Design, synthesis, and biological activity of novel semicarbazones as potent Ryanodine receptor1 inhibitors of Alzheimer's disease.

Ryanodine receptors (RyRs) are important ligand-gated Ca2+ channels; their excessive activation leads to Ca2+ leakage in the sarcoplasmic reticulum that may cause neurological diseases. In this study, three series of novel potent RyR1 inhibitors based on dantrolene and bearing semicarbazone and imidazolyl moieties were designed and synthesized, and their biological activity was evaluated. Using a single-cell calcium imaging method, the calcium overload inhibitory activities of 26 target compounds were tested in the R614C cell line, using dantrolene as a positive control. The preliminary investigation showed that compound 12a suppressed Ca2+ release as evidenced by store overload-induced Ca2+release (SOICR) (31.5 ± 0.1%, 77.2 ± 0.1%, 93.7 ± 0.2%) at 0.1 µM, 3 µM and 10 µM, respectively. Docking simulation results showed that compound 12a could bind at the active site of the RyR1 protein. The Morris water-maze test showed that compound 12a significantly improved the cognitive behavior of AD-model mice. Further studies on the structural optimization of this series of derivatives are currently underway in our laboratory.

Synthesis of New Thiosemicarbazones and Semicarbazones Containing the 1,2,3-1H-triazole-isatin Scaffold: Trypanocidal, Cytotoxicity, Electrochemical Assays, and Molecular Docking.

BACKGROUND: Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most important neglected diseases by the World Health Organization. The only drugs with proven efficacy against Chagas disease are benznidazole and nifurtimox, however both show adverse effects, poor clinical efficacy, and development of resistance. For these reasons, the search for new effective chemical entities is a challenge to research groups and the pharmaceutical industry. OBJECTIVE: Synthesis and evaluation of antitrypanosomal activities of a series of thiosemicarbazones and semicarbazones containing 1,2,3-1H triazole isatin scaffold. METHOD: 5'-(4-alkyl/aryl)-1H-1,2,3-triazole-isatins were prepared by Huisgen 1,3-dipolar cycloaddition and the thiosemicarbazones and semicarbazones were obtained by the 1:1 reactions of the carbonylated derivatives with thiosemicarbazide and semicarbazide hydrochloride, respectively, in methanol, using conventional reflux or microwave heating. The compounds were assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the aetiological agent of Chagas disease. Beyond the thio/semicarbazone derivatives, isatin and triazole synthetic intermediates were also evaluated for comparison. RESULTS: A series of compounds were prepared in good yields. Among the 37 compounds evaluated, 18 were found to be active, in particular thiosemicarbazones containing a non-polar saturated alkyl chain (IC50 = 24.1, 38.6, and 83.2 µM; SI = 11.6, 11.8, and 14.0, respectively). To further elucidate the mechanism of action of these new compounds, the redox behaviour of some active and inactive derivatives was studied by cyclic voltammetry. Molecular docking studies were also performed in two validated protein targets of Trypanosoma cruzi, i.e., cruzipain (CRZ) and phosphodiesterase C (TcrPDEC). CONCLUSION: A class of thio/semicarbazones structurally simple and easily accessible was synthesized. Compounds containing thiosemicarbazone moieties showed the best results in the series, being more active than the corresponding semicarbazones. Our results indicated that the activity of these compounds does not originate from an oxidation-reduction pathway but probably from the interactions with trypanosomal enzymes.

New semicarbazones as gorge-spanning ligands of acetylcholinesterase and potential new drugs against Alzheimer's disease: Synthesis, molecular modeling, NMR, and biological evaluation.

Two new compounds (E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dihydroacridin-1(2H)-ylidene)hydrazinecarbothiomide (3) and (E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dhihydroacridin-1(2H)-ylidene)hydrazinecarboxamide (4) were synthesized and evaluated for their anticholinesterase activities. In vitro tests performed by NMR and Ellman's tests, pointed to a mixed kinetic mechanism for the inhibition of acetylcholinesterase (AChE). This result was corroborated through further docking and molecular dynamics studies, suggesting that the new compounds can work as gorge-spanning ligands by interacting with two different binding sites inside AChE. Also, in silico toxicity evaluation suggested that these new compounds can be less toxic than tacrine.

