Dissertations / Theses on the topic 'Pharmacomodulations'
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Dumonteil, Geoffrey. "Synthèse et pharmacomodulations de composés naturels issus de plantes." Thesis, Orléans, 2015. http://www.theses.fr/2015ORLE2061/document.
Full textPolyene units constitute an important function from organic compounds and are present in many natural products in the form of 1,3-conjugated dienes. It is therefore essential to develop methods to access these dienes while wearing a careful look at the environmental impact. During this work, we were able to synthesize a natural compound which has activity on type II diabetes: the abscisic acid. The key step leading to the success of this synthesis is the Heck reaction. From these results, we have developed a robust and efficient method to obtain various diene compounds (E, Z) and trienes (E, E, Z) without ligand or solvent. The compounds thus obtained are considered as potential analogues of the abscisic acid and are involved in various reactions in order to obtain the corresponding carboxylic acid or its bioisostere. In parallel with this synthesis application, we have developed a pathway to obtain benzo[d]thiazole compounds substituted in position 2 with an N-aryl or N-alkyl. This synthetic methodology is part of a context of environmental compatibility by using iodine catalyst
Perri, Vittoria. "Synthèse, pharmacomodulations et évaluation biologique de « tripentones » à visée anticancéreuse." Caen, 2010. http://www.theses.fr/2010CAEN4001.
Full textThe work described in this document deals with the synthesis, the physico-chemical study and the biological evaluation of new 3-aryl-8H-thieno[2,3-b]pyrrolizin-8-ones, the “Tripentones”. The discovery of this new family of compounds derives from many research programs developed at the “Centre d’Etude et de Recherche sur le Médicament de Normandie”. Following a description of different classes of kinases and their inhibitors, previous works carried out in our laboratory about the tripentones are reviewed. The main subject of this thesis concerns the pharmacomodulation of the hit compound of this family called MR 22388. The synthesis are followed by the description of pharmacological results obtained by our compounds on biological targets in the field of oncology. This work also opens up new prospects for pharmacomodulation of the tripentones and the development of new methodologies of synthesis. Lastly, the experimental part of this document describes the chemical structures, the procedures and the physicochemical properties of all the presented compounds. Finally, the bibliography comprises more than 150 references
LE, GOFF-BEVIERE CORINNE. "Pharmacomodulations de quinolones a structure benzo-ij-quinolizine : synthese et activite antibacterienne." Orléans, 1995. http://www.theses.fr/1995ORLE2019.
Full textGrisel, Clément. "Conception de cyclopeptides antiviraux inspirés d'un produit naturel." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASQ055.
Full textAccording to the WHO, arboviruses such as Zika virus, dengue, and chikungunya represent a major public health challenge, frequently causing outbreaks with sometimes severe symptoms. In collaboration with the PIMIT laboratory, we performed a screening of the ICSN plant extract library, leading to the discovery of a new family of cyclopeptides with potent antiviral properties. To identify an orally bioavailable candidate for in vivo trials, I first developed an efficient synthetic route to access these types of compounds. The preparation of two non-canonical amino acids was initially developed before completing the total synthesis of two natural molecules via SPPS. Building on this synthetic strategy, we then created a library of 36 analogs by modifying four positions on the lead natural cyclopeptide. The antiviral activity results highlighted strong structure-activity relationship (SAR) data, complemented by pharmacokinetic studies. These findings guided us in selecting key amino acids for designing new orally bioavailable antiviral cyclopeptides derived from nature
Dardenne, Jérémy. "Premières pharmacomodulations de la meiogynine A, un sesquiterpène dimère inhibiteur de l'interaction Bcl-xL/Bak, régulant l'apoptose." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00774836.
Full textVidaillac, Céline. "Pharmacomodulations en série pyrrolo[1,2-a]quinoxaline : application à la mise au point d'inhibiteurs de pompes d'efflux." Bordeaux 2, 2007. http://www.theses.fr/2007BOR21439.
Full textEfflux systems are transmembrane transporters, involved in antibiotic and anticancer resistances. The discovery of efflux pump inhibitors (EPIs) is an essential way of research in chemotherapy. The aim of this thesis was to synthesize and evaluate the in vitro activity of new EPIs. Three series of pyrrolo [1,2a]quinoxaline molecules have been elaborated on the basis of structural criteria of reference EPIs (omeprazole, quinoline derivatives and INF), and have been assessed as inhibitors of bacterial efflux systems. A strategy of evaluation has been defined using NorA of Staphylococcus aureus, which is considered as the prototype of Gram positive MDR (MultiDrug Resistance) systems. This strategy included screening tests, evidence of EPI-antibiotic synergy, and investigation of the inhibition lechanism. Among each series, several molecules were more active than reference EPIs. Preliminary structure-activity relationship studies highlighted the influence of particular chemical elements (heterocycle, sulphur atom, protonable functions) on the EPI activity. Some molecules (1e, 11g, 11m and 17) might provide the basis for further pharmacomodulation to obtain therapeutically useful drugs. However, the third series, compared to 8 reference EPIs on 10 efflux systems representative of the 5 classes of transporters, has confirmed that the hypothesis of a very wide-spectrum EPI is unlikely. Finally, two other series of pyrrolo [1,2-a] quinoxaline molecules have been designed on the basis of the chemical structures of MS-073 and MS-207 and pyrrolopyrimidine derivatives, in order to broaden the biological application to cancerology
Dardenne, Jérémy. "Premières pharmacomodulations de la meiogynine A, un sesquiterpène dimère inhibiteur de l’interaction Bcl-xL/Bak, régulant l’apoptose." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114852/document.
