Semicarbazone derivatives as promising therapeutic alternatives in leishmaniasis.

In the present study, we investigated the in vitro and in vivo leishmanicidal activity of synthetic compounds, containing a semicarbazone scaffold as a peptide mimetic framework. The leishmanicidal effect against amastigotes of Leishmania amazonensis was also evaluated at concentration of 100 µM-0.01 nM. The derivatives 2e, 2f, 2g and 1g, beyond the standards miltefosine and pentamidine, significantly diminished the number of L. amazonensis amastigotes in macrophages. These derivatives were also active against amastigotes of L. braziliensis. As 2g presented potent leishmanicidal activity against the amastigotes of L. amazonensis in macrophages, we also investigated the in vivo leishmanicidal activity of this compound against L. amazonensis. Approximately 105L. amazonensis promastigotes were subcutaneously inoculated into the dermis of the right ear of BALB/c mice, which were subsequently treated with 2g (p.o. or i.p.), miltefosine (p.o.) or glucantime (i.p.) at 30 µmol/kg/day x 28 days. Thus, a similar reduction in the lesion size was observed after the administration of 2g through oral (63.7 ±â€¯10.1%) and intraperitoneal (61.8 ±â€¯3.7%) routes. A larger effect was observed after treatment with miltefosine (97.7 ±â€¯0.4%), and glucantime did not exhibit activity at the dose administered. With respect to the ear parasite load, 2g diminished the number of parasites by p.o. (30.5 ±â€¯5.1%) and i.p. (33.3 ±â€¯4.3%) administration. In addition, 2g induced in vitro apoptosis, autophagy and cell cycle alterations on L. amazonensis promastigotes. In summary, the derivative 2g might represent a lead candidate for antileishmanial drugs, as this compound displayed pronounced leishmanicidal activity.

Semicarbazone analogs as anticonvulsant agents: a review.

Semicarbazones are synthesized by the condensation of semicarbazide and aldehyde/ketone. The literature survey revealed that semicarbazones had been emerged as compounds with diverse biological activities including anticonvulsant, antitubercular, anticancer, and antimicrobial activities. The anticonvulsant activity of semicarbazones is mainly attributed due to the presence of an aryl binding site with aryl/alkyl hydrophobic group, a hydrogen bonding domain and an electron donor group and they are suggested to act by inhibiting sodium ion (Na(+)) channel. Dimmock et al., reported an extensive series of semicarbazones and reported 4-(4-fluorophenoxy) benzaldehyde semicarbazone (C0102862, V102862) as lead molecule. In MES (oral) screening C0102862 showed protective index (PI > 315) more than carbamazepine (PI 101), phenytoin (PI > 21.6) and valproate (PI > 2.17). This review briefly describes the information available about semicarbazone analogs and their anticonvulsant activity.

Hepatoprotective effect of acetone semicarbazone on Ehrlich ascites carcinoma induced carcinogenesis in experimental mice.

OBJECTIVE: To determine the hepatoprotective effect of acetone semicarbazone (ASC) in vivo in normal and Ehrlich ascites carcinoma (EAC) bearing male Swiss albino mice. METHODS: Drug-induced changes in biochemical and behavioral parameters at dose of 2.0 mg/kg body weight for 14 d and nullifying the toxicity induced by EAC cells were studied. The histopathology studies of the protective effects of ASC on vital organs were also assessed. RESULTS: The administration of ASC made insignificant changes in body weight and behavioral (salivation, diarrhea, muscular numbness) changes during treatment period due to minor toxicity were minimized after the treatment in normal mice. The biochemical parameters, including serum glutamate pyruvate transaminase, glutamate oxaloactate transaminase, alkaline phosphatase, serum glucose, cholesterol, urea, triglyceride and billirubin changed modestly in normal mice receiving ASC. Though the treatment continued, these values gradually decreased to normal level after the treatment. In EAC bearing mice, the toxic effects due to EAC cells in all cases were nullified by treatment with the ASC. Significant abnormalities were not detected in histology of the various organs of the normal mice treated with ASC. CONCLUSIONS: ASC can, therefore, be considered safe in formulating novel anticancer drug, as it exhibits strong protective effect against EAC cell bearing mice.

SC68896, a novel small molecule proteasome inhibitor, exerts antiglioma activity in vitro and in vivo.

