Patrice Vanelle

1,3-Diphenylpyrazoles: synthesis and antiparasitic activities of azomethine derivatives

1,3-Diphenylpyrazole-4-carboxaldehyde and 1-(4-nitrophenyl)-3-phenylpyrazole-4-carboxaldehyde were obtained from the appropriated phenylhydrazones via the Vilsmeier-Haack reaction. These two aldehydes were functionalized by various substituted anilines or substituted benzylamines. Antiparasitic activities of the corresponding azomethines were assessed. In the most cases, nitrated compounds were found to be more efficient than non-nitrated ones against Plasmodium falciparum, Trichomonas vaginalis and Leishmania infantum.

5-Nitroimidazole Drugs Effective against Metronidazole-Resistant Trichomonas vaginalis and Giardia duodenalis

ABSTRACT Metronidazole (Mz)-resistant Giardia and Trichomonas were inhibited by 1 of 30 new 5-nitroimidazole drugs. Another five drugs were effective against some but not all of the Mz-resistant parasites. This study provides the incentive for the continued design of 5-nitroimidazole drugs to bypass cross-resistance among established 5-nitromidazole antiparasitic drugs.

Organic Electron Donors as Powerful Single-Electron Reducing Agents in Organic Synthesis

One-electron reduction is commonly used in organic chemistry for the formation of radicals by the stepwise transfer of one or two electrons from a donor to an organic substrate. Besides metallic reagents, single-electron reducers based on neutral organic molecules have emerged as an attractive novel source of reducing electrons. The past 20 years have seen the blossoming of a particular class of organic reducing agents, the electron-rich olefins, and their application in organic synthesis. This Review gives an overview of the different types of organic donors and their specific characteristics in organic transformations.

Original quinazoline derivatives displaying antiplasmodial properties.

The multistep synthesis of new quinazoline-derived molecules and their in vitro antiplasmodial evaluation on the W2 chloroquino-resistant Plasmodium falciparum strain is described herein. These molecules have also been studied concerning their in vitro cytotoxicity toward two human cell lines (K652 and HepG2) in order to calculate their respective selectivity indexes (S.I.). Among the fourteen tested molecules, two exhibited both significant antiplasmodial activity (IC(50)=0.95 and 1.3 microM) and low toxicity (IC(50)>100 or 125 microM), compared with two reference drugs: chloroquine and doxycycline. The structure activity relationships establish that the molecular scaffold which exerts the best profile is the 6-nitro-2-(tosylmethyl)-N-(3-substituted-phenyl)-quinazolin-4-amine. The hit molecules were finally investigated regarding their potential action toward two other protozoa, Leishmania donovani and Toxoplasma gondii, showing that these molecules display a selective antiplasmodial activity.

Clinical Pharmacokinetics and Delivery of Bovine Superoxide Dismutase

SummaryExperimentally, superoxide dismutase (SOD) protects against cytotoxological and histotoxological effects of superoxide anions, which play a fundamental role where inflammatory processes are involved. Currently, only bovine copper containing SOD (Cu-SOD) is available for clinical application in the treatment of patients with various arthritic diseases.The intramuscular route is the principal route to administer usual dosages of bovine Cu-SOD 4 to 32mg, 2 or 3 times weekly. A single dose corresponds to an optimal dose ranging from 30 to 200 µg/kg, determined from an established dose-response curve. After intramuscular injection of bovine Cu-SOD 8, 16 and 32mg the peak plasma concentration occurs 4 to 8 hours postdose and is 0.05, 0.16 and 0.39 mg/L, respectively.Clinically this metallo-protein is particularly effective for the treatment of inflammation and toxicity resulting from ionising irradiations, ischaemia and tumours. The major advantages of liposomally encapsulated bovine Cu-SOD are its improved pharmacokinetic characteristics, leading to a longer plasma half-life and a slower release of free bovine Cu-SOD.In humans, bovine Cu-SOD (free or liposomal), although a foreign protein, is well tolerated and produces no acute or delayed toxic effects.

Microwave-assisted synthesis in aqueous medium of new quinazoline derivatives as anticancer agent precursors

Fast and eco-friendly microwave-irradiated reactions permitting the “green synthesis” of new 2-substituted quinazoline derivatives in aqueous medium via S-alkylation or SRN1 reaction from 2-chloromethyl-3-methylquinazolin-4(3H)-one derivatives with different benzenesulfinic acids and nitronate anions, are reported herein.