Full textThe control of the apoptosis is one of the new modern key to fight against the cancer. The apoptosis is the self destruction of cells, part of the homeostasis, which regulates the cell developement. In several cancers, the over-expression of anti-apoptotic proteins, as Bcl-xL and Mcl-1 parts of the Bcl-2 proteins family, inhibate this naturel process. This phenomenum induce the tumoral cells developement and the chemotherapy’s resistance. In order to find new compounds which can regulate the apoptosis, our group in the Institut de Chimie des Substances Naturelles has screened different tropical plants on these targets. A Malaysian plant, Meiogynine Cylindrocarpa, was selected and the phyotchemist work on this plant gave us a new sesquiterpen , the meiogynin A (Ki = 10.7 M on Bcl-xL). Its total synthesis was realised in our laboratory in order to determine its absolute configuration and find the first structure activity relation. One of the synthetised diastereoisomers has presented a better affinity toward the protein. In order to precise these first structure activity relations, the modulation of the meiogynin A was initiated. The synthesis of the acid dienophiles was optimised, the main compounds are the precursors of the active decalins. New triene was also obtained in order to modulate the South Part of the meiogynin A. Thanks to a Diels-Alder reaction, these precursors were combined in order to form new analogues of the meiogynin A. All these compounds were biologically tested (in vitro et ex vivo). Experiments of molecular docking and 2D NMR were also realised
ANDRIAMANANTENA, RICHARD. "Trifluoromethylphenols : chimie et pharmacomodulation." Aix-Marseille 2, 1991. http://www.theses.fr/1991AIX22952.
Full textAmrane, Dyhia. "Pharmacomodulation d'hétérocycles α-trichlorométhylés ciblant l'apicoplaste chez P. falciparum." Electronic Thesis or Diss., Aix-Marseille, 2021. http://www.theses.fr/2021AIXM0379.
Full textMalaria remains the leading cause of death among parasitic infections worldwide. Currently, there are major concerns about the spread of resistance to artemisinin derivatives that are the basis of first-line antimalarial treatment. Therefore, there is an urgent need to develop new antiplasmodial molecules with a novel mechanism of action. For this purpose, our laboratory has previously described the synthesis and biological activities of a chemical library of α-trichloromethylated azaheterocycles including a hit molecule in the quinazoline series which presents the best biological profile.The first part of this work focused on 4-carboxamide quinazoline pharmacomodulation. In order to complete the SARs, scaffold hopping strategies allowed us to obtain new compounds in the quinoxaline and phthalazine series. By structural simplification, new compounds in the pyrimidine, pyridazine and pyrazine series were obtained. Finally, in order to explore the benzene part of the quinazoline and quinoxaline rings, new thienopyrimidine and pyrido[2,3-b]pyrazine derivatives were also synthesized. More than 110 new original molecules were obtained, among them several new hit molecules were obtained. The physicochemical and in vitro pharmacokinetic properties were determined in order to initiate the study of their in vivo activity on Plasmodium berghei. In addition, in order to elucidate the mechanism of action of these compounds, which differs from those of commercial antimalarials, we have recently identified by immunofluorescence that these molecules target the apicoplast of P. falciparum, an organelle essential to parasite survival
Delahousse, Julia. "De l’ifosfamide au géranyloxy-ifosfamide : pharmacomodulation pour cibler et moduler l’immunité." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS535.
Full textIfosfamide (IFO) is an alkylating agent of the DNA from Oxazaphosphorine family, widely used in various chemotherapy protocols. However, its clinical use is limited due to nephrotoxicity and neurotoxicity related to metabolites such as chloroacetaldehyde. Indeed, IFO is a prodrug characterized by complex pharmacokinetic profile with a minority activating metabolic pathway and a majority toxicogenic pathway. Chemical pharmacomodulation is one of the strategies proposed to bypass the toxicogenic pathway and thus improve its clinical use. IFO analogues (geranyloxy-, farnesyloxy-, squalenyloxy-, squalenyloxy-IFO), able to self-assembly, have been developed and pharmacological studies have demonstrated the proof of concept for the pre-activation of IFO. Galenic optimizations have been tested for pre-clinical and clinical application. In addition, due to the chemical similarity of IFO and cyclophosphamide, immunomodulation studies have been conducted to investigate the immunomodulatory properties of IFO and geranyloxy-IFO with the hope of new perspectives in the use of these compounds in combination with immunotherapy
Daveu, Cyril. "Etudes des relations structure-activité et pharmacomodulation de ligands sérotoninergiques." Caen, 2000. http://www.theses.fr/2000CAEN4044.
Full textBlanchard, Stéphanie. "Synthèse d'hétérocycles via les hétarynes : fonctionnalisation et pharmacomodulation des dihydrodipyridopyrazines." Orléans, 2001. http://www.theses.fr/2001ORLE2008.
Full textChang-Fong, Jean. "Pharmacomodulation des dérivés de structure 2-iminoimidazolidine à visée antihypertensive." Université Joseph Fourier (Grenoble), 1999. http://www.theses.fr/1999GRE18001.
Full textJezequel, Gwenaëlle. "Synthèse et pharmacomodulation de composés antitumoraux naturels à motif hexahydroxanthène." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS424.
Full textORPphilins are a set of several families of natural molecules with strong cytotoxic activity, that have an original mechanism of action by inhibiting OSBP, a protein responsible for the intracellular transport of cholesterol. However, they are all difficult to access, either by extraction from the organisms from which they are derived or by chemical synthesis.Schweinfurthins (SWs), isolated from plants of the genus Macaranga, are part of these ORPphilins, and have been studied by our team for several years. In these studies, it was shown that a non-active but probable bioprecursor analogue of these SWs was present in large amounts in these plants. The first objective of this thesis was to hemisynthezise SWs, and non-natural analogues from this bioprecursor.SWs are particularly active on multiform glioblastoma, which is currently a very poor prognosis. Today, the treatment consists of surgery followed by radiotherapy combined with chemotherapy using temozolomide (TMZ), an alkylating agent of DNA. Many resistances to TMZ develop and recurrences are frequent. However, it has been shown that a dual molecule covalently binding two anti-cancer molecules with a complementary mode of action may present a synergy of effects. The second objective of this thesis was therefore to synthesize and biologically evaluate different SW-TMZ dual molecules.Finally, a new molecule with an original structure has been isolated and identified from plants of the genus Macaranga. This compound has cytotoxic activity on glioblastoma similar to that of SWs, and has the same protein target as ORPphilins. The last part of this thesis focused on the total synthesis of this molecule, and of analogues, their biological evaluation and the determination of the first structure-activity relationships on this new chemical series.In conclusion, the work carried out during this thesis made it possible to synthesize cytotoxic molecules that are either natural or inspired by natural products, targeting OSBP. These molecules can later be used as molecular tools to highlight their as yet poorly understood mechanism of action and identify the links between cholesterol transport and cancer
Genoux, Estelle. "Dérivés de flavonoïdes et de vérapamil comme ligands des transporteurs MRP1 et ABCG2 : de la conception à l'activité anticancéreuse." Phd thesis, Université de Grenoble, 2011. http://tel.archives-ouvertes.fr/tel-00596929.
