Fluoroquinolones are broad-spectrum antibacterial agents based on the structure of nalidixic acid. For nearly five decades it has been known that fluoroquinolones inhibit bacterial growth by blocking the enzymatic action of type II topoisomerases such as DNA gyrase and topoisomerase IV. Only recently has it been discovered that some fluoroquinolones are capable of a mechanism that results in fragmented DNA and leads to rapid bacterial cell death. This mechanism is not well understood. Presented here are studies towards understanding the structure activity relationship (SAR) of fluoroquinolones, specifically to determine what leads to the novel mechanism termed "rapid lethality." This work is based on the hypothesis that structurally unique fluoroquinolones interact with the DNA-topoisomerase complex in a unique manner that ultimately leads to rapid cell death. The first approach to understand SAR for killing was to evaluate the effect of a ring fusion between N-1 and C-8 of the fluoroquinolone core. Known lethal fluoroquinolones are substituted by N-1 cyclopropyl and C-8 methoxy, but some clinically important fluoroquinolones contain a 2-methylmopholino moiety between these two positions. Novel fluoroquinolones were synthesized and clinically available agents were obtained to create a panel of drug molecules with one of six C-7 substituents and either the morpholine ring system or N-1 cyclopropyl and C-8 methoxy. Bacteriostatic and bactericidal activities of these compounds were determined. Bactericidal studies were conducted both in the presence and absence of chloramphenicol, a protein synthesis inhibitor used to simulate non-growing bacteria. Lethality in the presence of chloramphenicol is also important when considering co-administration of fluoroquinolones with other antibiotic classes. In a second study, fluoroquinolones were synthesized with a C-2 thioalkyl substitution. Substitutions at the C-2 position are severely lacking in clinical fluoroquinolones, with only prulifloxacin, a newly developed antibiotic, being substituted by an N-1 to C-2 thiazetidine ring structure. Analogs of ciprofloxacin and moxifloxacin were synthesized such that the N-1, C-2, and C-8 positions were substituted with cyclopropyl, thioethyl/thioisopropyl, and methoxy groups, respectively. The compounds were then evaluated for antibiotic activity against three different bacterial strains to evaluate the contribution of the C-2 thioalkyl substituent to antibacterial activity. In a third study, quinazoline-2,4-diones, a new antibiotic class structurally and mechanistically similar to fluoroquinolones, were modified at the C-4 position in an effort to understand the binding interaction between these compounds and the target enzyme. Importantly, the quinazoline-2,4-diones typically retain activity against bacterial cells known to be resistant to fluoroquinolones and are less likely to select for resistant mutants. In this study, the C-4 carbonyl was replaced with either a thiocarbonyl or a hydroxylimine and the new compounds, bearing C-7 substituents common to potent antibiotic fluoroquinolones and quinazolines, were evaluated for activity against bacterial cells. Despite the findings of recently published X-ray crystallography, it was determined that one of the greatest determinants in antibiotic activity of fluoroquinolones is the C-7 substituent. Additionally, there is increasing evidence that the C-2 carbonyl of quinazoline-2,4-diones affords the increase in activity against resistant mutants by creating a unique binding interaction. Collectively, the conclusions reached here add to our understanding of the structure activity relationship of the fluoroquinolone antibiotic class for rapidly killing bacterial cells and overcoming resistant mutants.

Yes / Vandetanib is an orally available tyrosine kinase inhibitor used in the treatment of cancer. The current synthesis proceeds via an unstable 4-chloroquinazoline, using harsh reagents, in addition to requiring sequential protection and deprotection steps. In the present work, use of the Dimroth rearrangement in the key quinazoline forming step enabled the synthesis of Vandetanib in nine steps (compared to the previously reported 12–14). / This work was supported by the Cancer Research UK-Cancer Imaging Centre (grant: C1060/ A16464), the Institute of Cancer Research and the University of Hull.

