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Thirty compounds having 1-[2-(5-substituted-2-benzoxazolinone-3-yl) acetyl]-3,5-disubstitutedphenyl-2-pyrazoline structure and nine compounds having N '-(1,3-disubstitutedphenylallylidene)-2-(5-substituted-2-benzoxazolinone-3-yl)acetohydrazide skeleton were synthesized and evaluated as monoamine oxidase (MAO) inhibitors. All of the compounds exhibited selective MAO-A inhibitor activity in the nanomolar or low micromolar range. The results of the molecular docking for hydrazone derivatives supported the in vitro results. Five compounds, 6 (0.008 μM, Selectivity Index (SI): 9.70 × 10 -4 ), 7 (0.009 μM, SI: 4.55 × 10 -5 ), 14 (0.001 μM, SI: 8.00 × 10 -4 ), 21 (0.009 μM, SI: 1.37 × 10 -5 ), and 42 (0.010 μM, SI: 5.40 × 10 -6 ), exhibiting the highest inhibition and selectivity toward hMAO-A and nontoxic to hepatocytes were assessed for antidepressant activity as acute and subchronic in mice. All of these five compounds showed significant antidepressant activity with subchronic administration consistent with the increase in the brain serotonin levels and the compounds crossed the blood-brain barrier according to parallel artificial membrane permeation assay. Compounds 14, 21 , and 42 exhibited an ex vivo MAO-A profile, which is highly consistent with the in vitro data.

Systemic candidiasis is a rampant bloodstream infection of Candida spp. and C. albicans is the major pathogen isolated from infected humans. Azoles, the most common class of antifungals which suffer from increasing resistance, and especially intrinsically resistant non-albicans Candida (NAC) species, act by inhibiting fungal lanosterol 14α-demethylase (CYP51). In this study we identified a number of azole compounds in 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol/ethanone oxime ester structure through virtual screening using consensus scoring approach, synthesized and tested them for their antifungal properties. We reached several hits with potent activity against azole-susceptible and azole-resistant Candida spp. as well as biofilms of C. albicans. 5i's minimum inhibitor concentration (MIC) was 0.125 μg/ml against C. albicans, 0.5 μg/ml against C. krusei and 1 μg/ml against azole-resistant C. tropicalis isolate. Considering the MIC values of fluconazole against these fungi (0.5, 32 and 512 μg/ml, respectively), 5i emerged as a highly potent derivative. The minimum biofilm inhibitor concentration (MBIC) of 5c, 5j, and 5p were 0.5 μg/ml (and 5i was 2 μg/ml) against C. albicans biofilms, lower than that of amphotericin B (4 μg/ml), a first-line antifungal with antibiofilm activity. In addition, the active compounds showed neglectable toxicity to human monocytic cell line. We further analyzed the docking poses of the active compounds in C. albicans CYP51 (CACYP51) homology model catalytic site and identified molecular interactions in agreement with those of known azoles with fungal CYP51s and mutagenesis studies of CACYP51. We observed the stability of CACYP51 in complex with 5i in molecular dynamics simulations., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Currently available antiepileptic drugs offer limited symptomatic treatment and fail to cure more than 30% of the epileptic seizures. (Arylalkyl)azoles are a class of anticonvulsants including nafimidone and loreclezole. Here, we report the design and synthesis of new (arylalkyl)azoles in N-[1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene]hydroxylamine ester structure, their anticonvulsant screening and in silico prediction studies of their pharmacokinetic properties., Methods: The title compounds were synthesized according to the Steglich esterification of N-[1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene]hydroxylamine with various carboxylic acids. Anticonvulsant identification and quantification tests were performed in mice by the Epilepsy Therapy Screening Program (ETSP) of the National Institutes of Health (NIH) using 6Hz psychomotor, maximal electroshock (MES), and rotorod tests. Their physicochemical and pharmacokinetic properties were calculated using QikProp., Results: Most of the compounds showed protection against 6Hz- and/or MES-induced seizures. 4a, 4b, and 4g were active at 100mg/kg, 4g was active in both tests without neurotoxicity. According to the QikProp calculations the title compounds were druglike and had some favourable properties such as high membrane permeability and oral absorptivity., Conclusion: Anticonvulsant screening of a set N-[1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethylidene]hydroxylamine esters yielded some active derivatives in 6Hz and MES test. Especially, 4g emerged as a promising compound with activity at 100mg/kg and no toxicity. The compounds were predicted to be drug like and have good pharmacokinetic properties except hERG inhibition, which needs to be addressed in further optimization studies., (Copyright © 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

