Au cours de ce travail, nous avons développé des voies de synthèses convergentes et énantiosélectives en vue de préparer des analogues pyrrolidiniques des alcaloïdes de Lobelia comme nouveaux ligands des récepteurs nicotiniques à l’acétylcholine. Deux familles de ligands ont été réalisées par des méthodes d’élongation mono- ou bi-directionnelle basées respectivement sur des stratégies de désymétrisation précoce ou tardive au départ du succinaldéhyde.La première partie de ce manuscrit aborde la conception d’hybrides de lobéline, nicotine et d’agonistes naturels. Ces structures originales ont été obtenues diastéréosélectivement grâce à un intermédiaire commun issu d’une élongation monodirectionnelle du succinaldéhyde. Cette voie exploitera la chimie des iminiums masqués. La mise au point de cette synthèse s’est enrichie par la découverte et la valorisation d’une nouvelle famille de ligands chimériques.La seconde partie étudie la voie d’élongation bidirectionnelle basée sur des réactions de double aza-Michael suivies de la réduction désymétrisante tardive de pyrrolidines 2,5-phénacyl méso et pseudo-méso. Cette stratégie asymétrique s’inscrit dans une démarche d’économie d’atomes et d’étapes. La perspective majeure de ce travail est l’évaluation par électrophysiologie sur différents sous-types de récepteurs à l’acétylcholine d’une sélection de ligands hybrides.Les études de RSA menées sur ces familles de composés de haute homologie structurale permettront in fine d’améliorer les modèles prédictifs décrivant les transitions allostériques des récepteurs nicotiniques à l’acétylcholine / During this PhD work, convergent and diastereoselective routes for the preparation of pyrrolidine Lobelia alkaloid analogues have been developed as novel neuronal nicotinic receptor ligands. Two families of ligands have been synthesized by a strategy of mono- or bi-directional elongation of the succinaldehyde including early or late desymmetrization process respectively.The first part of this manuscript is dedicated to the preparation of hybrids of lobeline, nicotine and other natural agonists. These original structures have been diastereoselectively obtained thanks to a common intermediate resulting of the mono-elongation of succinaldehyde. This synthetic pathway uses the chemistry of masked iminium. The development of this strategy has been enriched by the discovery and the valorisation of a new chimeric ligand family.The second part studies the “bidirectional” elongation route, based on a ring-closing double aza-Michael reaction followed by the desymmetrizing reduction of meso and pseudo-meso 2,5-diphenacyl pyrrolidines. This asymmetric strategy constitutes a step- and atom-economical approach. The major perspective of this work is the biological evaluation of selected ligands by electrophysiology made on different nAChR subtypes.The SAR studies realized on these structurally homologue ligand families could allow the improvement of the predictive molecular models describing the allosteric conformations of the nAChRs.

Tuberculosis affects millions of people worldwide every year. The current treatment for TB is divided into a regimen of both first- and second-line drugs, where first-line treatments are more tolerated and require shorter treatment lengths. With rising levels of resistance, alternative treatment regimes are urgently needed to fight this disease. Ethionamide, a second-line drug is administered as a prodrug which is activated in vivo by the enzyme EthA, which is in turn regulated by EthR. The disruption of the action of EthR could lead to novel therapeutics which could enhance the efficacy of ethionamide, and raise it to a first-line treatment. The work reported in this thesis examines the elaboration of three chemical scaffolds using fragment-based approaches to develop novel inhibitors capable of disrupting the EthR-DNA interaction. The first scaffold, 5-(furan-2-yl)isoxazole was investigated by fragment-merging approaches and produced compounds with the best of these having a KD of 7.4 uM. The second scaffold, an aryl sulfone was elaborated using fragment-merging strategies. This led to several modifications of the fragment, leading to several variants with KDs around 20 uM. With both of these series the affinity could not be improved below 10 uM and due to the synthetic complexity a further scaffold was prioritised. The third scaffold was explored was a 4-(4-(trifluoromethyl)phenyl)piperazine using fragmentgrowing from the NH of the piperazine to probe deeper into the EthR binding pocket. In addition to this, SAR around the 4-(trifluoromethyl)phenyl group was assessed to explore the interactions with EthR. These modifications led to compounds with nanomolar IC50s. A range of compounds were then screened by REMAssay to determine the boosting effect on ethionamide, and this identified compounds with up to 30 times boosting in the ethionamide MIC. The final chapter examines a concept where compounds were designed to exploit the dimeric nature of EthR by linking two chemical warheads with a flexible linker. These compounds are examined using mass spectrometry to investigate the stoichiometry of the interaction to provide insight into the binding of these extended compounds and exploring an alternative strategy to inhibit EthR. The work in this thesis demonstrated the successful use of fragment-based approaches for development of novel EthR inhibitors which showed significant ethionamide boosting effects.