New approach towards the synthesis of selenosemicarbazones, useful compounds for Chagas' disease.

Herein, we describe a new approach towards the synthesis of selenosemicarbazones. The reaction involves an O-Se exchange of semicarbazones using Ishihara reagent. Eleven selenosemicarbazones were prepared using this methodology, with low to moderate yields. Among the prepared compounds the m-bromo phenyl methyl derivative 1b was selected to be evaluated in vivo, in a murine model of acute Chagas' disease. Compound 1b 10 mg/kg bw/day reduced 50% of parasitaemia profile compared with the control group, but was less effective than Benznidazole (50 mg/kg bw/day reduced 90%) and toxic. These studies are important to guide future Chagas drug design.

Influence of susceptibility to hydrolysis and hydrophobicity of arylsemicarbazones on their anti-nociceptive and anti-inflammatory activities.

Benzaldehyde semicarbazone (BS) inhibited zymosan writhing response, carrageenan paw edema and both phases of formaldehyde nociceptive response. 2-hydroxybenzaldehyde semicarbazone (2-OHBS) and semicarbazide inhibited carrageenan paw edema and the second phase of formaldehyde nociceptive response. 2-OHBS inhibited zymosan writhing response. 3- and 4-OHBS did not show such activities. 2-OHBS showed the lowest LUMO energy, the highest contribution of the iminic carbon to LUMO energy, the highest positive charge on the iminic carbon, the highest negative charge on the iminic nitrogen and the highest susceptibility to hydrolysis. Hence semicarbazide may play important roles in 2-OHBS's activities. Inhibition of the first phase of formaldehyde response by BS could be attributed to its higher hydrophobicity and lower susceptibility to hydrolysis in comparison to 2-OHBS.

Preparation, crystallography and spectroscopic properties of the polymeric {(1-(E)-2-pyridinylmethylidene)semicarbazone)(aqua)copper(II)} sulphate dihydrate complex: evidence of dynamic Jahn-Teller effect.

Pyridine-2-carbaldehyde semicarbazone ligand (HL) reacts with copper(II) sulphate in water solution to yield the coordination polymer [{Cu(II)(HL)(H(2)O)(SO(4))}(n)] (1). The crystals are triclinic with space group P(-1) and the metal ion is occupying a distorted octahedral geometry. EPR results show that a dynamic Jahn-Teller (J-T) effect is operative in water solutions and also support the stability of the polymeric chains as they continue to show a characteristic half-field Δm(S)=±2 transitions. UV-visible spectrum analysis allowed access to the J-T stabilization energy of 5995 cm(-1) in water. Thermogravimetric/differential thermal analysis curves showed a step-by-step decomposition of complex 1 with loss of water, release of SO(3) and oxidation of the semicarbazone ligand in the 30-422°C range.

Thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones: anti-Mycobacterium tuberculosis activity and cytotoxicity.

The aim of this study was to identify a candidate drug for the development of anti-tuberculosis therapy from previously synthesized compounds based on the thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones compounds. The minimal inhibitory concentration (MIC) of these compounds against Mycobacterium tuberculosis was determined. Their in vitro cytotoxicity to J774 cells (IC50) was determined to establish a selectivity index (SI) (SI=IC50/MIC). The best compounds were the thiosemicarbazones (2, 3 and 4) and the hydrazide/hydrazones (14, 15, 16 and 18). The results are comparable to or better than those of "first line" or "second line" drugs commonly used to treat TB, suggesting these compounds as anti-TB drug candidates.

Synthesis and antimalarial activity of semicarbazone and thiosemicarbazone derivatives.