(Arylalkyl)azoles are a class of antiepileptic compounds including nafimidone, denzimol, and loreclezole (LRZ). Nafimidone and denzimol are thought to inhibit voltage-gated sodium channels (VGSCs) and enhance γ-aminobutyric acid (GABA)-mediated response. LRZ, a positive allosteric modulator of A-type GABA receptors (GABA A Rs), was reported to be sensitive to Asn265 of the β2/β3 subunit. Here, we report new N-[1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene]hydroxylamine esters showing anticonvulsant activity in animal models, including the 6-Hz psychomotor seizure test, a model for therapy-resistant partial seizure. We performed molecular docking studies for our active compounds using GABA A R and VGSC homology models. They predicted high affinity to the benzodiazepine binding site of GABA A R in line with the experimental results. Also, the binding mode and interactions of LRZ in its putative allosteric binding site of GABA A R is elucidated., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

(Arylalkyl)azoles (AAAs) emerged as a novel class of antiepileptic agents with the invention of nafimidone and denzimol. Several AAA derivatives with potent anticonvulsant activities have been reported so far, however neurotoxicity was usually an issue. We prepared a set of ester derivatives of 1-(2-naphthyl)-2-(1H-1,2,4-triazol-1-yl)ethanone oxime and evaluated their anticonvulsant and neurotoxic effects in mice. Most of our compounds were protective against maximal electroshock (MES)- and/or subcutaneous metrazol (s.c. MET)-induced seizures whereas none of them showed neurotoxicity. Nafimidone and denzimol have an activity profile similar to that of phenytoin or carbamazepine, both of which are known to inhibit voltage-gated sodium channels (VGSCs) as well as to enhance γ-aminobutiric acid (GABA)-mediated response. In order to get insights into the effects of our compounds on VGSCs and A-type GABA receptors (GABA A Rs) we performed docking studies using homology model of Na + channel inner pore and GABA A R as docking scaffolds. We found that our compounds bind VGSCs in similar ways as phenytoin, carbamazepine, and lamotrigine. They showed strong affinity to benzodiazepine (BZD) binding site and their binding interactions were mainly complied with the experimental data and the reported BZD binding model., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

In this study, a new class of 4-amino-3-substituted-1,2,4-triazole-5-thiones (1-4) and their corresponding condensed derivatives 3,6-disubstituted 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (1a-4c) were synthesized and evaluated for their analgesic/anti-inflammatory activities. All synthesized compounds were also tested for their gastric toxicity and antioxidant activity on acute administration. Most of the compounds showed significant activity in both carrageenan-induced oedema and acetic acid-induced writhing tests besides negligible gastrointestinal toxicity. The compounds showing less ulcerogenic effect also showed less lipid peroxidation (LPO) level. Most promising results were obtained with the compounds that placed a fluoro or a chloride on the phenyl ring at the sixth position of the fused ring.

Some novel 1-methyl-4-(2-(2-substitutedphenyl-1H-benzimidazol-1-yl)acetyl)thiosemicarbazides (16a-20a), 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl]-N-methyl-1,3,4-thiadiazol-2-amines (17b-20b), and 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl-4-methyl-2H-1,2,4-triazole-3(4H)-thiones (16c-20c) were synthesized and tested for antioxidant properties by using various in vitro systems. Compounds 16a-20a were found to be a good scavenger of DPPH radical (IC(50), 26 microM; IC(50), 30 microM; IC(50), 43 microM; IC(50), 55 microM; IC(50), 74 microM, respectively) when compared to BHT (IC(50), 54 microM). Noteworthy results could not be found on superoxide radical. Compound 19b, which is the most active derivative inhibited slightly lipid peroxidation (28%) at 10(-3)M concentration. Compound 17c inhibited the microsomal ethoxyresorufin O-deethylase (EROD) activity with an IC(50)=4.5 x 10(-4)M which is similarly better than the specific inhibitor caffeine IC(50)=5.2 x 10(-4)M.

