Carbonic anhydases (CAs) are ubiquitous enzymes present in human under 15 different isozymes. Each active one catalyzes the hydration reaction of carbon dioxide into bicarbonate anion and proton. Some isozymes contribute to basic physiological processes like among other respiration and acid-base homeostasis while other isozymes are involved in pathologies such as epilepsy (CA VII) and cancer (CA IX). Convulsions observed during epileptic seizures are partly attributed to carbonic anhydrase VII which play a role in neuronal excitation phenomenon. Carbonic anhydrase IX (CA IX) is overexpressed in most cancer tissues and is absent from their normal counterparts. It can acidify the extratumoral medium leading to metastatic behavior. To improve our knowledge on the role of these isozymes, the design of selective CA VII and IX inhibitors is of a great interest. Otherwise, such compounds can potentially be developed as antiepileptic or anticancer agents. A molecular modeling study which combines a direct (homology modelling, docking) and an indirect (pharmacophore, virtual screening) approach of drug design was conducted to create novel and selective inhibitors. In parallel, original indanesulfonamides were designed, synthesized and their inhibitory potencies against the CAs were determined. Docking studies of some derivatives allowed to rationalize the enzymatic data. Then, we evaluated the effect of some indanesulfonamides on a model of cancer cells. The study of the anticonvulsant activity was performed on an in vivo model. Finally, during this work other series of potentially CA inhibitors were also evaluated for their CA inhibitory activities and for one of them for its anticonvulsant effect.

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Medicinal Chemistry. Title from title-page of electronic thesis. Bibliography: leaves 169-185.

Epilepsy is a common neurological disorder for which the development of new and improved therapies is essential. Thus, the central theme of this thesis pertains to the design and synthesis of putative antiepileptic drugs. A substructure search was performed on a database of exogenous compounds to find those that contain a known sodium channel pharmacophore. The anticonvulsant activity of several compounds identified by this search was evaluated, resulting in the recognition of multiple molecular classes from which new anticonvulsant scaffolds could be derived. A series of analogues derived from uracil (an endogenous molecule) were synthesized and evaluated for anticonvulsant activity. Several of these analogues displayed promising activity and minimal toxicity, further supporting the theory that uracils could serve as potent, non-toxic, broad-range antiepileptic drugs capable of targeting both ictogenesis and epileptogenesis. A uracil QSAR model was also developed that could be used in the future to guide further analogue synthesis.

This thesis explores the use of cell theory calculations to characterise hydration thermodynamics in small molecules (cations, ions, hydrophobic molecules), proteins and protein-ligand complexes. Cell theory uses the average energies, forces and torques of a water molecule measured in its molecular frame of reference to parameterise a harmonic potential. From this harmonic potential analytical expressions for entropies and enthalpies are derived. In order to spatially resolve these thermodynamic quantities grid points are used to store the forces, torques, and energies of nearby waters which giving rise to the new grid cell theory (GCT) model. GCT allows one to monitor hydration thermodynamics at heterogeneous environments such as that of a protein surface. Through an understanding of the hydration thermodynamics around the protein and particularly around binding sites, robust protein-ligand scoring functions are created to estimate and rank protein-ligand binding affinities. GCT was then able to retrospectively rationalise the structure activity relationships made during lead optimisation of various ligand-protein systems including Hsp90, FXa, scytalone dehydratase among others. As well as this it was also used to analyse water behaviour in various protein environments with a dataset of 17 proteins. The grid cell theory implementation provides a theoretical framework which can aid the iterative design of ligands during the drug discovery and lead optimisation processes, and can provide insight into the effect of protein environment to hydration thermodynamics in general.

Metal catalysis of symmetric and asymmetric carbene transfer reactions has been widely applied in natural product synthesis and material science over years. Metal carbene can be easily generated from the extrusion of nitrogen under the catalysis of metal complexes to further undergo various organic reactions, O/N/C-H insertions, cycloadditions, and ylide formations. Currently, the dominant effective catalysts for carbene reactions are built with expensive precious metal, for example, rhodium, ruthenium, palladium, gold. Notably, the effective reactivity and enantioselectivity of the dirhodium(II) catalysts are researched and established over the decades. However, the use of precious metal catalysts is the major source of metal residues in pharmaceutical products; thus, it becomes a concerning safety factor towards the environment. Iron, instead, to our interest, is an economical and ecofriendly element. Iron has been used in different catalytic reactions but achieved moderate reactivity and low enantioselectivity towards carbene transfer reactions. Within, the electronic environment and the mechanism of iron catalysts are underdeveloped. A new series of ligands named bis(imino)pyridine family has been found to be able to offer coordinate sites for transition metals to build effective metal complexes can be used for different organic reactions. This type of ligand can be easily synthesized in relatively short steps and the structure of the substituents can be facially tuned. These advantages show the great potential of bis(imino)pyridine ligands in organic catalysis. In this project, bis(imino)pyridine ligands were applied as the backbone structure to construct a series of achiral and chiral iron catalysts that were investigated in catalytic metal carbene reactions in terms of reactivity and selectivity. By manipulating the structure of the ligands, the high reactivity of the achiral iron(II) complexes towards various carbene reactions was achieved, while moderate enantioselectivity was observed by the catalysis of chiral iron(II) complexes. To our delight, the bis(imino)pyridine iron(II) complex, for the first time, is shown as an effective metal carbene catalyst for carbene transfer reactions of donor–acceptor diazo compounds. Its broad catalytic capability is demonstrated by a range of metal carbene reactions, from cyclopropanation, cyclopropenation, epoxidation, and Doyle–Kirmse reaction to O–H insertion, N–H insertion, and C–H insertion reactions. The asymmetric cyclopropanation of styrene and methyl phenyldiazoacetate was successfully achieved by the new chiral bis(imino)pyridine iron catalyst, which delivers a new gateway for the development of chiral iron catalysis for metal carbene reactions.

