Development of new chiral 1,2,4-triazole-3-thiones and 1,3,4-thiadiazoles with promising in vivo anticonvulsant activity targeting GABAergic system and voltage-gated sodium channels (VGSCs).

Antiepileptic drugs (AEDs) are used in the treatment of epilepsy, a neurodegenerative disease characterized by recurrent and untriggered seizures that aim to prevent seizures as a symptomatic treatment. However, they still have significant side effects as well as drug resistance. In recent years, especially 1,3,4-thiadiazoles and 1,2,4-triazoles have attracted attention in preclinical and clinical studies as important drug candidates owing to their anticonvulsant properties. Therefore, in this study, which was conducted to discover AED candidate molecules with reduced side effects at low doses, a series of chiral 2,5-disubstituted-1,3,4-thiadiazoles (4a-d) and 4,5-disubstituted-1,2,4-triazole-3 thiones (5a-d) were designed and synthesized starting from l-phenylalanine ethyl ester hydrochloride. The anticonvulsant activities of the new chiral compounds were assessed in several animal seizure models in mice and rats for initial (phase I) screening after their chemical structures including the configuration of the chiral center were elucidated using spectroscopic methods and elemental analysis. First, all chiral compounds were pre-screened using acute seizure tests induced electrically (maximal electroshock test, 6 Hz psychomotor seizure model) and induced chemically (subcutaneous metrazol seizure model) in mice and also their neurotoxicity (TOX) was determined in the rotorad assay. Two of the tested compounds were used for quantitative testing, and (S)-(+)5-[1-(4-fluorobenzamido)-2-phenylethyl]-4-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5b) and (S)-(+)-(5-[1-(4-fluorobenzamido)-2-phenylethyl]-4-(4-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5c) emerged as the most promising anticonvulsant drug candidates and also showed low neurotoxicity. The antiepileptogenic potential of these compounds was determined using a chronic seizure induced electrically corneal kindled mouse model. Furthermore, all chiral compounds were tested for their neuroprotective effect against excitotoxic kainic acid (KA) and N-methyl-d-aspartate (NMDA) induced in vitro neuroprotection assay using an organotypic hippocampal slice culture. The KA-induced neuroprotection assay results revealed that compounds 5b and 5c, which are the leading compounds for anticonvulsant activity, also had the strongest neuroprotective effects with IC50 values of 103.30 ± 1.14 and 113.40 ± 1.20 µM respectively. Molecular docking studies conducted to investigate the molecular binding mechanism of the tested compounds on the GABAA receptor showed that compound 5b exhibits a strong affinity to the benzodiazepine (BZD) binding site on GABA. It also revealed that the NaV1.3 binding interactions were consistent with the experimental data and the reported binding mode of the ICA121431 inhibitor. This suggests that compound 5b has a high affinity for these specific binding sites, indicating its potential as a ligand for modulating GABAA and NaV1.3 receptor activity. Furthermore, the ADME properties displayed that all the physicochemical and pharmacological parameters of the compounds stayed within the specified limits and revealed a high bioavailability profile.

Chalcones bearing nitrogen-containing heterocyclics as multi-targeted inhibitors: Design, synthesis, biological evaluation and molecular docking studies.

In this work, a series of chalcones (1a-d, 2a-d, 3a-d, 4a-d, and 5a-d) were designed and synthesized by Claisen-Schmidt condensation. Also, their chemical structures were elucidated using UV-Vis, FT IR, 1 H NMR, 13 C NMR, MS spectral data, and elemental analyses. Subsequently, the anticholinesterase, tyrosinase, urease inhibitory activities and antioxidant activities of all chalcones were evaluated. The inhibitory potential of all chalcones in terms of IC50 value was observed to range from 7.18 ± 0.43 to 29.62 ± 0.30 µM against BChE by comparing with Galantamine (IC50 46.06 ± 0.10 µM) as a reference drug. Also, compounds 2c, 3c, 4c, 4b, and 4d exhibited high anticholinesterase activity against both AChE and BChE enzymes. The tyrosinase inhibitory activity results revealed that three compounds (IC50 1.75 ± 0.83 µM for 2b, IC50 2.24 ± 0.11 µM for 3b, and IC50 1.90 ± 0.64 µM for 4b) displayed good inhibitory activity against tyrosinase compared with kojic acid (IC50 0.64 ± 0.12 µM). In addition, other different three chalcones (IC50 22.34 ± 0.25 µM for 2c, IC50 20.98 ± 0.08 µM for 3c, and IC50 18.26 ± 0.13 µM for 4c) showed excellent inhibitory activity against the urease by comparing with thiourea (IC50 23.08 ± 0.19 µM). Compounds 3c and 4c showed the best potency in all antioxidant activity tests. In light of these findings, the structure-activity relationship for compounds was also described. Furthermore, molecular modeling studies, including molecular docking, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and pharmacophore analyses of compounds, gave important information about the interactions and drug-likeness properties. As a result, all chalcones exhibited suitable ADMET findings, predicting good oral bioavailability.

Design, in Silico Studies and Biological Evaluation of New Chiral Thiourea and 1,3-Thiazolidine-4,5-dione Derivatives.

