Trypanocidal activity of a thioacyl-thiosemicarbazide derivative associating both immunostimulating thalidomide and anti-parasitic thiosemicarbazide pharmacophores

African trypanosomiasis remains a life-threatening disease and there is nowadays an urgent need for improved therapeutic agents for this pathology. In this context, in order to create novel anti-protozoa prototype containing both a trypanocidal thiosemicarbazide moiety and an immuno-potentiating thalidomide-like, a hybrid structure was designed on the basis of a convergent synthesis process, synthesized and assayed for its potential trypanocidal activity. Initial biological results are very promising. The structure of the target compound was ascertained on the basis of 13C-NMR, IR spectroscopy and semi-empirical AM1/PM3 quantum-mechanical calculations

A concise synthesis of 2-(1,2,3,4-tetrahydro-6-methoxynaphthalen-4-yl) ethanamine, a key intermediate in the elaboration compound library of agomelatine analogs

Agomelatine, a melatonin-like antidepressant drug based on a naphthalene scaffold, has received consid erable attention these last twenty years. This drug molecu le undergoes important liver first pass effect and suffers therefore of a short plasma half-life. In an effort to circum vent this drawback, we designed an approch based on the use of a tetraline scaffold to replace the original naphthalene template. Using a concise synthetic method involving a three-step approach and starting a commercially available tetralone precursor,we successfully designed a tetraline scaffold, a pivotal template which could be further elaborated into a compound library of agomelatine analogs. Further work is now under progress along this lin

Synthesis and Antiepileptic Activity Assessment of 5-Benzoyloxindole, a Novel Phenytoinergic Template

Based on a rational approach using merely bioisosterism as euristic tool, we designed and tested a short series of congeners of 6-benzoyl-2(3H)-benzoxazolone as phenytoinergic lead. Among them, 5-benzoyloxindole showed an impressive activity in the Maximal Electroshock seizure test in mice at the same level of activity as phenytoin, carbamazepine and primidone, all these drugs nowadays considered worldwide as reference molecules, and only surpassed by ameltolide. Additional preliminary pharmacomodulations of this lead were unsuccessful. In view of its molecular concision and good druggability characteristics, 5-benzoyloxindole represents a valid platform for further medicinal chemistry elaborations

Insight into the Diels-Alder reaction : A green chemistry revisitation of the synthesis of a cantharidine-like trypanocidal pilot-molecule

Relying on a straightforward « Green-Chemistry » based approach, this article reports an optimized Diels-Alder (DA) experimental set-up allowing for this reaction to be cleanly operated in the presence of water used both as solvent and catalyst. This work was initiated to synthesize a cantharidine-derived trypanocidal pilot-molecule. Diels-Alder cyclo-addition between anthracene-9-methanol and maleimide in water was selected as benchmark reaction and demonstrated how water as a solvent can be used not only because of its more benign impact on the environment but also because it improves some key aspects (rate, yield, ease of isolation) of the reaction. Adjunction of lithium chloride into the reaction medium adds a significant incremental benefit to the overall yield due to its oxophilic character increasing electron demand at dienophile’s double bond. Our set-up illustrates a typical condition of « on-water » reaction rather then « in-water » reaction conditions. Conclusively, in the DA reaction of our benchmark reaction, water not only behaves as a green solvent but also as a powerful catalys

Solar light photo-catalyzed condensation of aldones with 4-phenylthiosemicarbazide, a green chemistry approach

A significant photo-activating effect was evidenced upon investigating the condensation of aldehydes and ketones with 4-phenylthiosemicarbazide in the absence of any type of catalyst (either acido-basic or nucleophilic catalysis). Actual yields were not found superior to those obtained using nucleophilic catalysts; however, the reaction can be run at room temperature with the absence of an additional solvent. A positive hydrophobic effect was also noted. Furthermore, it was found that, the described photo-chemical method did not require an expensive and energy-consuming photo-chemical equipment since the whole process was carried out using natural solar light in regular laboratory glass ware