No description available.

Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Master of Science in the School of Informatics, Indiana University December 2005 / The approach of exploiting highly conserved protein folds and structure in understanding protein function and in designing drugs leads to drugs that are less selective due to association with similar proteins. Over the years an open problem for researchers has been to develop drug design models based on non-conserved features to have higher selectivity. Recently a new structural feature, the dehydron, has been demonstrated to vary across proteins with conserved folds. Dehydrons are backbone hydrogen bonds that are not adequately protected from water. The importance of wrapping dehydrons in ligand binding and non-conservation of dehydrons across similar proteins makes them important candidates for markers in drug design. Investigation on a series of proteins – PDB entries: 1IA8, 1NVQ, 1NVS, 1NVR, 1OKZ, and 1PKD – revealed the potential impact of wrapping on binding affinity of the ligands. Unlike in 1NVS, 1NVR, 1OKZ, and 1PKD, inhibitor UCN in 1NVQ wrapped both the dehydrons in active site region of the checkpoint protein kinase, thereby indicating an increased potency and higher selectivity. On detailed analysis of 193 protein kinases, roughly 70% were found to have two or more dehydrons in the neighborhood of the bound ligand. Also, about 70% of proteins had dehydrons within the active site region. Only around 20% of ligands, however, actually wrapped two or more dehydrons. These statistics clearly illustrate the significance of dehydrons and their potential use as markers for drug design to enhance drug efficacy as well as selectivity, and to reduce side effects in the process.

Macrocycles (MCs) have become an increasing area of interest for drug design efforts, especially for classically “difficult” targets like protein-protein interactions (PPIs). And although there are many examples of successful MC drugs derived from natural products, there is little information about the characteristics of compounds with effective pharmacological and physicochemical properties. In this dissertation, I describe the development of design guidelines for new MC drugs based on a representative set of known inhibitor MCs and their target proteins. Analysis of both the individual MC structures and their interactions in the protein complex resulted in identification of several structural and physicochemical features likely to promote favorable binding and bioavailability. Additionally, investigation of the binding sites on the proteins suggest that MCs can bind targets conventionally considered “non-druggable,” strengthening the argument for exploring MC compounds to increase the druggable target space. Furthermore, this work includes the application of the proposed design guidelines to the development of synthetic MC libraries for a PPI target, the NEMO/IKKβ complex.