Ce travail porte sur la conception de dérivés d'aminoacridine et de quinazoline. Dans une première partie, nous avons préparé des dérivés d'aminoacridine ortho-hydroxyméthylée. Pour synthétiser ces dérivés nous avons mis au point une stratégie efficace et générale mettant en jeu la préparation d'un intermédiaire-clé qui peut ensuite être fonctionnalisé. A partir de ce dernier nous avons préparé des dérivés substitués par un motif guanidine. Nous avons également préparé un dérivé iodé afin d'étudier sa distribution cellulaire par microscopie ionique (SIMS). Les propriétés biologiques (IC50 et distribution cellulaire) de ces nouveaux composés ont été évaluées sur des cellules cancéreuses et les résultats obtenus ont confirmé l'intérêt de cette nouvelle famille d'aminoacridine comme anticancéreux.<br />Dans une seconde partie nous avons mis au point une nouvelle méthodologie de synthèse de 2-alkylamino-4(3H)-quinazolinones. Nous avons ainsi préparé différents dérivés comportant un motif quinazolinone à partir d'amines aromatiques et hétérocycliques. Certains de ces dérivés ont fait l'objet d'études biologiques préliminaires (effet cytostatique, ligand ADN-quadruplex) et les résultats obtenus sont très encourageants.

Le rétrécissement valvulaire aortique calcifié (RAC) est le trouble valvulaire le plus fréquent chez les personnes âgées des pays développés. La seule option de traitement possible le remplacement de la valve aortique. L'identification du rôle de l’enzyme ecto-nucleotidase NPP1 dans le processus de calcification suggère que cette enzyme pourrait être une cible potentielle pour le développement d'un inhibiteur pharmacologique contre la calcification de la valve aortique. Jusqu’à présent, les composés qui ont été développés en tant qu'inhibiteurs de NPP1 manquent de puissance et de spécificité. Dans la présente étude, nous avons démontré que les dérivés de sulfonamides quinazolin-4-pipéridine sont des inhibiteurs puissants, spécifiques, et non-compétitifs de NPP1. In vitro, dans des cellules isolées de valve aortique nous avons fourni des preuves que l’inhibition de NPP1 par ces dérivés bloque la minéralisation, l’apoptose et la transition ostéogénique des cellules interstitielles de valve aortique. / Calcific aortic valve disease (CAVD) is the most common valvular disorder in the elderly population in the developed counties with the only valid treatment option today remains the aortic valve repair or replacement. The identification of the role of an ectonucleotidase enzyme NPP1 in the process of calcification shed new light into the development of a pharmacological inhibitor that may prevent the calcification of the aortic valve. By far, the compounds that have been developed as inhibitors of NPP1 lack potency and specificity. In the current study, we showed that the quinazolin-4-piperidin sulfamide derivatives to be a potent, specific, and non-competitive inhibitors of NPP1. We also provided evidence that by inhibiting NPP1 enzyme activity these derivatives are able to prevent phosphate-induced mineralization of valve interstitial cells (VICs), the main cellular component of the aortic valve, by preventing both apoptosis and osteoblastic transitions of VICs.