Full textPouget, Christelle. "Pharmacomodulation de flavonoi͏̈des : conception et synthese de nouveaux inhibiteurs de l'aromatase." Limoges, 2001. http://www.theses.fr/2001LIMO308H.
Full textAuzeloux, Philippe. "Pharmacomodulation de chelates techneties : application potentielle au diagnostic du melanome malin." Clermont-Ferrand 1, 1998. http://www.theses.fr/1998CLF1MM02.
Full textGhezali, Saïd. "Pharmacomodulation et étude de réactions de transfert monoélectronique en série hétérocyclique." Aix-Marseille 3, 1993. http://www.theses.fr/1993AIX30020.
Full textVivier, Magali. "Pharmacomodulation d'inhibiteurs du protéasome : application potentielle à la thérapie du mélanome malin." Clermont-Ferrand 1, 2005. http://www.theses.fr/2005CLF1MM09.
Full textDue to the aggressive nature of malignant melanoma, there is actually no successful therapy of this disease. Chemotherapy has less specificity and some tumoral cells resistances. The proteasome is a multicatalytic protease present in the nucleus and cytoplasm of all eukaryotic cells. This multicatalytic protein complex constitutes the principal pathway for intracellular protein degradation and plays a major role in cell function and proliferation. Controlling proteasome activity and function in tumoral cells will thus give us mew potential investigation tools for the treatment of cancer diseases like malignant melanoma. However proteasome is ubiquitous. Moreau et al. Have developed a new radiopharmaceutic [123I]-N-(2-diethylaminoethyl)-4-iodobenzamide (123I-BZA) which binds to malignant pigmented cells with high affinity. Scintigraphic studies in humans present for this radiopharmaceutic a sensitivity superior to 80% and a specificity of 100% on malignant melanoma and metastases. Therefore we synthesized new proteasone inhibitors which are peptide aldhyde or vinylsulfone linked them to a N-(2-diethylaminoethyl)-benzamide structure (BZA-CO) and pharmacomodulated BZA-CO, in order to target the cytotoxic activity of these inhibitors to the malignant melanoma cells. Preliminary "in vitro" and "in vivo" biological studies demonstrated the influence of length and composition of the amino acid chain, of BZA-CO pharmacomodulated and of inhibition function on the cytotoxic activity of our compounds. The measurement of the 3 main proteasome activities, i. E. Chymotrypsin - like (ChT-L), trypsin-like (T-L) and peptidyl-glutamyl peptide hydrolase (PGPH) activities, confirmed that the cytotoxicity observed after incubation in presence of our compounds was linked to an inhibition of the proteasome activity. The highest activity obtained is with the trileucine aldehyde. Radiosynthesis of [125I]trileucine aldehyde and in vivo experiments on tumor-bearing animals with 125I radiolabelled compounds was performed in order to examine the selectivity of the compounds to malignant melanoma and metastases
Othman, Arige. "Pharmacomodulation on the piperidinol skeleton: Synthesis of novel PIPD1 derivatives as Mycobacterium abscessus agents." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2017. http://amslaurea.unibo.it/13396/.
Full textRémusat, Vincent. "Synthèse, réactivité par transfert monoélectronique et pharmacomodulation de nouvelles quinones azahétérocycliques à potentialités anticancéreuses." Aix-Marseille 2, 2004. http://www.theses.fr/2004AIX22953.
Full textKabri, Youssef. "Synthèse, pharmacomodulation et évaluation biologique de nouveaux dérivés de quinazoline à visées antiparasitaire et anticancéreuse." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX22951/document.
Full textThis work focuses on the synthesis of new bioactive quinazoline derivatives under microwave irradiation. In the first chapter, we indicate the main methods for preparing the quinazoline ring, the pharmacological properties associated to the quinazoline-derivated drug compounds and we present the SRN1 reaction updated bibliography. In the second chapter, the synthesis and reactivity of 2-chloromethyl-3-methylquinazolin-4(3H)-one with nitronate and sulfinate anions are successively described. A mechanistic study permits to demonstrate the SRN1 radical chain mechanism for the reaction with nitronate anions and a SN2 one for sulfinate anions. Afterwards, we prepared new original quinazolines, under microwave irradiation, by studying SNAr and Suzuki-Miyaura coupling reactions in 4-chloroquinazoline series. From these results, we have developed a regioselective Suzuki-Miyaura reaction on the 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline and prepared a new series of highly functionalized 4,7-diarylquinazolines. Finally, the biological evaluation of the products prepared by SNAr, showed interesting antiplasmodial and anti-leishmania activities along with EGFR1 inhibition properties
Neilde, Kevin. "Pharmacomodulation anti-infectieuse en série 5-nitroimidazole : couplages pallado-catalysés et réactions par transfert monoélectronique." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5502.
