 ± 0.41, while MIC ranged from 8.18 ± 2.00, 10.60 ± 1.83, 10.84 ± 3.00, 9.81 ± 1.86 and 11.73 ± 5.00 μmoles/L for S. typhi, E. coli, P. aeruginosa, B. subtilis and S. aureus, respectively. Compounds 5d, 5e and 5g showed good antibacterial activity against S. typhi and B. subtilis bacterial strains. Conclusion : The results suggest that compound 5e bearing n-pentyl group is a potent lipoxygenase inhibitor, while compound 5b with n-propyl substitution is a strong antibacterial agent. In addition, compounds 5d, 5e and 5g bearing n-butyl, n-pentyl and n-octyl groups, respectively, are good antibacterial agents against S. typhi and B. subtilis. Keywords : Sulfides, Antibacterial activity, Lipoxygenase activity, Spectral analysis

Synthesis and antibacterial study of some s-substituted aliphatic analogues of 2-mercapto-5-(1-(4-toluenesulfonyl) piperidin-4-yl)-1,3,4-oxadiazole

Purpose: To synthesize a series of analogues of 1,3,4-oxadiazole and to evaluate their antibacterial activity.Methods: Ethyl piperidin-4-carboxylate (1) was mixed with 4-toluenesulfonyl chloride (2) in benignant conditions to yield ethyl 1-(4-toluenesulfonyl)piperidin-4-carboxylate (3) and then 1-(4- toluenesulfonyl)piperidin-4-carbohydrazide (4). Intermolecular cyclization of 4 into 2-mercapto-5-(1-(4- toluenesulfonyl) piperidin-4-yl)-1,3,4-oxadiazole (5) was obtained on reflux with CS2 in the presence of KOH. Molecule 5 was stirred with alkyl halides, 6a-i, in DMF in the presence of LiH to synthesize the final compounds, 7a-i. The structures of these molecules were elucidated by Fourier transform infra-red (FTIR) spectroscopy, proton nuclear magnetic resonance (1H-NMR) and electron impact mass spectrometry (EI-MS). Antibacterial activity was evaluated against five bacterial strains, namely, Salmonella typhi, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis, with ciprofloxacin used as standard antibacterial agent.Results: Out of nine synthesized derivatives, compound 7a was the most active against three bacterial strains, S. typhi, E. coli and P. aeruginosa, with minimum inhibitory concentration (MIC) of 9.11 ± 0.40, 9.89 ± 0.45 and 9.14 ± 0.72 μM, respectively, compared with 7.45 ± 0.58, 7.16 ± 0.58 and 7.14 ± 0.18 μM, respectively, for the reference standard (ciprofloxacin). Similarly, compounds 7a - 7c showed relatively good antibacterial activity against B. subtilis strain while compound 7e - 7g revealed good results against S. typhi bacterial strain.Conclusion: The results indicate that S-substituted derivatives of the parent compound are more effective antibacterial agents than the parent compound, even with minor differences in substituents.Keywords: 1,3,4-Oxadiazole, Antibacterial activity, Ethyl piperidin-4-carboxylate, Sulfonamide

Synthesis of some novel enzyme inhibitors and antibacterial agents derived from 5-(1-(4-tosyl)piperidin-4-yl)-1,3,4-oxadiazol-2-thiol

ABSTRACT Keeping in mind the pharmacological importance of the 1,3,4-oxadiazole moiety, a series of new S-substituted derivatives, 5a-h, of 5-(1-(4-tosyl)piperidin-4-yl)-1,3,4-oxadiazol-2-thiol (3) were synthesized. The reaction of p-toluenesulfonyl chloride (a) and ethyl isonipecotate (b) produced ethyl 1-(4-tosyl)piperidin-4-carboxylate (1) which was further transformed into 1-(4-tosyl)piperidin-4-carbohydrazide (2) by hydrazine hydrate in methanol. Compound 2 was refluxed with CS2 in the presence of KOH to synthesize 5-(1-(4-tosyl)piperidin-4-yl)-1,3,4-oxadiazol-2-thiol (3). The desired compounds, 5a-h, were synthesized by stirring 3 with aralkyl halides, 4a-h, in DMF using NaH as an activator. The structures of synthesized compounds were elucidated by 1H-NMR, IR and EI-MS spectral studies. These compounds were further evaluated for enzyme inhibitory activity against lipoxygenase and alpha-glucosidase, along with antibacterial activity against Gram-negative and Gram-positive bacteria.

Synthesis and biological activity of 1,3,4-oxa(thia)diazole, 1,2,4-triazole-5-(thio)one and S-substituted derivatives of 3-((2-carboxyethyl)phenylamino)propanoic acid

