No description available.

No description available.

Depuis son apparition dans les années 80, le SIDA est déjà responsable de la mort de 25 millions de personnes et reste un défi majeur pour les chercheurs. En raison de son fort taux de mutation, le VIH-1, agent causal du SIDA, développe des résistances vis-à-vis des médicaments utilisés en multithérapies, ce qui nécessite la mise en place de nouvelles stratégies. Après la mise sur le marché du Raltegravir (2007), premier inhibiteur de l’intégrase, des résistances ont déjà été constatées. Le laboratoire s’est intéressé à la synthèse de deux nouvelles séries d’inhibiteurs de fonctions enzymatiques du VIH: l’intégrase (IN) et la fonction ribonucléase H (RNase H) de la transcriptase inverse. Ces 2 étapes clés de la réplication virale nous ont paru pertinentes à cause de la structure similaire des sites catalytiques de ces deux enzymes capables de complexer deux cations magnésium. Nous avons, dans un premier temps, élaboré une série de 3-hydroxyquinoléin-2(1H)-ones. Nous présentons ici la synthèse de ces composés, leurs capacités de complexation des ions magnésium ainsi que leurs activités biologiques sur IN et RNase H (inhibition des activités enzymatiques, inhibition de la réplication virale et cytotoxicité sur cellules MT-4). Dans un deuxième temps, nous avons développé une série de 2-hydroxyisoquinoléine-1,3-diones qui présente un profil antiviral différent de celui du raltegravir tout en agissant sur l’IN du VIH-1. La synthèse et les résultats biologiques sur IN seront détaillés. Pour ces deux séries de molécules, une étude de docking moléculaire a été réalisée afin de mieux comprendre les relations structure/activité. / Since it appeared in the eighties, AIDS has been responsible for the death of more than 25 million people and has become the most challenging pandemic of the 21st century. Multi-therapies can achieve a significant reduction of the viral load in HIV-1 infected patients but is noticeably limited by the emergence of multidrug resistant viral strains. New strategies aimed at inhibiting virus replication are still necessary. In 2007, the FDA approved raltegravir, the first drug inhibiting the HIV-1 integrase (HIV-1 IN). It led to strongly encouraging clinical results but resistant viral strains have already appeared. The laboratory was interested in the synthesis of two series of new HIV-1 enzymatic functions inhibitors: integrase and ribonuclease H of reverse transcriptase. These two key steps of the viral replication are promoted by structurally-related catalytic cores, which are able to chelate two magnesium cations. First, we decided to investigate a series of 3-hydroxyquinolin-2(1H)-ones. Herein we present the synthesis of these compounds, their magnesium chelating properties and their biological activities (integrase and RNase H inhibitory activities, viral replication inhibition and cytotoxicity on MT-4 cells). Then, we developed a series of 2-hydroxyisoquinolin-1,3-diones which inhibits integrase with different profiles from that of raltegravir. The synthesis and biological activities of this series will be described. Finally, docking studies were made to better understand structure/activities relationships.

No description available.

Σκοπός της παρούσης εργασίας είναι η στατιστική ανάλυση της σχέσης δομής-δράσης των χημικών ενώσεων που παράγονται από οξινδόλια και πουρίνες πάνω στα σύμπλοκα CDKs/Cyclins και η εξαγωγή συμπερασμάτων πάνω στις σχέσεις αυτές. Για το σκοπό αυτό ανατρέξαμε στην διεθνή βιβλιογραφία για να συλλέξουμε όσες πληροφορίες έχουν δημοσιευτεί έως τώρα για τις δύο αυτές ομάδες ενώσεων. Έπειτα μέσω ειδικών προγραμμάτων έγινε η επεξεργασία τους και η ανάλυση τους. Σκοπός είναι να συσχετίσουμε τη δομή των ενώσεων αυτών με τη δράση και τη βιολογική τους απόκριση πάνω στα σύμπλοκα των CDKs με τις κυκλίνες. / -

MSc (Chemistry) / Department of Chemistry / Quinolines are well known naturally occurring heterocyclic compounds with nitrogen as a heteroatom. Quinolines are also one of the major classes of naturally occurring compounds and the interest in their chemistry is due to the wide range of their biological activities. The objective of the project was the synthesis of novel tetra-substituted quinoline-3carboxamides and subsequent transformation to other novel derivatives and evaluation of their biological activities against malaria and cytotoxicity. In achieving the objective, 2-chloroquinoline-3-carbaldehyde analogues 54A-G were synthesised from the reaction of acetanilides 53A-G and acetic acid. Knoevenagal reaction of 2chloroquinoline-3-carbaldehydes 54A-G with thiazolidinedi-2,4-one 62 provided 2chloroquinoline-3-methylene thiazolidinedi-2,4-one 55A-G which then underwent nucleophilic substitution reaction with sodium azide and afforded (Z)-5-((tetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56A-F. (Z)-ethyl-2-(2-5-((7bromotetrazolo [1,5a] quinolin-4-yl) methylene-2,4-dioxothiazolidin-3-yl) acetamido) acetate 57 was synthesised from the reaction of (Z)-5-((7-bromotetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56D and ethyl-2-(2-chloroacetamido) acetate 65. The structures of the compounds were characterised by 1D NMR (1H, 13C, and DEPT 135), IR spectroscopy, elemental analysis and high-resolution mass spectroscopy. Novel selected synthesised quinoline compounds were evaluated of in vitro for two biological assays; namely anti-malarial activity and cytotoxicity. The anti-malaria activities of the novel quinoline compounds against 3D7 strain of the malaria parasite Plasmodium falciparum displayed that 2,6-dichloroquinoline-3-methylene thiazolidinedi-2,4-one 55C, (Z)-5-((7-fluorotetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56B and (Z)-5((7-ethoxytetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56F are potential malaria drugs since they reduced the percentage parasite viability to 25.80, 12.40 and 20.40 respectively. These results were further substantiated by their IC50 values 0.40, 0.04 and 0.50 µg/mL. Compound 56B displayed the highest cytotoxicity activity against human cervix adenocarcinoma cells displaying percentage viability of 14.22 %. Compounds 56F and 56C displayed moderate cytotoxicity activity at 56.60 and 59.81 % viability. / NRF