Full textThis work focuses on the synthesis of novel functionalized 5-nitroimidazoles possessing therapeutic activities. New 4-substituted-5-nitroimidazoles were obtained using Suzuki, Stille or Sonogashira cross-coupling using the 4-bromo-1,2 dimethyl-5-nitro-1H-imidazole. Moreover, access to functionalized products at both 2 and 4 positions of imidazole ring was developed thanks to a regioselective Suzuki cross-coupling on the 2,4-dibromo-1-methyl-5-nitro-1H-imidazole. Among cross-coupling products, those possessing chloromethyle substituent conjugated with the nitro group, were employed as starting material in the single electron transfer reaction (SRN1, TDAE) studies. Therefore, in a second part, we described the reaction between the 4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole and several nitronate anions in SRN1 conditions. This reactivity was applied to the 2,4-bis(3-chloroprop-1-ynyl)-1-méthyl-5-nitro-1H-imidazole allowing the formation of bis-SRN1 products. TDAE methodology was implemented on the 4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole, however poor yields were observed. TDAE strategy on the (E)-4-[4-(chlorométhyl)styryl]-1,2-diméthyl-5-nitro-1H-imidazole were more successful, addition products with different electrophilic species were obtained. Finally, mutagenic power and potential of reduction of synthesized 5-nitroimidazole were assayed. The anti-infective properties of these novel 5-nitroimidazole are currently under investigation
Kabri, Youssef. "Synthèse, pharmacomodulation et évaluation biologique de nouveaux dérivés de quinazoline à visées antiparasitaire et anticancéreuse." Electronic Thesis or Diss., Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX22951.
Full textThis work focuses on the synthesis of new bioactive quinazoline derivatives under microwave irradiation. In the first chapter, we indicate the main methods for preparing the quinazoline ring, the pharmacological properties associated to the quinazoline-derivated drug compounds and we present the SRN1 reaction updated bibliography. In the second chapter, the synthesis and reactivity of 2-chloromethyl-3-methylquinazolin-4(3H)-one with nitronate and sulfinate anions are successively described. A mechanistic study permits to demonstrate the SRN1 radical chain mechanism for the reaction with nitronate anions and a SN2 one for sulfinate anions. Afterwards, we prepared new original quinazolines, under microwave irradiation, by studying SNAr and Suzuki-Miyaura coupling reactions in 4-chloroquinazoline series. From these results, we have developed a regioselective Suzuki-Miyaura reaction on the 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline and prepared a new series of highly functionalized 4,7-diarylquinazolines. Finally, the biological evaluation of the products prepared by SNAr, showed interesting antiplasmodial and anti-leishmania activities along with EGFR1 inhibition properties
Neilde, Kevin. "Pharmacomodulation anti-infectieuse en série 5-nitroimidazole : couplages pallado-catalysés et réactions par transfert monoélectronique." Electronic Thesis or Diss., Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5502.
Full textThis work focuses on the synthesis of novel functionalized 5-nitroimidazoles possessing therapeutic activities. New 4-substituted-5-nitroimidazoles were obtained using Suzuki, Stille or Sonogashira cross-coupling using the 4-bromo-1,2 dimethyl-5-nitro-1H-imidazole. Moreover, access to functionalized products at both 2 and 4 positions of imidazole ring was developed thanks to a regioselective Suzuki cross-coupling on the 2,4-dibromo-1-methyl-5-nitro-1H-imidazole. Among cross-coupling products, those possessing chloromethyle substituent conjugated with the nitro group, were employed as starting material in the single electron transfer reaction (SRN1, TDAE) studies. Therefore, in a second part, we described the reaction between the 4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole and several nitronate anions in SRN1 conditions. This reactivity was applied to the 2,4-bis(3-chloroprop-1-ynyl)-1-méthyl-5-nitro-1H-imidazole allowing the formation of bis-SRN1 products. TDAE methodology was implemented on the 4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole, however poor yields were observed. TDAE strategy on the (E)-4-[4-(chlorométhyl)styryl]-1,2-diméthyl-5-nitro-1H-imidazole were more successful, addition products with different electrophilic species were obtained. Finally, mutagenic power and potential of reduction of synthesized 5-nitroimidazole were assayed. The anti-infective properties of these novel 5-nitroimidazole are currently under investigation
Ghaib, Amar. "Pharmacomodulation autour du squelette octahydropyrimido[3,4-a]-s-triazines : introduction de restes alkyles de lipophilie croissante." Rouen, 2001. http://www.theses.fr/2001ROUE03NR.
Full textIminodimethylation of 6 monoalkyl and dialkyl 5-aminopyrimidinediones by various primary amines was studied. The synthesis of these synthons was performed from ethyl cyanacetates, previously alkylated in 2 position, which reacted with area in alkaline medium. Alkylation of the strongly activated methylenes, situated between a nitrile and an ester groupe, in alkaline medium, leads to a mixture of unalkylated, monoalkylated and dialkylated derivatives. It was then necessary to use the différences of solubilities of the salts of theses compounds to separated them. In order to avoid these difficulties, two other synthetic pathways were used. Iminodimethylation of these synthons yielded 24 octahydropyrimido[3,4-a]-striazines, variously dialkylated, which were submitted to an automated pharmacological screening, especially in the area of antimicrobial agents. A series of 23 pyrimido[3,4-a]-s-triazines monoalkylated in position 9 were synthetized by iminodimethylation of 5-monoalkyl-6-aminopyrimidine 1,3-diones. It was shown that the structure was triazinic and not pyrimido pyrimidinic as it could have been. These compounds, despite a good overlay with Ketanserin, a well known anti 5-HT2, only showed a weak activity in automated screening
Chaimbault, Corinne. "Pharmacomodulation en série oxazoline : application à la mise au point de ligands des récepteurs aux imidazolines." Bordeaux 2, 1999. http://www.theses.fr/1999BOR2PB01.
Full textHenry, Nicolas. "Synthèse d'imidazoazines à activité antivirale à l'encontre du virus de l'hépatite C et de la diarrhée virale bovine." Thesis, Tours, 2009. http://www.theses.fr/2009TOUR3805.