In this study, new chiral thiourea and 1,3-thiazolidine-4,5-dione derivatives were synthesized, it was aimed to evaluate the various biological activities and molecular docking of these compounds. Firstly, the new thioureas (1-16) were obtained by reacting 1-naphthylisothiocyanate with different chiral amines. Then, the chiral thioureas were cyclized with oxalyl chloride to obtain 1,3-thiazolidine-4,5-dione derivatives (17-32). All compounds were evaluated with several in vitro antioxidant and enzyme inhibition activities. Compound 30 was the most active compound against AChE, with a value of IC50 =8.09±0.58 µM. On the other hand, all compounds were tested in silico absorption, distribution, metabolism, and excretion (ADME) assays to better understand their bioavailability. These physicochemical properties, pharmacokinetics, and drug-likeness of all compounds were calculated using SwissADME. Furthermore, according to molecular docking analyses compound 30 exhibited significant binding affinities for all enzymes. Based on our overall observations, compound 30 could be recommended as a potential lead for the therapuetic of Alzheimer's.

Novel fluorine-containing chiral hydrazide-hydrazones: Design, synthesis, structural elucidation, antioxidant and anticholinesterase activity, and in silico studies.

In this study, a series of fluorine-containing chiral hydrazide-hydrazone derivatives [III-XII] from ʟ-cysteine ethyl ester hydrochloride was synthesized as new antioxidant and anticholinesterase agents. The antioxidant activity of these derivatives was evaluated by ABTS+· and DPPH· scavenging and CUPRAC assays and the anticholinesterase activity by the Ellman method spectrophotometrically. The results of the antioxidant assay showed that compounds V, IX, and X exhibited higher activity than BHT and α-tocopherol used as positive standards. Among the synthesized derivatives, compound IX (IC50 : 2.3 ± 1.6 µM) exhibited higher acetylcholinesterase inhibitory activity than galantamine (IC50 : 4.5 ± 0.8 µM). Compounds XI (IC50 : 9.6 ± 1.0 µM), IX (IC50 : 12.5 ± 1.6 µM), III (IC50 : 16.0 ± 1.6 µM), X (IC50 : 17.2 ± 1.8 µM), VI (IC50 : 20.2 ± 0.8 µM), XII (IC50 : 21.5 ± 1.0 µM), and VII (IC50 : 24.6 ± 0.6 µM) displayed better butyrylcholinesterase inhibitory activity than galantamine (IC50 : 46.03 ± 0.14 µM). ADME-Tox analysis was used to probe the drug-like properties of the compounds. Molecular docking studies were also applied to understand the interactions between compounds and targets. The docking calculations were supported by the experimental data. In particular, compound IX, having better activity than galantamine against acetylcholinesterase and butyrylcholinesterase enzymes, was visualized using molecular docking.

Synthesis of novel chiral metal complexes derived from chiral thiosemicarbazide ligands as potential antioxidant agents.

Two new chiral thiosemicarbazide ligands and their Cu (II), Ni (II), Pd (II), and Zn (II) complexes were synthesized and characterized by nuclear magnetic resonance (NMR) (only for ligand), Fourier transform infrared (FT-IR), ultraviolet visible (UV-Vis), mass, and elemental analysis. The antioxidant activity of ligands and their metal complexes was examined. It was found that the antioxidant activity of metal complexes was better than their ligands. In addition, the antioxidant activity, as reflected by free radical scavenging, was evaluated. Besides, Pd (II) complexes exhibited better antioxidant activity than Ni (II), Cu (II), and Zn (II) complexes. Therefore, complexes (3a-Pd and 3b-Pd) can be used as an antioxidant agent or antioxidant test standard.

Design and evaluation of biological activities of 1,3-oxazolidinone derivatives bearing amide, sulfonamide, and thiourea moieties.

1,3-Oxazolidine-2-one is an important heterocyclic ring participating in the chemical structure of many drugs. In this research, 22 new amide/sulfonamide/thiourea derivatives (1-22) were obtained by the reaction of (S)-4-(4-aminobenzyl)-2(1H)-1,3-oxazolidinone with 4-substituted benzoyl chlorides, 4-substituted benzene sulfonyl chlorides, and 4-substituted phenyl isothiocyanates. The structures of all synthesized compounds were clarified by FT-IR, NMR, and mass spectroscopic and elemental analysis techniques. The synthesized compounds were screened for their antimicrobial activity. Antimicrobial susceptibility and cellular physiology were evaluated using the microbroth dilution assay and the flow cytometry method. As a result, it was determined that compound 16 displayed better antimicrobial activity than chloramphenicol against Gram-positive bacteria, especially Staphylococcus aureus. In order to understand the mechanism of effect of the compounds on the cell membrane, fluorescence microscopy was used. Cell membrane damage of the Gram positive bacteria treated with compound 16 was observed as a result of intense staining with propidium iodide. In addition, genotoxicity, cytotoxicity, and absorption, distribution, metabolism, and excretion (ADME) parameters of compound 16 were examined and it was found as non-mutagenic and non-cytotoxic at the concentration at which it showed antimicrobial activity. According to the calculated ADME parameters and drug likeness scores, the compounds can be good drug candidates, especially compound 16.