[ES] Se ha desarrollado un método de síntesis "verde" de compuestos metal orgánicos en medio acuoso, a temperatura y presión ambientes, fácilmente escalable y con tiempos de cristalización muy cortos (10 min). El método se ha aplicado con éxito a la síntesis de trimesatos de metales divalentes isoreticulares y con fórmula general M3(BTC)2·12 H2O (M = Ni2+, Co2+, Cu2+ y Zn2+; BTC = trimesato). La estructura de estos materiales presenta dos tipos de centros metálicos ("puente" y "ter-minales") en proporción 2 a 1, ambos con coordinación octaédrica y unidos a 4 moléculas de H2O y a dos oxígenos carboxilato del ligando. Usando este método de síntesis, se han preparado también series de compuestos bimetálicos isoreticulares de Co-Ni y Co-Zn en todo el rango de concentraciones, así como compues-tos de Mn-Ni con una concentración máxima de Mn2+ del 50%. Mediante la combinación de difracción de rayos X (en polvo y de monocristal) y microscopía EDX/SEM se ha demostrado que los compuestos bimetálicos forman verdaderas disoluciones sólidas (no meras mezclas de fases) y que los iones metálicos se dis-tribuyen homogéneamente en todo el cristal. Además, el análisis detallado de la variación de los parámetros de celda con la composición en compuestos Co-Ni y Co-Zn aporta fuertes evidencias de que los iones Co2+ ocupan preferentemente las posiciones "terminales". Se ha evaluado la actividad de los compuestos preparados como catalizadores para la oxidación aeróbica de cumeno (CM) a cumeno hidroperóxido (CHP). El com-puesto monometálico de Co2+, Co-BTC, presentó una elevada actividad, aunque la selectividad a CHP obtenida fue relativamente baja (69%), ya que los iones Co2+ catalizan también la descomposición del CHP formado. Una buena estrategia para optimizar esta selectividad consistió en aislar los iones Co2+ en una matriz de Ni-BTC (que es inerte tanto para la oxidación de CM como para la descomposición de CHP). Así, al disminuir la concentración de iones Co2+ en compuestos bimetálicos Co-Ni se observó un aumento de la selectividad a CHP de hasta el 91% para el material con un 5% de Co. Se ha calculado que estadísticamente el 73% de los iones Co2+ en este material se encuentran aislados, por lo que la des-composición/sobreoxidación del CHP se ve muy limitada. Usando una variación del método de síntesis, se han obtenido también compuestos isoreticulares de Co2+ en los que los ligandos trimesato se han reemplazado parcialmente por ligandos isoftálico o 5-aminoisoftálico. Al utilizar estos com-puestos como catalizadores para la oxidación aeróbica de CM, se ha observado que la introducción de este segundo ligando (y en particular del 5-aminoisoftálico) en la red metal-orgánica facilita la descomposición del CHP formado y aumenta la selectividad final a 2-fenil-2-propanol (PP). Esto se ha atribuido a la creación de defectos puntuales en la red del material, que presentan una mayor actividad para la descomposición de CHP. Siguiendo con la oxidación de CM como reacción modelo, se ha evaluado la actividad catalítica de compuestos isoreticulares de cobalto con ligandos bispirazolato funcionalizados con distintos grupos (CoBPZ, CoBPZ-NO2 y CoBPZ-NH2). En este caso se ha observado una clara influencia del ligando utilizado sobre la acti-vidad catalítica y la selectividad a CHP o PP del material. Mientras que el Co-BPZ presenta una baja conversión de CM y una elevada selectividad a CHP, Co-BPZ-NH2 presenta las características opuestas: una elevada velocidad de reacción pero una baja selectividad a CHP. En este último caso, el producto mayoritario forma-do es el PP. Por último, el estudio de MOFs de cationes divalentes como catalizadores de oxidación se ha completado con una reacción de síntesis de quinazolina mediante acoplamiento oxidativo de bencilamina y 2-aminoacetofenona usando TBHP co-mo oxidante. Como catalizadores para esta reacción se ha utilizado el trimesato de / [CA] S'ha desenvolupat un mètode de síntesi "verda" de compostos metall orgànics en medi aquós, a temperatura i pressió ambients, fàcilment escalable i amb temps de cristal·lització molt curts (10 min). El mètode s'ha aplicat amb èxit a la síntesi