Full textThe style of research developed at the therapeutics chemistry laboratory at Université François - Rabelais department of Pharmaceutical Sciences in Tours focuses on the pharmacology of angular nitrogen heterocyclic systems. In this context, my PhD thesis has consisted of synthesizing antiviral imidazo[1,2-a]pyridins et [1,2-b]pyridazins. Following the screening of 120 molecules of the laboratory's chemical library, five leads stood out for their properties in countering HCV and BVDV. The first part of this current work consisted of optimising the molecule’s therapeutic activity by achieving the pharmacomodulation of the positions 2 and 6 as a imidazo[1,2-a]pyridin through [1,2-b]pyridazin series. The effects observed by moving the position 6 grouping towards the position 7 grouping in the imidazo[1,2-a]pyridinique series was also studied. As a final step, the nature was changed from phenyl terminal to biphenyl in both series. The second part consisted of trying to optimize a second lead, that of a benzylamide. Different aromatic groupings were introduced, amides reversed were prepared and the biological effect of moving this grouping to position 7 was studied. The influence of the position 2 substituent and in particular the poly-fluorophenyls derivatives was also studied. Many prepared compounds present a significant amount of activity on BVDV and HCV
ANASTASSIADOU, MARIA. "Conception et pharmacomodulation de ligands des recepteurs i#2. Optimisation de la synthese d'imidazolines et d'analogues structuraux." Toulouse 3, 1999. http://www.theses.fr/1999TOU30004.
Full textBen, Nasr Nesrine. "Optimisation de méthodes de criblage virtuel et synthèse de molécules à visée thérapeutique pour le traitement des maladies auto-immunes." Thesis, Paris, CNAM, 2014. http://www.theses.fr/2014CNAM0907.
Full textVirtual screening is widely used in drug discovery programs. The increasing number of resolved structures favored the use of Structure Based Virtual Ligand Screening methods like docking. Nevertheless, the choice of the structure(s) used as reference remains a topical issue when several are available. In this work, DUD database docking results were analyzed taking into account the properties of the query structure(s) binding sites. Interesting results were obtained highlighting the influence of active site volume and opening on methods performances. These simple and inexpensive “binding site properties-based” guidelines could be helpful to optimize future docking protocols.Despite important effort, no active small molecule targeting TNFα has been released so far. The use of a virtual/ in vitro hierarchical approach screening allowed identifying some active hits. Starting from one of them with a benzenesulfonamide structure, pharmacomodulation was achieved in order to obtain optimized analogs. Twenty new chemical derivatives with an original structure were synthesized and tested in vitro. Some of them exhibited an interesting activity. Moreover, data obtained provide important elements of structure-activity relationship. These results could constitute the basis for innovative small molecule TNFα-targeted therapeutics which would be a promising step for the treatment of diseases related to overproduction of this cytokine such as rheumatoid arthritis and Crohn's disease
Ciccolini, Joseph. "Etude de l'activation métabolique des fluoropyrimidines : application à la pharmacomodulation in vitro et in vivo du 5-fluorouracile." Aix-Marseille 2, 2000. http://theses.univ-amu.fr.lama.univ-amu.fr/PHA_2000_1527.pdf.
Full textMontagut-Romans, Adrien. "Réactivité et pharmacomodulation de la 4-hydroxycoumarine : conception, synthèse et évaluation biologique de nouvelles molécules rodonticides éco-compatibles." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10028.
Full textTo reduce the ecological impact of pesticides in UE many new legislations were put in place, in other hand, most of secondary intoxications of rodent's predators are due to rodenticides available on the market. That why it’s crucial to find alternative rodenticide more eco-friendly. This work describes optimization of new coumarinics compounds synthesis and their biological studies. The new anticoagulant should be active on wild and mutant rat, and must have a low hepatic persistence in the rat body. Organic syntheses were driven with biological studies and have converged to discover the lead. Three different new molecular tools were optimized and have allowed the synthesis and the evaluation of a large number of candidates. The first two through homogeneous catalysis by using micro-waves have reduced the time needed for the alkylation of 4-hydroxycoumarin on the carbon 3. The third methodology allows the synthesis of same kind of compounds in large scale. This methodology opens news potentials reactions to add structural diversity. All the molecules were evaluated in vitro on different types of VKORC1 and have participated to a better understanding of the enzyme/inhibitor interactions. After this first evaluation, in vivo tests were performed on a selection of candidates, and have brought a crucial structural relationship between structure and in vivo persistence/activity. The best compound produced by now seems to answer at all specifications established linked to the single-feeding strategy. Multiple-feeding strategy is today planned to better correspond to the field reality. On the base of this one the number of candidates usable as rodenticides is increased
Evrard, Alexandre. "Pharmacomodulation génétiquement contrôlée des fluoropyrimidines : application à la thérapie génique du cancer : [thèse soutenue sur un ensemble de travaux]." Montpellier 1, 1999. http://www.theses.fr/1999MON13501.
Full textAIT, MANSOUR HAMID. "Recherches dans la serie des acyl-6 benzoxazolinones : metabolites de la benzoyl-6 benzoxazolinone et pharmacomodulation des derives halogenoacyles." Lille 2, 1991. http://www.theses.fr/1991LIL2T007.
Full textPatry, Cédric Robert Jean-Michel. "Pharmacomodulation de structures polyhétérocycliques d'origine marine synthèse d'analogues structuraux des grossularines comme inhibiteurs potentiels de kinases, à visée antitumorale /." [S.l.] : [s.n.], 2008. http://castore.univ-nantes.fr/castore/GetOAIRef?idDoc=49506.
Full textPatry, Cédric. "Pharmacomodulation de structures polyhétérocycliques d'origine marine : synthèse d'analogues structuraux des grossularines comme inhibiteurs potentiels de kinases, à visée antitumorale." Nantes, 2008. https://archive.bu.univ-nantes.fr/pollux/show/show?id=9b150883-617c-4422-8ab5-79ec1b93969c.