Synthesis of Novel Chiral Sulfonamide-Bearing 1,2,4-Triazole-3-thione Analogs Derived from D- and L-Phenylalanine Esters as Potential Anti-Influenza Agents.

Novel enantiopure 1,2,4-trizole-3-thiones containing a benzensulfonamide moiety were synthesized via multistep reaction sequence starting with D-phenylalanine methyl ester and L-phenylalanine ethyl ester as a source of chirality. The chemical structures of all compounds were characterized by elemental analysis, UV, IR, (1) H NMR, (13) C NMR, 2D NMR (HETCOR), and mass spectral data. All compounds were tested in vitro antiviral activity against a broad variety of DNA and RNA viruses and in vitro cytostatic activity against murine leukemia (L1210), human T-lymphocyte (CEM) and human cervix carcinoma (HeLa) cell lines. Although enantiopure 1,2,4-triazole-3-thione analogs in (R) configuration emerged as promising anti-influenza A H1N1 subtype in Madin Darby canine kidney cell cultures (MDCK), their enantiomers exhibited no activity. Especially compounds , , , , and (EC50 : 6.5, 6.1, 2.4, 1.6, 1.7 µM, respectively) had excellent activity against influenza A H1N1 subtype compared to the reference drug ribavirin (EC50 : 8.0 µM). Several compounds have been found to inhibit proliferation of L1210, CEM and HeLa cell cultures with IC50 in the 12-53 µM range. Compound and in (R) configuration were the most active compounds (IC50 : 12-22 µM for and IC50 : 19-23 µM for ). Chirality 28:495-513, 2016. © 2016 Wiley Periodicals, Inc.

Synthesis, molecular modeling, and biological evaluation of novel chiral thiosemicarbazone derivatives as potent anticancer agents.

A series of new chiral thiosemicarbazones derived from homochiral amines in both enantiomeric forms were synthesized and evaluated for their in vitro antiproliferative activity against A549 (human alveolar adenocarcinoma), MCF-7 (human breast adenocarcinoma), HeLa (human cervical adenocarcinoma), and HGC-27 (human stomach carcinoma) cell lines. Some of compounds showed inhibitory activities on the growth of cancer cell lines. Especially, compound exhibited the most potent activity (IC50 4.6 µM) against HGC-27 as compared with the reference compound, sindaxel (IC50 10.3 µM), and could be used as a lead compound to search new chiral thiosemicarbazone derivatives as antiproliferative agents.

New piperidine-hydrazone derivatives: Synthesis, biological evaluations and molecular docking studies as AChE and BChE inhibitors.

Hydrazones and the piperidine ring containing compounds were considered as beneficial substrates in drug design. Therefore, this study was aimed at the synthesis of new benzoyl hydrazones derived from ethyl 4-oxopiperidine-1-carboxylate and 2,6-diphenylpiperidin-4-one. The synthesized compounds (1-19) were screened for their antioxidant, anticholinesterase and anticancer activities. The antioxidant capacity of the compounds was evaluated by using four complementary tests. The results showed that compound 7 and 17 have the higher lipid peroxidation inhibitory activity than the other compounds. In DPPH˙ scavenging assay, compounds 5, 6, 10, 14, 17 demonstrated better activity than that of standard BHT, while in ABTS+˙ scavenging assay compound 6 and 17 exhibited better activity among the other compounds. The CUPRAC assay disclosed that compound 2 displayed better activity than α-tocopherol. The anticholinesterase activity was performed against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Compound 11 (IC50: 35.30 ± 1.11 µM) inhibited BChE better than galantamine (IC50: 46.03 ± 0.14 µM). We conclude that the compound 11 can be considered as a candidate for BChE inhibitor. Moreover docking method was applied to elucidate the AChE and BChE inhibitory mechanism of the compound 11. Molecular docking analysis revealed that compound 11 bound to BChE enzyme more efficiently when compared to the AChE due to its orientations and different types of interactions. In addition, the non-cytotoxic properties of the compounds brought them into prominence, although they did not show significant anticancer properties.

Novel platinum(II) and palladium(II) complexes of thiosemicarbazones derived from 5-substitutedthiophene-2-carboxaldehydes and their antiviral and cytotoxic activities.

A series of thiosemicarbazones and their platinum(II) and palladium(II) complexes have been synthesized. The chemical structures of ligands and their complexes were characterized by UV-Vis, IR, (1)H NMR, (13)C NMR, MS spectra, elemental analysis and TGA. The antiviral and cytotoxic activities of all compounds have been tested. Results of broad antiviral evaluation showed that none of the compounds evaluated endowed with anti-DNA or -RNA virus activity at subtoxic concentrations except for the palladium complex 1b. This compound exhibited slightly selective inhibition against cytomegalovirus. The platinum complex 4a exhibited the best cytostatic activities against human cervix carcinoma. Ligands 2, 4 and 5 showed cytostatic potential. The palladium complexes were in general less cytostatic than the corresponding platinum complexes or unliganded congeners.