New series of 5-fluoro-1H-indole-2,3-dione-3-thiosemicarbazones 2a-k and 5-fluoro-1-morpholino/piperidinomethyl-1H-indole-2,3-dione-3-thiosemicarbazones 3a-r were synthesized. The structures of the synthesized compounds were confirmed by spectral data, elemental and single crystal X-ray diffraction analysis. The new 5-fluoro-1H-indole-2,3-dione derivatives, along with previously reported 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones 2l-v, 1-morpholino/piperidinomethyl-5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones 4a-l, and 5-nitro-1H-indole-2,3-dione-3-[(4-oxo-1,3-thiazolidin-2-ylidene)hydrazones] 5a-s, were evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis H37Rv. Among the tested compounds, 5-nitro-1H-indole-2,3-dione-3-thiosemicarbazones (2p, 2r, and 2s) and its 1-morpholinomethyl derivatives (4a, 4e, 4g, and 4i) exhibited significant inhibitory activity in the primary screen. The antituberculosis activity of molecules with diverse skeletons was investigated by means of the Electronic-Topological Method (ETM). Ten pharmacophores and ten anti-pharmacophores that have been found by this form the basis of the system capable of predicting the structures of potentially active compounds. The forecasting ability of the system has been tested on structures that differ from those synthesized. The probability of correct identification for active compounds was found as equal to 93% in average. To obtain the algorithmic base for the activity prediction, Artificial Neural Networks were used after the ETM (the so-called combined ETM-ANN method). As the result, only 9 pharmacophores and anti-pharmacophores were chosen as the most important ones for the activity. By this, ANNs classified correctly 94.4%, or 67 compounds from 71.

In the course of our ongoing studies, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones substituted with flurbiprofen (CAS 5104-49-4) has been prepared. The compounds were synthesized by the cyclization of the 3-[(2-fluoro-4-biphenyl)ethyl]-5-mercapto-1,2,4-triazole (3) with chloroacetic acid and relevant benzaldehydes in the presence of acetic acid, acetic anhydride and anhydrous sodium acetate in one step. The product of this one-pot synthesis that precipitated on cooling of the reaction mixture was identified undoubtedly by X-ray crystallographic analysis as thiazolo[3,2-b]-1,2,4-triazole. In-vivo anti-inflammatory and analgesic activities of the compounds were assessed by carrageenan-induced hind paw edema and p-benzoquinone-induced abdominal constriction tests in mice, respectively. In addition, the ulcerogenic risks were evaluated. It is worthy of saying that the compounds which maintained analgesic/antiinflammatory activity of the starting compound were found to be safer with regard to gastric lesion risks at 100 mg/kg oral dose when compared with flurbiprofen. Among the synthesized compounds 3d showed the highest analgesic and antiinflammatory activity without inducing any gastric lesion and deserves further attention in order to develop new lead drug candidates.

The first ruthenium-diiron complex [(mu-pdt)Fe2(CO)5{PPh2(C6H4CCbpy)}Ru(bpy)2]2+ 1 (pdt = propyldithiolate, bpy = 2,2'-bipyridine) is described in which the photoactive ruthenium trisbipyridyl unit is linked to a model of the iron hydrogenase active site by a ligand directly attached to one of the iron centers. Electrochemical and photophysical studies show that the light-induced MLCT excited state of the title complex is localized towards the potential diiron acceptor unit. However, the relatively mild potential required for the reduction of the acetylenic bipyridine together with the easily oxidized diiron portion leads to a reductive quenching of the excited state, instead. This process results in a transiently oxidized diiron unit which may explain the surprisingly high light sensitivity of complex 1.