Full textCancer is a major problem of public health. The research in chemotherapy advances, to develop new more specific compounds, diminishing side effects and resistances. So, the synthesis of new structures was inspired by molecules, as grossularines, exits of marine organism could allow to bring to light of new anticancerous agent. In a first part, this job syntheses and pharmacomodulations of analogues of reversed grossularines were accomplished. 3,5-dihydro-4H-imidazo[4,5-c]quinolin-4-one was synthetized by palladocatalysed annelation of N-aryl-2-imidazocarboxamides and the synthesis of 1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one envisaged from isatoic anhydrides by malonic synthesis. In a second part, a new structure has been developed with the support of molecular modelling. This comprehension « de novo » has allows the getting of a structure which will be synthetized by an efficient method in two stages. This structure 3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one allows the introduction of numerous groups by acylation of Friedel-Craft during the synthesis. These molecules were assessed on kinases and on cancerous cell descendants. On kinases the most active compound has IC50 in the order of 5 μM. On cells, IC50 of the most active compounds is less than 1 μM
Hadj, Mohamed Ameni. "Développement de nouvelles molécules de type di et triarylméthanes à visée antibactérienne et anticancéreuse : synthèse, caractérisation et études biologiques." Thesis, Sorbonne université, 2020. https://accesdistant.sorbonne-universite.fr/login?url=http://theses-intra.upmc.fr/modules/resources/download/theses/2020SORUS107.pdf.
Full textDi and triarylmethane molecules are described in the literature as privileged structures in medicinal chemistry. This thesis project concerns the development of new di and triarylmethane compounds for therapeutic purposes using tools used in medicinal chemistry. Two series, olefinic and alkyloxide diarylmethanes have been synthesized. Three series of triarylmethanes have been developed: triazole TAMs, macrocyclic TAMs and hybrid TAMs. Antibacterial and anticancer activity as well as cytotoxicity were studied in vitro for the synthesized compounds. Prediction of the ADME profile of the best molecules was also performed. From these studies, we demonstrated the interesting antiproliferative potential of some compounds on colorectal cancer cells and the absence of cytotoxicity of these compounds on normal cells
LOUBIERE, LAURENCE. "Pharmacomodulation genetiquement controlee d'analogues nucleosidiques. Applications en therapie genique du cancer et de l'infection par le virus de l'immunodeficience humaine (vih)." Paris 7, 1999. http://www.theses.fr/1999PA077149.
Full textCortelazzo-Polisini, Elodie. "Les Benzylidène-thiazolidinediones et -pyrrolidinediones, des synthons à fort potentiel : synthèse, activité biologique et photoisomérisation." Electronic Thesis or Diss., Université de Lorraine, 2022. http://www.theses.fr/2022LORR0042.
Full textHigh valuable Benzylidene-thiazolidinedione and -pyrrolidinedione moieties : synthesis, biological activity and photoisomerization.Abstract : This PhD work deals with the preparation of new benzylidene-heterocycles derivatives for anti-cancer therapy. In order to improve their selectivity towards cancer cell lines, we synthesized new analogs of our previous lead compound by modulating the relative position of the benzylidene-heterocycle moiety, changing the central heteroatom and the nature of the central cycle. A multistep synthesis was developed, and in spite of the encountered difficulties, due to the high complexity of the structures of the target compounds, more than 20 molecules were obtained. Antiproliferative properties of these compounds were evaluated on several cell lines leading to a structure-activity relationship study. Intrinsic fluorescent properties of our molecules allowed us to follow them inside the cells and further studies were achieved in order to understand their mechanism of action. In a second, part we explored the photoisomerization of the double bond of the benzylidene-thiazolidinedione moiety. An important in-depth study combining organic synthesis and UV-visible and NMR spectroscopies allowed us to understand this reaction. Thanks to an in-situ irradiation procedure monitored by NMR and UV-visible spectroscopy, we could determine kinetic parameters of this reaction as well as determinant factors to control the isomerization. Eventually, the extension of this sequence to o-aminobenzylidene-heterocycles led to the development of a fast and original synthesis pathway to new fused heterocyclic quinoline
Broudic, Nathan. "Chimie du Sel d'Appel et des Acides Anthraniliques pour la synthèse de nouveaux hétérocycles." Electronic Thesis or Diss., Normandie, 2024. http://www.theses.fr/2024NORMR036.
Full textFor more than twenty years, our research group has been synthesizing original heterocyclic structures to identify new inhibitors of the DYRK1A kinase, involved in neurodegenerative diseases. The thiazolo[5,4-f]quinazolines and quinazolinones EHT1610 and FC162, discovered in our laboratory, have been shown to significantly inhibit DYRK1A activity. This thesis aims to develop novel synthetic routes for linear regioisomers of EHT1610 and FC162 to verify experimentally the impact of angular geometry on their biological activity. A pallado-catalysed cyclisation of N-arylcyanothioformamides to 2-cyanobenzo[d]thiazoles was developed and applied for the synthesis of new linear polyfunctional benzothiazoles. These compounds were then used in a reaction inspired by Niementowski and Bischler-Napieralski condensations to create a new chemical library of original thiazolo-alkaloids. At least, linear analogues of EHT1610 and FC162 were also isolated for the first time. Their biological evaluation showed that the linear geometries were inactive on eight kinases, while the thiazolo[5,4-g]quinazolinone structure was cytotoxic at micromolar concentrations on seven cancer lines. A divergent modulation strategy was used to synthesise fifty new compounds. Compound 261 was shown to be active at nanomolar concentrations on all cancer lines by inducing senescence, without affecting healthy cells
Marie, Emilie. "Synthèse d'imidazo (1,2-a) pyridines à activité antivirale à l'encontre des virus de l'hépatite C et de la diarrhée virale bovine." Thesis, Tours, 2012. http://www.theses.fr/2012TOUR3802/document.