A series of novel derivatives of 3-((2-carboxyethyl)phenylamino)propanoic acid bearing two identical substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole, or 1,2,4-triazole moieties were synthesized and their molecular structures were confirmed by IR, 1H, 13C NMR spectroscopy, and elemental analysis data. The synthesized compounds were screened for their reducing power, free radical scavenging, plant growth regulating, and antimicrobial properties. 5,5′-((Phenylazanediyl)bis(ethane-2,1-diyl))bis(4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione) showed excellent antioxidant activity, three times higher than that of the antibiotic control (cefazolin). 2,2′-((((Phenylazanediyl)bis(ethane-2,1-diyl))bis(4-phenyl-4H-1,2,4-triazole-5,3-diyl))bis(sulfanediyl))diacetate exhibited notable bactericidal activity against Pseudomonas aeruginosa with MBC and MIC values 7.3 µg/ml, whereas 12 compounds displayed significant fungicidal activity against Candida albicans with MIC value 3.9 µg/ml. Synthesis of compounds 2–27. R: 2, 5, 7, 10, 13, 15-27 C6H5–; 3, 8, 11 4-Cl-C6H4–; 4, 9, 12 CH3–; 6, 14 2.6-(CH3)2-C6H3–; R′: 15 CH3CH2–; 16 (CH3)2CH–; 17 (CH3)2CHCH2–; 18 CH3CH2CH2CH2–; 19 (CH3)2CHCH2CH2–; 20 CH3CH2CH2CH2CH2–; 21 NH2COCH2–; 22 C6H5CH2–; 23 C6H5COCH2–; 24 4-ClC6H4COCH2–; 25 4-NO2C6H4COCH2–; 26 C2H5OCOCH2–.

Synthesis and physical-chemical properties of 3-benzyl-8-(5-mercapto-4-phenyl-[1,2,4]-triazole-3-ylmethylthiomethyl)xanthine and its s-substituted derivatives

Aim. Currently, researches, devoted to obtain new active compounds, are carried out among various classes of organic compounds, and combination of several active heterocyclic fragments in one molecule is considered the key way in such researches.Methods and results. For this purpose, we have developed a preparative method of synthesis of 3-benzyl-8-(5-mercapto-4-phenyl-[1,2,4]-triazole-3-ylmethylthiomethyl)xanthine and its S-substituted derivatives. On example of propyl ester of [5-(3-benzylxanthinyl-8-methylthiomethyl)-4-phenyl-[1,2,4]triazole-3-yl]thioacetic acid the possibility of further functionalization of triazolylmethylthiomethylxanthines has been shown.Conclusion. The structures and identity of all synthesized compounds have been proved by elemental analysis, IR-, 1H NMR-spectroscopy, mass-spectrometry and by thin layer chromatography.

Synthesis, Characterization and Antibacterial Activity of some Novel Thiosemicarbazides, 1,2,4-Triazol-3-thiols and their S-substituted Derivatives.

The thiosemicarbazides 3a-c were appeared by reaction of the corresponding substituted hydrazides 1a-c with allylisothiocyanate 2. Synthesis of some novel 1,2,4-triazole-thiols 4a-c bearing a pyridyl unit using 1-(x-picolinoyl)-4-allyl-thiosemicarbazides (x = 2,3,4) in an alkaline solution, is reported. Also, the S-alkylation of triazole derivatives 5-7a-c is described. The structure of the synthesized compounds resulted from the IR, (1)H and -(13)C NMR spectroscopy and elemental analysis data. The antibacterial studies to all of the synthesized compounds against B. cereus, E. coli, P. aeroginosa, S. aureus and E. faecalis as MIC values are reported. Some of these compounds such as 7a, 4a and 3a exhibited a good to significant antibacterial activity.

SYNTHESIS, STRUCTURAL CHARACTERIZATION AND ENZYME INHIBITION STUDIES ON 5-(2-NITROSTYRYL)-1,3,4-OXADIAZOLE-2-THIOL DERIVATIVES

In the present work, S-substituted derivatives of 5-(2-nitrostyryl)-1,3,4-oxadiazole-2-thiol (4) were synthesized by successive conversions of 3-(2-nitrophenyl) acrylic acid (1) into its respective ester, hydrazide and 1,3,4-oxadiazole. Finally the target compounds were obtained by reaction of 5-(2-nitrostyryl)-1,3,4oxadiazole-2-thiol (4) with a series of various electrophiles, (5a-I), in N,N-dimethyl formamide (DMF) in the presence of sodium hydride (NaH). The structural characterization of these newly synthesized compounds was done by IR, 1H-NMR, HR-MS and EI-MS spectral data. All these compounds were evaluated for their

The synthesis of S-substituted derivatives of 3-[2-[(4-methylphenyl)amino]ethyl]-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thiones and their antioxidative activity

A series of novel S-substituted derivatives of 3-[2-[(4-methylphenyl)amino]ethyl]-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thiones was synthesized by the reaction of 1,2,4-triazole-5-thiones with alkyl, benzyl, and phenacyl halides as well as halogen-containing esters or amides. The reactions were carried out in DMF in the presence of KOH, K2CO3, or triethylamine, or in dioxane in the presence of NaH. The synthesized compounds were screened for their free radical scavenging activity. N-[2-[5-(Butylsulfanyl)-4-phenyl-4H-1,2,4-triazol-3-yl]ethyl]-4-methylaniline showed excellent antioxidant activity, 2.5 times higher than that of the antibiotic control (cefazolin).

Microwave-assisted synthesis and anticonvulsant activity of 5,6-bisaryl-1,2,4-triazine-3-thiol derivatives

A series of 5,6-bisaryl-1,2,4-triazine-3-thiol derivatives were synthesized through microwave-promoted chemistry by condensation of the aromatic 1,2-diketones and thiosemicarbazide in a mixed green solvent. Subsequently, S-alkylation of 1,2,4-triazine-3-thiols afforded S-substituted derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo by electroshock and pentylenetetrazole (PTZ)-induced seizures tests. Among them, compound 4a bearing 4-pyridylmethylthio moiety on the triazine ring showed the highest protection in both electroshock and PTZ-induced seizures tests. Compound 4a showed no sign of neurotoxicity at the dose of 100 mg/kg in both rotarod and chimney tests.