A range of ruthenium cyclopentadienyl (Cp) complexes have been prepared and used for isomerization of allylic alcohols to the corresponding saturated carbonyl compounds. Complexes bearing CO ligands show higher activity than those with PPh3 ligands. The isomerization rate is highly affected by the substituents on the Cp ring. Tetra(phenyl)methyl-substituted catalysts rapidly isomerize allylic alcohols under very mild reaction conditions (ambient temperature) with short reaction times. Substituted allylic alcohols have been isomerized by employing Ru-Cp complexes. A study of the isomerization catalyzed by [Ru(Ph5Cp)(CO)2H] (14) indicates that the isomerization catalyzed by ruthenium hydrides partly follows a different mechanism than that of ruthenium halides activated by KOtBu. Furthermore, the lack of ketone exchange when the isomerization was performed in the presence of an unsaturated ketone (1 equiv), different from that obtained by dehydrogenation of the starting allylic alcohol, supports a mechanism in which the isomerization takes place within the coordination sphere of the ruthenium catalyst.

Pentaphenylcyclopentadienyl ruthenium complexes (3) are excellent catalysts for the racemization of secondary alcohols at ambient temperature. The combination of this process with enzymatic resolution of the alcohols results in a highly efficient synthesis of enantiomerically pure acetates at room temperature with short reaction times for most substrates. This new reaction was applied to a wide range of functionalized alcohols including heteroaromatic alcohols, and for many of the latter, enantiopure acetates were efficiently prepared for the first time via dynamic kinetic resolution (DKR). Different substituted cyclopentadienyl ruthenium complexes were prepared and studied as catalysts for racemization of alcohols. Pentaaryl-substituted cyclopentadienyl complexes were found to be highly efficient catalysts for the racemization. Substitution of one of the aryl groups by an alkyl group considerably slows down the racemization process. A study of the racemization of (S)-1-phenylethanol catalyzed by ruthenium hydride eta(5)-Ph(5)CpRu(CO)(2)H (8) indicates that the racemization takes place within the coordination sphere of the ruthenium catalyst. This conclusion was supported by the lack of ketone exchange in the racemization of (S)-1-phenylethanol performed in the presence of p-tolyl methyl ketone (1 equiv), which gave <1% of 1-(p-tolyl)ethanol. The structures of ruthenium chloride and iodide complexes 3a and 3c and of ruthenium hydride complex 8 were confirmed by X-ray analysis.

A new type of thiophene derivative having alpha-thioketone groups at the 3- and 4-positions, viz. the title compound, C22H20O4S3, has been prepared and studied by NMR spectroscopy and single-crystal X-ray diffraction techniques. The molecule is nearly planar, the dihedral angles between the essentially planar thiophene and benzene rings being 9.4 (1) and 10.6 (1) degrees. One of the thioketone O atoms is involved in an intermolecular C-H...O hydrogen-bonding interaction.

The title compound is a double oxygen-bridged dimeric heteronuclear metal complex. The coordination around the Cu atom is distorted square-planar involving two O and two N atoms from the bis(salicylidene)-1,3-propanediamine ligand. The Zn atom in the molecule has a distorted tetrahedral coordination sphere consisting of the two O atoms of the ligand and the two Br atoms. The bridging plane between the metal atoms is not planar.

The title compound, C(17)H(10)S(4), has two independent molecules in the asymmetric unit. In both molecules, the fused heterocycle is almost planar and the phenyl groups make dihedral angles of 42.88 (9) and 52.79 (8) degrees with the fused heterocycle in one molecule, and angles of 40.62 (9) and 52.28 (8) degrees in the other. The crystal packing is governed by short intermolecular S.S interactions, the shortest contact being 3.333 (1) A.

In the title compound, C(17)H(10)S(5), the dithiine ring adopts a boat conformation while the dithiole ring has an envelope conformation. The phenyl groups are planar and make dihedral angles of 40.7 (2) and 59.8 (2) degrees with the best plane of the thiine ring. The shortest intermolecular S...S contact is 3.305 (2) A.

In the title compound, C(17)H(12)S(5), the dithiole ring bearing the aryl substituents assumes an envelope conformation with the maximum deviation from planarity being -0.053 A. The phenyl and benzyl rings are twisted by 33.0 (1) and 31.1 (1) degrees, respectively, out of the dithiole plane. The crystal packing is governed by short S...S interactions, with the shortest being 3.550 (2) A.