Cette thèse est consacrée à la conception, la synthèse et l'évaluation biologique de différents dérivés quinoliniques en vue de développer de nouveaux médicaments contre les maladies infectieuses, en particulier la tuberculosis (TB) et le paludisme. La première partie de cette étude décrit la synthèse de dérivés de la méfloquine (MFL) et leur évaluation sur Mycobacterium tuberculosis. Une série de 26 composés a été synthétisée par une réaction de condensation entre la MFL et des dérivés d’aldéhyde diversement substitués. Les activités ont été évaluées sur la souche standard de M. tuberculosis H37Rv, qui est sensible aux différents médicaments existants, et sur la souche multirésistante T113 (résistante à trois médicaments de premier choix, l'isoniazide, la rifampicine et l'éthambutol, ainsi qu'à l'ofloxacine, une fluoroquinolone utilisée dans le traitement de second choix). La seconde partie de cette étude concerne la synthèse et l'évaluation pharmacologique des dérivés hybrides contenant un groupement 7-chloro-4-aminoquinoléine, et un dérivé fluoré d’artémisinine dans leurs structures. Nous avons décrit deux séries de dérivés d’artémisinine: le CF3-artésunate, et une seconde série où un acide est introduit en position 16 d’une artémisinine modifiée, dont la fonction cétal a été supprimée. Les produits ont été évaluées in vitro contre la souche de P. falciparum 3D7, sensible à la chloroquine. Toutes les substances ont montré une excellente activité de l'ordre du nM. / The present work describes the design, synthesis and biological evaluation of several substances containing the quinoline nucleus, with potential activity against infectious diseases, with a focus on tuberculosis (TB) and malaria. In the first part of this work, we have been particularly interested in the synthesis of new mefloquine (MFL) derivatives which could help in the development of treatments against the Mycobacterium tuberculosis. A total of 26 new compounds were synthesized from reactions between MFL and a substituted arenealdehyde. The biological activities were evaluated against the standard strain of M. tuberculosis H37Rv, sensitive to the different drugs used in TB treatment and the multi-drug resistant (MDR) strain T113, resistant to three first line drugs (isoniazid, rifampicin and ethambutol) and ofloxacine, a fluoroquinolone used as a second choice treatment. The second part of this work presents the development of new hybrid molecules, containing a 7-chloro-4-aminoquinoline moiety and a CF3-artemisinin moiety. Two series were described, one containing a CF3-artesunate moiety and another one where a carboxylic acid functional group was introduced in position 16 of a modified artemisinin, where the ketal function was suppressed. The final products were assayed in vitro against the Plasmodium falciparum strain 3D7, sensitive to chloroquine. The substances displayed excellent activities, in the nM range. / O presente trabalho descreve a concepção, a síntese e a avaliação biológica de diferentes derivados quinolínicos, com potencial atividade contra doenças negligenciadas, tendo como foco principal a tuberculose (TB) e a malária. A primeira parte desse estudo teve como objetivo a síntese de derivados da mefloquina (MFL) que pudessem auxiliar no desenvolvimento de novos tratamentos contra o Mycobacterium tuberculosis. Uma série de 26 compostos foi preparada a partir de uma reação de condensação entre a MFL e arenaldeídos substituídos. Os derivados tiveram sua atividade biológica verificada frente à cepa padrão de M. tuberculosis H37Rv, sensível aos diferentes tuberculostáticos e à cepa multirresistente T113, resistente a três fármacos utilizados no tratamento de primeira escolha (isoniazida, rifampicina e etambutol) e uma fluoroquinolona utilizada no tratamento de segunda escolha, o ofloxacino. A segunda parte desse trabalho visou à síntese e à avaliação biológica de derivados híbridos contendo um grupo 7-cloro-4-aminoquinolina e um grupamento trifluorometil-artemisinina em sua estrutura. Duas séries foram descritas, uma contendo um grupamento CF3-artesunato e a outra contendo um grupamento ácido carboxílico na posição 16 de uma artemisinina modificada, onde a função cetal foi suprimida. Os produtos finais foram testados in vitro contra a cepa de P. falciparum 3D7, susceptível à cloroquina. Todas as substâncias apresentaram uma excelente atividade, na ordem de nM.

Nous nous intéressons à l'utilisation de la technologie manycore des cartes graphiques dans le cadre de la Chimie théorique. Nous soutenons la nécessité pour ce domaine d'être capable de tirer profit de cette technologie. Nous montrons la faisabilité et les limites de l'utilisation de cartes graphiques en Chimie théorique par le portage sur GPU de deux méthodes de calcul en modélisation moléculaire. Ces deux méthodes n’intégrerons ultérieurement au programme de docking moléculaire AlgoGen. L'accélération et la performance énergétique ont été examinées au cours de ce travail.Le premier programme NCIplot implémente la méthodologie NCI qui permet de détecter et de caractériser les interactions non-covalentes dans un système chimique. L'approche NCI se révèle être idéale pour l'utilisation de cartes graphiques comme notre analyse et nos résultats le montrent. Le meilleur portage que nous avons obtenu, a permis de constater des facteurs d'accélération allant jusqu'à 100 fois plus vite par rapport au programme NCIplot. Nous diffusons actuellement librement notre portage GPU : cuNCI.Le second travail de portage sur GPU se base sur GAMESS qui est un logiciel complexe de portée internationale implémentant de nombreuses méthodes quantiques. Nous nous sommes intéressés à la méthode combinée DFTB/FMO/PCM pour le calcul quantique de l'énergie potentielle d'un complexe. Nous sommes intervenus dans la partie du programme calculant l'effet du solvant. Ce cas s'avère moins favorable à l'utilisation de cartes graphiques, cependant nous avons su obtenir une accélération. / In this research work we are interested in the use of the manycore technology of graphics cards in the framework of approaches coming from the field of Theoretical Chemistry. We support the need for Theoretical Chemistry to be able to take advantage of the use of graphics cards. We show the feasibility as well as the limits of the use of graphics cards in the framework of the theoretical chemistry through two usage of GPU on different approaches.We first base our research work on the GPU implementation of the NCIplot program. The NCIplot program has been distributed since 2011 by Julia CONTRERAS-GARCIA implementing the NCI methodology published in 2010. The NCI approach is proving to be an ideal candidate for the use of graphics cards as demonstrated by our analysis of the NCIplot program, as well as the performance achieved by our GPU implementations. Our best implementation (VHY) shows an acceleration factors up to 100 times faster than the NCIplot program. We are currently freely distributing this implementation in the cuNCI program.The second GPU accelerated work is based on the software GAMESS-US, a free competitor of GAUSSIAN. GAMESS is an international software that implements many quantum methods. We were interested in the simultaneous use of DTFB, FMO and PCM methods. The frame is less favorable to the use of graphics cards however we have been able to accelerate the part carried by two K20X graphics cards.