PURPOSE: Glioblastomas are among the most lethal neoplasms, with a median survival of <1 year. Modulation of the proteasome function has emerged as a novel approach to cancer pharmacotherapy. Here, we characterized the antitumor properties of SC68896, a novel small molecule proteasome inhibitor. EXPERIMENTAL DESIGN: Different tumor cell lines were tested by crystal violet staining for sensitivity to SC68896, given alone or in combination with death ligands. The molecular mechanisms mediating SC68896-induced cell death and changes in cell cycle progression were assessed by immunoblot and flow cytometry. An orthotopic human glioma xenograft model in nude mice was used to examine the in vivo activity of SC68896. RESULTS: SC68896 inhibits the proliferation of cell lines of different types of cancer, including malignant glioma. Exposure of LNT-229 glioma cells to SC68896 results in a concentration- and time-dependent inhibition of the proteasome, with a consequent accumulation of p21 and p27 proteins, cell cycle arrest, caspase cleavage, and induction of apoptosis. Using RNA interference, we show that the effect of SC68896 on glioma cells is facilitated by wild-type p53. SC68896 sensitizes glioma cells to tumor necrosis factor-related apoptosis-inducing ligand and CD95 ligand and up-regulates the cell surface expression of the tumor necrosis factor-related apoptosis-inducing ligand receptor cell death receptors 4 and 5, which may contribute to this sensitization. Intracerebral glioma-bearing nude mice treated either i.p. or intratumorally with SC68896 experience prolonged survival. CONCLUSIONS: SC68896 is the first proteasome inhibitor that exerts antiglioma activity in vivo. It may represent a novel prototype agent for the treatment of malignant gliomas and warrants clinical evaluation.

The peptide-semicarbazone S-2209, a representative of a new class of proteasome inhibitors, induces apoptosis and cell growth arrest in multiple myeloma cells.

Bortezomib is the first approved member of a new class of anti-myeloma agents, the proteasome inhibitors. Further proteasome inhibitors are needed to optimise this promising treatment option. S-2209 [1-[1-{1-[(2,4-Dioxo-imidazolidin-1-ylimino)-methyl]-2-phenyl-ethylcarbamoyl}-2-(1H-indol-3-yl)-ethylcarbamoyl]-2-(1H-indol)] inhibits the chymotryptic activity of the human 20S proteasome (half maximal effective concentration, IC(50) approximately 220 nmol/l) which was determined by a proteasome inhibition assay. A nuclear factor kappaB inhibition assay revealed a half maximal effective concentration (EC(50)) of 0.9 micromol/l. The WST-1 growth assay showed inhibition of cell growth of all tested multiple myeloma (MM) cell lines with an IC(50) between 100 nmol/l and 600 nmol/l. Strong induction of apoptosis was seen in MM cells at nanomolar concentrations (IC(50) approximately 300 nm) as well as in primary myeloma cells. No induction of apoptosis was detected in peripheral blood mononuclear cells from healthy humans. Upregulation of p53, activation of JNK protein, and downregulation of Mcl-1 was revealed. Despite the administration of 15 mg S-2209/kg/d in wistar rats, no toxicity with respect to body weight, hepatic enzymes, creatinine or haemoglobin was seen. Proteasome inhibition in white blood cells isolated from the treated rats was higher in the S-2209 treated animals in comparison with the control animals treated with 0.1 mg/kg/d bortezomib. S-2209 is active in myeloma cells and shows a favourable toxicity profile in first in-vivo studies. S-2209 is a promising agent for further clinical development.

[Synthesis and antitumor activity of substituted benzaldehyde/cinnamicaldehyde selenosemicarbazones].

According to drug combination principle 26 substituted benzaldehyde/cinnamicaldehyde semicarbazones were synthesized. Twelve of which were not found in literature. The structures of the title compounds were confirmed by elemental and IR, UV, 1HNMR and MS analyses. Thirteen compounds were screened in vivo against Ehrlich ascites tumor cells. Four compounds (VIIf, VIIg, VIIh, VIIm) showed strong antitumor activity. The percent increase in life span were between 46.1%-91.1%. 3-Methoxy-4-hydroxy and 3-methoxy-4-acetyloxy-cinnamicaldehyde selenosemicarbazones showed stronger activity and less toxicity with increase of life span of 76.5% (300 mg/kg) and 91.1% (60 mg/kg), respectively. They were worthy to be studied further.