de trimesats de metalls divalents isoreticular i amb fórmula general M3(BTC)2·12 H2O (M = Ni2+, Co2+, Cu2+ y Zn2+; BTC = trimesat). L'estructura d'aquests materials presenta dos tipus de centres metàl·lics ("pon" i "terminals") en una proporció de 2 a 1, ambdós amb coordinació octaèdrica i units a 4 molècules d'aigua i a 2 oxígens carboxilat del lligand. Emprant aquest mètode de síntesi, s'han preparat també sèries de compostos bimetàl·lics isoreticular de Co-Ni i Co-Zn en tot el rang de concentracions, així com compostos de Mn-Ni amb una concentració màxima de Mn2+ del 50%. Mitjançant l'ús combinat de difracció de raigs X (en pols i de monocristall) i microscòpia EDX/SEM s'ha demostrat que els compostos bimetàl·lics formen vertaderes dissolucions sòlides (no simples mescles de fase) i que els ions metàl·lics es distribueixen homogèniament en tot el cristall. A més, l'anàlisi detallat de la variació dels paràmetres de cel·la amb la composició de compostos Co-Ni i Co-Zn aporta fortes evidències de que els ions Co2+ ocupen preferentment les posicions "terminals". S'ha avaluat l'activitat dels compostos preparats com a catalitzador per a l'oxidació aeròbica de cumè (CM) a cumè hidroperòxid (CHP). El compost monometàl·lic de Co2+, Co-BTC, presenta una elevada activitat, encara que la selectivitat a CHP obtinguda és relativament baixa (69%), ja que els ions Co2+ catalitzen també la descomposició del CHP format. Una bona estratègia per optimitzar aquesta selectivitat consisteix en aïllar els ions Co2+ en una matriu de Ni-BTC (que és inert tant per a l'oxidació de CM com per a la descomposició de CHP). Així, a mesura que disminueix la concentració d'ions Co2+ en compostos bimetàl·lics Co-Ni s'observa un augment de la selectivitat a CHP de fins el 91% per al material amb un 5% de cobalt. S'ha calculat que estadísticament el 73% dels ions Co2+ d'aquest material es troben aïllats, de manera que la descomposició/sobreoxidació del CHP es veu molt limitada. Emprant una variació del mètode de síntesi, s'han obtingut també compostosisoreticulars de Co2+ en els que els lligands trimesat s'han reemplaçat parcialment per lligands isoftàlic o 5-aminoisoftàlic. Quan aquest compostos s'usen com a catalitzadors per a l'oxidació aeròbica de CM, sobserva que la introducció d'aquest segon lligand (i en particular del 5-aminoisoftàlic) en la xarxa metallorgànica es facilita la descomposició del CHP format i augmenta la selectivitat final a 2-fenil-2-propanol (PP). Això s'ha atribuït a la creació de defectes puntuals en la xarxa del material, que presenten una major activitat per a la descomposició del CHP. Seguint amb l'oxidació de CM com a reacció model, s'ha avaluat l'activitat catalítica de compostosisoreticulars de cobalt amb lligands bispirazolat funcionalitzats amb distints grups (CoBPZ, CoBPZ-NO2 i CoBPZ-NH2). En aquest cas s'ha observat una clara influència del lligand utilitzat sobre l'activitat catalítica i la selectivitat a CHP o PP del material. Mentre que el CoBPZ presenta una baixa conversió de CM i una elevada selectivitat a CHP, CoBPZ-NH2 presenta les característiques oposades: una elevada velocitat de reacció però una baixa selectivitat a CHP. En aquest últim cas, el producte majoritari format és el PP. Per últim, l'estudi de MOFs amb cations divalent como a catalitzadors d'oxidació s'ha completat amb una reacció de síntesi de quinazolina mitjançant acoblament oxidatiu de benzilamina i 2-aminoacetofenona emprant TBHP como a oxidant. Com a catalitzadors per aquesta reacció s'ha utilitzat el trimesat de coure, HKUST-1, així com materials isoreticular amb lligands mixtes obtinguts reemplaçant pa / [EN] A "green" synthesis method has been developed for the preparation of metal organic frameworks in aqueous media, which is easily scalable, at room tempera-ture, ambient pressure and very short crystallization times (10 min). This method has been successfully applied to the synthesis of isoreticular divalent metal trimesates of general formula M3(BTC)2·12 H2O (M = Ni2+, Co2+, Cu2+ y Zn2+; BTC = trimesate). The structure of these compounds features two types of metal centers ("bridging" and "terminal") in a 2 to 