Synthesis and cytotoxicity evaluation of some benzimidazole-4,7-diones as bioreductive anticancer agents

New benzimidazole-4,7-diones substituted at 2-position were synthesized via a microwave-assisted reaction using 2-chloromethyl-1,5,6-trimethyl-1H-benzimidazole-4,7-dione 5b as a key intermediate compound. Their cytotoxicity has been evaluated on colon, breast and lung cancer cell lines. The dimer 17 was shown to possess excellent cytotoxicity comparable to that of mitomycin C.

Evaluation of the genotoxic activity of metronidazole and dimetridazole in human lymphocytes by the comet assay

The genotoxicity of metronidazole (MZ) and dimetridazole (DZ) has been evaluated in human lymphocytes using the comet assay. The test has been performed using 3 doses (58.4, 175.2 and 292.1 microM for MZ; and 70.9, 212.6 and 354.3 microM for DZ) under 3 experimental protocols: aerobiosis, anaerobiosis (90% N2, 10% CO2) and with the presence of the microsomal fraction S9 mix. The effects of 4 antioxidants (8-hydroxyquinoline (8HQ), vitamin C (VitC), catalase (CAT) and superoxide dismutase (SOD), have been investigated on DNA damage generated by fixed concentrations of MZ (292.1 microM) and DZ (354.4 microM). In aerobic conditions, MZ and DZ produced significant dose-response relationships. The dose-related effects of both drugs decreased or were abolished in anaerobic conditions or in presence of S9 mix. 8HQ, VitC, CAT and SOD induced dose-related protective responses against DNA damage due to MZ and DZ. These findings suggest that MZ and DZ induce DNA damage in human lymphocytes through the futile cycle. The one-electron reduction of the drugs leads to the production of nitro radical anions. In the presence of oxygen, these radicals are reoxidized and generate oxygen-activated species.

Albumin-Bound Paclitaxel: The Benefit of This New Formulation in the Treatment of Various Cancers

Abstract Paclitaxel and docetaxel are established as the standards of care, either as monotherapy or in combination with other cytotoxic agents in metastasic breast cancer. In order to improve the efficiency of solvent-based paclitaxel and to overcome its drawbacks in terms of safety, a solvent-free formulation has been developed. This work is a review of the albumin-bound paclitaxel data relative to its pharmacodynamic and pharmacokinetic profiles, its therapeutic efficiency and its safety of use. The activity of albumin-bound paclitaxel in phase II and III trials indicates its significant clinical efficiency in the treatment of metastatic breast cancer. In lung and pancreatic cancer and in melanoma, the use of albumin-bound paclitaxel leads to interesting results which require further investigations. Preclinical and clinical studies have shown that albumin-bound paclitaxel is associated with a better tolerance compared to standard paclitaxel.

A new-generation 5-nitroimidazole can induce highly metronidazole-resistant Giardia lamblia in vitro

The 5-nitroimidazole (NI) compound C17, with a side chain carrying a remote phenyl group in the 2-position of the imidazole ring, is at least 14-fold more active against the gut protozoan parasite Giardialamblia than the 5-NI drug metronidazole (MTR), with a side chain in the 1-position of the imidazole ring, which is the primary drug for the treatment of giardiasis. Over 10 months, lines resistant to C17 were induced in vitro and were at least 12-fold more resistant to C17 than the parent strains. However, these lines had ID(90) values (concentration of drug at which 10% of control parasite ATP levels are detected) for MTR of >200 microM, whilst lines induced to be highly resistant to MTR in vitro have maximum ID(90) values around 100 microM (MTR-susceptible isolates typically have an ID(90) of 5-12.8 microM). The mechanism of MTR activation in Giardia apparently involves reduction to toxic radicals by the activity of pyruvate:ferredoxin oxidoreductase (PFOR) and the electron acceptor ferredoxin. MTR-resistant Giardia have decreased PFOR activity, which is consistent with decreased activation of MTR in these lines, but C17-resistant lines have normal levels of PFOR. Therefore, an alternative mechanism of resistance in Giardia must account for these super-MTR-resistant cells.