Tackling the antibiotic resistance in tuberculosis: Synthesis and biological evaluation of novel antitubercular agents and development of novel methodologies for the synthesis of heterocycles

Mycobacterium tuberculosis (Mtb), the etiological agent of Tuberculosis (TB) is developing new multi drug-resistant (MDR) and extensively drug-resistant (XDR) strains to the current drugs used in therapy. Of particular concern the wide spreading of tuberculosis, the high rate of development of resistance, and the high mortality of the patients due to the lack of effective therapy against TB infections. In order to face this problem, two series of novel compounds were designed, synthesised and evaluated against a panel of mycobacterial strains. The first series of compounds includes analogues of the third line drug thioridazine (TZ). TZ is a known antipsychotic drug belonging to the phenothiazine drug group, which showed good activity against MDR-TB infections but causes severe side effects which limit its use in therapy. Among the first series of compounds, five new compounds showed anti-tubercular activity similar or higher than TZ. Moreover, two derivatives showed potent inhibition towards the whole-cell drug efflux pump activity of mycobacteria comparable to that of verapamil, and turning to be promising multi-drug resistance reversal agents. A second series of compounds consist of small molecules which have originally been designed as hybrids of the anti-tubercular drugs BM212 and SQ109. Computational studies revealed a perfect superposition of the structures of SQ109 and BM212 and showed that the two drugs share common features. Five of the resulting compounds showed micromolar anti-tubercular activity on pathogenic TB. Two of them proved to be highly active also against multi-drug resistant clinical isolates and one of these also showed minimal eukaryotic cell toxicity, and therefore would be an excellent lead candidate for preclinical trials. In parallel to the identification of novel compounds active against mycobacteria, new synthetic methodologies for the synthesis of antitubercular heterocyclic scaffolds have been developed. In particular two approaches for the synthesis of pyrrole compounds were developed. Both procedures involve an olefin or enyne metathesis reaction as a key step. The first approach involves the synthesis of 1,2,3-substituted pyrroles, through a tandem enyne cross metathesis-cyclization reaction of propargylamines with ethyl-vinyl ether. The reaction is rapid, procedurally simple and represents a facile entry to the synthetically challenging 4,5-unsubstituted pyrroles. The second methodology allows the synthesis of substituted pyrroles from diallyl-amines via a chemo-enzymatic cascade based on the combination of olefin metathesis together with monoamine oxidase (MAO) biocatalysts. These reactions were carried out in aqueous media and mild temperature leading to the formation of substituted pyrroles in a single step and in high yields

Unveiling the Biocatalytic Aromatizing Activity of Monoamine Oxidases MAO-N and 6-HDNO:Development of Chemoenzymatic Cascades for the Synthesis of Pyrroles

A chemoenzymatic cascade process for the sustainable production of pyrroles has been developed. Pyrroles were synthesized by exploiting the previously unexplored aromatizing activity of monoamine oxidase enzymes (MAO-N and 6-HDNO). MAO-N/6-HDNO whole cell biocatalysts are able to convert 3-pyrrolines into pyrroles under mild conditions and in high yields. Moreover, MAO-N can work in combination with the ruthenium Grubbs catalyst, leading to the synthesis of pyrroles from diallylamines/-anilines in a one-pot cascade metathesis–aromatization sequence

Microwave-assisted domino reactions of propargylamines with isothiocyanates: selective synthesis of 2-aminothiazoles and 2-amino-4-methylenethiazolines

A simple and versatile microwave-assisted protocol for the synthesis of 2-aminothiazoles has been developed. The domino reaction of propargylamines and isothiocyanates in the presence of catalytic PTSA leads to the selective synthesis of 2-aminothiazoles at temperatures above 130 °C and in a few minutes. The same reaction carried out at lower temperatures leads to the formation of the tautomeric 2-amino-4-methylenethiazolines