Full textHepatitis C is a silent disease, often asymptomatic, responsible for hepatic lesions which may lead to cirrhosis and in some cases, to cancer. Hepatocellular carcinoma caused by hepatitis C virus is the leading cause of liver transplantation. Bovine viral diarrhoea (BVDV) and hepatitis C (HCV) viruses are two pestiviruses from the Flaviviridae family that have a single-stranded RNA. Despite having different genomes, they present a similar structural organization and processes of development of the cell envelope.The laboratory’s chemical library screening has identified five hits, active against the HCV. Two of these compounds from the imidazo[1,2-a]pyridine serie were pharmacomodulated as part of the Ph.D. thesis of Jean-Baptiste Véron and Nicolas Henry.The first part of my research work was therefore to continue the pharmacomodulation study of these chemical series to improve their activity against HCV and their therapeutic index. To do so, the convergent synthesis of these molecules was performed using metal-catalyzed couplings.The second part of my project has focused on the study of the difunctionalization of positions 7 and 8 of the imidazo[1,2-a]pyridine nucleus. This work helped to develop new methodologies for introducing a functional diversity on these positions. The antiviral activity of these molecules was also assessed against HCV and one of them has shown interesting activity against this virus.In conclusion, activity against HCV and therapeutic index have been improved for two molecules, analogues of BPIP
Haroun, Michelyne. "Synthèse et études pharmacologiques de nouveaux ligands du petit sillon de l'ADN dans lesquels la nétropsine est couplée à deux chromophores et pharmacomodulation du chromophore phénazine dioxyde." Paris 5, 2001. http://www.theses.fr/2001PA05P620.
Full textBeaumont, Stéphane. "Synthèse d'indolobenzazépinones par des réactions de couplages catalysées au palladium et des réactions multicomposants : pharmacomodulation, propriétés antimitotiques et antitumorales. Aminohydroxylation d'indoles catalysée par des complexes de rhodium." Paris 11, 2008. http://www.theses.fr/2008PA112364.
Full textThis manuscript describes the synthesis of indolobenzazepinone analogues, the study of their cytotoxic and antimitotic properties and the development of a rhodium complex-catalyzed 2,3-aminohydroxylation of indoles. The first part of this work deals with the preparation of indolobenzazepinones using two palladium catalyzed coupling reactions. The first one implicates an intermolecular Suzuki-Miyaura cross-coupling between 3-iodoindole and N-Boc-α-alkylbenzylamine boronic acids. The second is an intramolecular direct arylation allowing formation of the biaryl bond. Cytotoxic and antimitotic activities of these compounds were evaluated. The most active compounds also showed in vitro antivascular and antiangiogenic properties. The second part describes access to indolob enzazepinones and isomeric paullone analogues having exocyclic amide groups by application of the Ugi four component reaction to a bifunctional aldehyde-acide. Cytotoxic and antimitotic activities of all synthesized compounds were evaluated. Finally, rhodium catalyzed nitrene transfer using hypervalent iodine reagents and oxygenated nucleophiles was studied and shown to allow aminohydroxylation of indoles. Application of optimized experimental conditions allowed efficient synthesis of 2,3-aminohydroxylindolines with a trans stereochemistry using methanol or a cis strereochemistry using carboxylic acids
MADADI, MESSAOUD NACER. "Recherche en pharmacochimie heterocyclique antiparasitaire : pharmacomodulation de derives thiopheniques et reactions de transfert monoelectronique en serie imadazo (1,2-a) pyridine et en serie imadazo (2,1-b) thiazole." Aix-Marseille 2, 1991. http://www.theses.fr/1991AIX22956.
Full textRodriguez, Ivan. "Étude de la synthèse arynique sélective d'indoles substitués en position C2 et de leurs propriétés mélatoninergiques ou sérotoninergiques : synthèse hétarynique et pharmacomodulation d'une nouvelle famille d'antitumoraux : les dihydrodipyridopyrazines." Nancy 1, 1998. http://www.theses.fr/1998NAN10203.
Full textVille, Alexia. "Métabolites secondaires et analogues hémisynthétiques en série vitaminique E : Obtention et évaluation du potentiel anti-inflammatoire." Thesis, Angers, 2018. http://www.theses.fr/2018ANGE0062.
Full textMany studies highlighted the biological potential of tocotrienols (T3), a vitamin E subfamily, especially in the field of cardiovascular diseases and chronic inflammation. A phytochemical study, previously conducted at SONAS, led to the isolation and characterization of δ-amplexichromanol (δ-AC) as the main and original secondary metabolite from Garcinia amplexicaulis barks (dichloromethane extract) along with other oxidized T3 analogs such as δ-garcinoic acid (δ-GA). A pharmacophore based virtual screening of these derivatives against various anti-inflammatory targets showed that this class of T3 analogs could be considered as potential 5-LOX inhibitors. It was confirmed by in vitro assays when δ-AC and δ-GA were evaluated as inhibitors of purified 5-LOX, or in polymorphonuclear leukocytes. We then decided to carry on our study to further understand the original mode of action of these metabolites while optimizing the anti-inflammatory properties of the first hits. Such approach requires large amounts of tocotrienolic derivatives. However, usual natural sources of T3 provide complex mixtures involving particularly challenging purification processes. Thus, this work aim at designing efficient semisynthesis towards pharmacologically relevant T3 derivatives were developed from -GA, the main T3 derivative isolated from Garcinia kola nuts, a renewable and easily available vegetal source. Moreover, pharmacomodulation of the tocotrienolic backbone relied on preliminary docking studies and then required the development of various synthetic strategies to access original vitamin E analogs as potential 5-LOX inhibitors
Cohen, Potier de Courcy Anita. "Synthèse et évaluation antiparasitaire de nouveaux dérivés du thiazole et apparentés." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM5503.