Seventeen semicarbazone and thiosemicarbazone derivatives were prepared and tested in vitro against a chloroquine resistant strain of Plasmodium falciparum (W2) to evaluate their antiplasmodial potential. Three thiosemicarbazones were found to be active against the parasite and non-toxic to human peripheral blood mononuclear cells (PBMC). Among these, compound 5b presented the lowest IC50 value against P. falciparum (7.2 microM) and was the least toxic in the PBMC proliferation assay (IC50=73.5 microM). It was selected for in vivo tests on mice infected with Plasmodium berghei (strain NK-65). The thiosemicarbazone 5b was able to reduce the parasitaemia by 61% at 20 mg/kg on day 7 after infection without any sign of toxicity to the animals. In comparison, the standard drug chloroquine at 15 mg/kg showed a reduction around 95%. These in vitro and in vivo results make 5b an interesting lead for further development.

Nitrofurylsemicarbazone rhenium and ruthenium complexes as anti-trypanosomal agents.

Rhenium and ruthenium complexes of the type [Re(V)OCl(2)(PPh(3))L] and [Ru(II)Cl(2)(DMSO)(2)L], where L are 5-nitrofurylsemicarbazone derivatives, were prepared in an effort to obtain new anti-trypanosomal agents combining the recognized biological activity of these metals and the trypanocidal activity of the free ligands. Rhenium complexes resulted unstable in aqueous solution not allowing their use as potential drugs. On the other hand, complexation to ruthenium of the bioactive ligands lead to the lack of antiprotozoa activity even though free radical production and redox cycling induction were detected when the compounds were incubated in presence of Trypanosoma cruzi cells. The lack of anti-trypanosomal activity of ruthenium complexes could be explained on the basis of their high protein binding capacity and their high hydrophilicity.

Synthesis and anti-trypanosomal activity of novel 5-nitro-2-furaldehyde and 5-nitrothiophene-2-carboxaldehyde semicarbazone derivatives.

Several novel semicarbazones derivatives were prepared from 5-nitro-2-furaldehyde or 5-nitrothiophene-2-carboxaldehyde, and tested in vitro as potential anti-trypanosomal agents. The compounds were prepared in good to excellent yields in 2-3 steps from readily available starting materials. Some derivatives were found to be active against Trypanosoma cruzi with an activity similar to that of Nifurtimox.

Síntese e atividade biológica de novas tiossemicarbazonas / Synthesis and biological activity of new thiosemicarbazones

Este trabalho descreve a síntese e avaliaçäo estrutural de nove tiossemicarbazonas, obtidas pela condensaçäo de ariltioacetaldeídos e artiopropanonas substituídas com cloridrato de tiossemicarbazida. Estes novos compostos foram testados in vitro pelo fitoteste Lepidium sativum. Todos eles apresentaram atividade inibidora do crescimento celular (pI50) superior àquela de 5-fluoruacila, composto anticancerígeno, utilizado como referência.

Synthesis, DNA interaction and antineoplastic activity of semicarbazone derivatives.

A number of antineoplastic agents including procarbazine and bisantrene derive from hydrazine, but so far none have been developed from semicarbazide. In order to assay active minimal structures, thirteen new compounds were prepared by replacing hydrogen atoms in semicarbazone amine group by alkylamine moieties, employing an improved procedure. DNA binding was evaluated by treatment of a drug solution with DNA-cellulose complex and further measurement of remaining drug by UV spectroscopy and the affinity observed to range from medium to weak. On testing these compounds against human neoplastic cell lines, only a nitroderivative proved active on CNS and Breast cell lines at 10(-4) M. This member was studied by cyclic voltammetry.

Semicarbazonas heterociclicas potencialmente antifungicas: 1. Preparacao e caracterizacao / Potentially antifungical heterocyclic semicarbazones: 1. Preparation and characterization

Com o objetivo de elucidar a estrutura de semicarbazonas heterociclicas potencialmente antifungicas, foram preparados quatro compostos desta classe. Eles foram analisados mediante espectrometria de infravermelho, ultravioleta e ressonancia magnetica protonica, que corresponderam as estruturas esperadas