A microwave-assisted multicomponent protocol for the synthesis of benzofuran-2-carboxamides

A fast, versatile and practical microwave-assisted multicomponent protocol for the synthesis of substituted benzofuran-2-carboxamides has been developed. The present method proved to be effective on a series of commercially available amines, 2′-hydroxyacetophenones, aldehydes, and benzonitriles and could be exploited in drug-discovery campaigns for the rapid identification of biologically active hit compounds

Rethinking the old antiviral drug moroxydine: discovery of novel analogues as anti-hepatitis C virus (HCV) agents

The discovery of a novel class of HCV inhibitors is described. The new amidinourea compounds were designed as isosteric analogues of the antiviral drug moroxydine. The two derivatives 11g and 11h showed excellent HCV inhibition activity and viability and proved to inhibit a step(s) of the RNA replication. The new compounds have been synthesized in only three synthetic steps from cheap building blocks and in high yields, thus turning to be promising drug candidates in the development of cheaper HCV treatments

Absence bilatérale de foramen mentonnier: mythe ou réalité ?

Le nerf mentonnier, entièrement sensitif, est une branche terminale du nerf alvéolaire inférieur émergeant bilatéralement en regard de l apex de la deuxième prémolaire mandibulaire à travers le foramen mentonnier. De nombreuses variations anatomiques concernant ce foramen ont été décrites dans la littérature, telles que des localisations inhabituelles ou la présence de foramina multiples. Cependant, les cas d absences de foramen mentonnier sont plus rares et très souvent découverts lors de dissections post-mortem. Une possible perte de neurosensibilité dans la région labio-mentonnière est alors évoquée. Le cas clinique étudié ici concerne la découverte fortuite d une absence bilatérale de foramen mentonnier sur les examens radiographiques (CBCT) d un patient. Des tests de vitalité et de sensibilité ont permis d objectiver une absence de troubles neurosensoriels de la région concernée. Parmi les hypothèses avancées, la plus probable paraît être celle d une suppléance nerveuse par le plexus cervical superficiel dont des ramifications peuvent atteindre la région mentonnière, impliquant l existence d une autre cartographie nerveuse de l innervation sensitive de la face.The mental nerve, entirely sensitive, is a terminal branch of the interior alveolar nerve emerging bilaterally around mandibular second premolar's apex through the mental foramen. Numerous anatomical variations concerning this foramen have been decsribed in the literature, such as unusual locations or occurrence of multiple foramina. However, the absence of mental foramina has only been detected in very occasions, usually during post-mortem dissections. A possible loss of neurosensibility in the area of lower lip and chin is then mentioned. The clinical case reviewed here concerns the fortuitous discovery of mental foramina's bilateral absence on cone beam computed tomography (CBCT) images of a living patient. Vitality and sensibility tests allowed us to objectivize a lack of neurosensorial disturbance in this area. The more likely hypothesis would be an anastomosis with the superficial cervical plexus whose branches have been shown to run through the mental area. This involves the existence of a new sensitive cartography of the face.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

A multicomponent pharmacophore fragment-decoration approach to identify selective LRRK2-targeting probes

Herein we report the development of a new versatile chemical tool for the rapid identification of LRRK2-targeting probes as potential anti-Parkinson's agents. Based on the structure of recently identified inhibitors, we decided to develop a new multicomponent approach to explore the biologically relevant space around their key pharmacophore fragment. The combination of organo/metal catalysis and microwave-assisted technology, allowed us to quickly generate highly functionalized heteroaryl-hydrazone derivatives for biological investigation. Enzymatic studies on the synthesized compounds allowed the identification of promising compounds endowed with a good LRRK2 specificity index (wt/G2019S activity ratio), low affinity towards a small panel of selected kinases and a mixed-type inhibition against the pathogenic G2019S mutant. These results show how a diversity-oriented approach based on a privileged pharmacophore fragment may play a key role in the identification of novel biologically relevant chemical probes