Full textThe objective of this work consists of the synthesis and the antiparasitic in vitro evaluation of new thiazole derivatives and related structures. Several synthetic strategies aiming at the pharmacomodulation on mono- and polycyclic series have been studied: in 2-methyl-5-nitrothiazole series, the anti-Trichomonas pharmacomodulation on position 4 by SRN1 strategy did not improve the activity previously demonstrated in 2-methyl-5-nitroimidazole series, but led to derivatives displaying a selective in vitro antiproliferative activity toward the HepG2 cell line. In 4-arylsulfonylmethyl-2-methylthiazole series, the pharmacomodulation on position 5, by Suzuki-Miyaura cross-coupling reaction on the one hand, and by direct arylation and intramolecular Knoevenagel reaction on the other hand, led to mono- and polycyclic derivatives among which some displayed an encouraging in vitro antiplasmodial activity. In 5H-thiazolo[3,2-a]pyrimidin-5-one series, a double Suzuki-Miyaura cross-coupling reaction revealed that the phenyl group on position 6 contributes to the antiplasmodial effect of this series. Finally, the in vitro biological evaluation of the thieno[3,2-d]pyrimidin-4(3H)-one scaffold let to characterize the pharmacophore responsible for the significant antiplasmodial activity. Some preliminary encouraging results regarding a mechanistic antiplasmodial study show the specific inhibition of plasmodial kinases, as a potential mechanism of action of some of these compounds
Fersing, Cyril. "Synthèse et étude des relations structure-activité de nouvelles 3-nitroimidazo (1,2-a) pyridines anti-kinétoplastidés." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0275/document.
Full textThe kinetoplastids of the Leishmania and Trypanosoma genus are the causative agents of neglected tropical diseases that threaten nearly half a billion people in the intertropical zone, resulting in 50 000 deaths per year. Among the molecules in clinical development to treat these pathologies, fexinidazole is a prodrug belonging to the 5-nitroimidazoles family, which exerts its anti-infectious action via a bioactivation step catalyzed by parasitic nitroreductases (NTR), enzymes whose cofactor is a flavin. In order to identify novel nitroheterocycles as parasitic NTR substrates, a small chemical library of imidazo[1,2-a]pyridines synthesized by our laboratory was screened in vitro, leading to the identification of a Hit molecule active both on Leishmania donovani and Trypanosoma brucei brucei. This compound served as a starting point for a pharmacomodulation work, initially in position 8 of the imidazo[1,2-a]pyridine ring: the introduction of various chemical groups using the pallado-catalyzed coupling reactions of Suzuki-Miyaura, Sonogashira and Buchwald-Hartwig, or SNAr reactions, highlighted several "lead" compounds with a significantly improved biological profile. In a second step, the pharmacomodulation work was extended to positions 2, 3 and 6 of the imidazo[1,2-a]pyridine ring in order to complete the structure-activity relationship data, to study in particular the impact of the redox potential and to optimize the physicochemical and in vitro pharmacokinetic parameters of the best compounds in order to initiate the study of their in vivo activity on a trypanosomiasis mouse model
Dupommier, Dorian. "Étude de la fonctionnalisation de 5-benzylidènethiazolidine-2,4-diones et application à la synthèse de nouveaux composés à visée anticancéreuse." Electronic Thesis or Diss., Université de Lorraine, 2020. http://www.theses.fr/2020LORR0133.
Full textThis PhD work is about the 5-benzylidenethiazolidine-2,4-dione, a very described scaffold thanks to its large array of biological activities. Our team has been interested for several years in the synthesis of new antiproliferative compounds, in which this moiety is a key-stone. To increase the selectivity of these compounds against cancer cells, we began a new pharmacomodulation work, starting from our lead compound, named AB 186. This study aimed to design new functionnalizations of the vinylic position in the 5-benzylidenethiazolidine-2,4-dione. To this end, several strategies were developed, according to the functionalization target and implying the synthesis of several substrates, bearing an array of different functional groups. These last were selected according to their reactivity in the different modulation reactions envisioned, such as Suzuki and Stille Pd-catalyzed cross coupling, Wittig olefinations, etc. Because of their high functionalizations, a study of the so-obtained compounds, 5-benzylidènethiazolidine-2,4-dione analogs, was shown to be very complex. It needed a methodologic approach to allow the reaction conditions optimization, whereas quantum chemistry calculations eased the structural determination of the obtained compounds. In a second time, we focused on the synthesis of the desulfured analog of AB 186, and on the development of a chiral synthesis for both the sulfured and desulfured compounds. This was done by setting an enzymatic deracemization sequence. Finally, the antiproliferative activity, the cell cycle and the mitochondrial respiration were measured in the presence of these compounds. It allowed us to bring to light the pro-apoptotic and inhibitor of the mitochondrial respiration effects of our new lead compound
Fersing, Cyril. "Synthèse et étude des relations structure-activité de nouvelles 3-nitroimidazo (1,2-a) pyridines anti-kinétoplastidés." Electronic Thesis or Diss., Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0275.
Full textThe kinetoplastids of the Leishmania and Trypanosoma genus are the causative agents of neglected tropical diseases that threaten nearly half a billion people in the intertropical zone, resulting in 50 000 deaths per year. Among the molecules in clinical development to treat these pathologies, fexinidazole is a prodrug belonging to the 5-nitroimidazoles family, which exerts its anti-infectious action via a bioactivation step catalyzed by parasitic nitroreductases (NTR), enzymes whose cofactor is a flavin. In order to identify novel nitroheterocycles as parasitic NTR substrates, a small chemical library of imidazo[1,2-a]pyridines synthesized by our laboratory was screened in vitro, leading to the identification of a Hit molecule active both on Leishmania donovani and Trypanosoma brucei brucei. This compound served as a starting point for a pharmacomodulation work, initially in position 8 of the imidazo[1,2-a]pyridine ring: the introduction of various chemical groups using the pallado-catalyzed coupling reactions of Suzuki-Miyaura, Sonogashira and Buchwald-Hartwig, or SNAr reactions, highlighted several "lead" compounds with a significantly improved biological profile. In a second step, the pharmacomodulation work was extended to positions 2, 3 and 6 of the imidazo[1,2-a]pyridine ring in order to complete the structure-activity relationship data, to study in particular the impact of the redox potential and to optimize the physicochemical and in vitro pharmacokinetic parameters of the best compounds in order to initiate the study of their in vivo activity on a trypanosomiasis mouse model