C42 - Optimisation d’une formule de comprime matriciel à base de spiruline enrichi en vitamine C

La spiruline est une algue fortement consommée dans le monde comme complément alimentaire en raison de son grand potentiel nutritionnel. Elle se trouve toutefois exempte de vitamine C, une vitamine capitale pour le bon fonctionnement de l’organisme humain compte tenu notamment de son pouvoir immunostimulant. L’objectif de notre travail était de formuler des comprimés matriciels de spiruline et de la vitamine C, qui assureront une libération prolongée et une meilleure absorption de la vitamine C ; cette dernière étant sujette à un mécanisme de saturation lors de son absorption. Nous sommes donc partis d’une formule galénique uniquement à base de vitamine C (A1), pour ensuite réduire la proportion de vitamine C au profit de la poudre de spiruline (S). Les comprimés fabriqués ont subi les différents tests pharmaco-techniques pour le contrôle de leur qualité. Les résultats de ce contrôle ont montré une bonne distribution des mélanges de poudres dans nos comprimés à l’issue du test d’uniformité de masse (A1 : 405±8,8 mg ; S : 665±9,4 mg), des résultats également satisfaisants pour les tests d’uniformité de teneur (A1 :175 ± 15,7 mg S : 41 ± 3,4 mg), de désagrégation (300 minutes) et de dissolution avec 45 % de la vitamine C dissoute au bout de 4 h de test (Comprimé S) contre 85% pour A1. Seul le test de friabilité était non satisfaisant témoignant la nécessité d’améliorer les propriétés physiques de nos poudres avant la compression. Ce travail sera approfondi en vue de l’installation sur place d’une unité de production desdits comprimés pour leur mise sur le marché.

Anomalous reactivity of benzopinacolone towards 4-phenylthiosemicarbazide, a nucleophile endowed with alpha-effect

In a medicinal chemistry-driven drug discovery program aimed at synthesizing new topicallyacting trypanocidal chemotherapeutic agents to treat the African trypanosomiasis, our research group became interested in new chemical entities bearing in their center a thiohydrazide (C=S) NHNH or thiosemicarbazide NH(C=S) NHNH central template flanked on both sides by lipophilic aryl moieties. In this context, benzopinacolone was found to react as a rather unusual acylating agent via a mechanism (addition/elimination) involving addition of the nucleophile (a thiosemicarbazide derivative), formation of a resulting tetrahedral adduct, and expulsion of a trityl anion moiety as leaving group, presumably through an anchimeric assistance effect by intramolecular participation of the thioureido side-chain via hydrogen bond formation. The present incidental discovery should be considered at this level as a first inception and further work is now being directed at closely examining the detailed mechanism of this exceptional chemical pathway; in a reaction involving the unusual breaking of a carbon-carbon bond (carbon acid as leaving group) in the rate-determining step and involving the decomposition of the intermediate tetrahedral adduct to get the final unexpected N-thiobenzoyl-thiosemicarbazide

Formulation and Optimization of Matrix Tablets Based on Spirulina and Vitamin C

Spirulina is a type of algae widely consumed around the world as a dietary supplement due to its great nutritional potential. However, it does not contain vitamin C, a vital vitamin for the proper functioning of the human body, particularly given its immunostimulant potential. The objective of this work was to formulate sustained release spirulina–vitamin C matrix tablets that would enhance particularly a prolonged release and better absorption of vitamin C. A galenic formula based only on vitamin C was made, and then the proportion of vitamin C was reduced in favor of spirulina powder. The manufactured tablets were then subjected to various pharmacopeial quality control tests. The results of these tests showed a good distribution of the powder mixtures in the formulated tablets (i.e., mass uniformity test) and satisfactory outcomes were found for the content uniformity, disintegration and dissolution tests (with 45 % of vitamin C dissolved after 4 hours). Only the results for the friability test were unsatisfactory, indicating the need to improve the physical properties of the powders before compression. These findings open a new area for developing supplementary dietary.            Keywords: Spirulina, Vitamin C, Matrix tablet, Quality control