1 ratio, both with octahedral coordina-tion and linked to 4 water molecules and 2 carboxylate oxygens of the ligand. Using this method, two series of bimetallic isoreticular compounds of Co-Ni and Co-Zn have also been prepared in all range of compositions, as well as bimetallic Mn-Ni compounds up to a maximum concentration of 50% of Mn2+. A combined X-ray diffraction (powder and single crystal) and EDX/SEM has shown that these bimetallic compounds form true solid solutions (not simple mixture of phases) and that both ions distribute homogeneously throughout the crystal. A detailed analysis of the variation of cell parameters with the composition strongly sug-gests that Co2+ ions occupy preferentially the "terminal" positions of the frame-work. The materials obtained with the above method have been evaluated as catalysts for the aerobic oxidation of cumene (CM) to cumene hydroperoxide (CHO). The monometallic Co2+ compound, Co-BTC, showed a high catalytic activity, but a relatively low selectivity to CHP 69%), since the Co2+ ions can also catalyze the decomposition of the formed CHP. A good strategy to optimize the CHP selectivity consisted in isolating the Co2+ ions into a Ni-BTC (which is inert for both CM oxidation and CHP decomposition). In this way, as the concentration of Co2+ ions in the bimetallic Co-Ni compound decreases, a parallel increase of the CHP selec-tivity was observed, up to 91% for the material with 5% of Co. In this compound, 73% of the total Co2+ ions are statistically isolated, so that decomposi-tion/overoxidation of CHP is unlikely to occur. By using a variation of the above synthesis method, additional isoreticular Co2+ compounds have been prepared in which the trimesate ligands have been partially replaced by either isophthalic or 5-aminoisophthalic. When these compounds were used as catalysts for the aerobic oxidation of cumene, we observed that the introduction of this second ligand (in particular in the case of 5-aminoisophthalic) into the framework facilitates decomposition of CHP and in-creases the final selectivity to 2-phenyl-2-propanol (PP). This has been attributed to the progressive creation of point defects in the framework, having a higher activity for CHP decomposition. Following with the aerobic oxidation of CM as model reaction, we evaluated the catalytic activity of isoreticular cobalt compounds having bispyrazolate ligands bearing differnent functional groups (CoBPZ, CoBPZ-NO2 and CoBPZ-NH2). In this case, there is a clear influence of the ligand used on the catalytic activity of the material and the obtained selectivity to CHP or PP. While CoBPZ showed a low CM conversion and high CHP selectivity, the opposite properties are obtained for the Co-BPZ-NH2: i.e., a high reaction rate but a low CHP selectivity. In this latter case, the major product of the reaction was PP. Finally, the evaluation of divalent MOFs as oxidation catalysts has been complet-ed by addressing the synthesis of quinazoline through the oxidative coupling reaction of benzylamine and 2-aminoacetophenone using TBHP as oxidant. As catalysts for this reaction we have used a copper trimesate, HKUST-1, as well as isoreticular mixed-ligand compounds obtained by partially replacing trimesate ligands by 5-hydroxyisophthalic (OH-isophthalic). / Nowacka, AE. (2019). Divalent Metal Organic Frameworks as Heterogeneous Oxidation Catalysts [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/129872

La maladie d’Alzheimer (MA) est la maladie neurodégénérative touchant le plus de personnes dans le monde. Jusqu’à présent, aucun traitement curatif n’existe pour soigner cette maladie, d’où la nécessité d’identifier et d’étudier de nouvelles cibles thérapeutiques.La découverte des effets bénéfiques de la caféine, antagoniste du récepteur à adénosine A2A (A2AR), conjuguée à une surexpression de ce dernier chez les patients atteints de la MA, font de ce récepteur une cible d’intérêt. En effet, des antagonistes des A2ARs ont montré leur capacité à améliorer les performances cognitives de par une diminution de la charge amyloïde associée à une diminution la phosphorylation de la protéine Tau.Bien que plusieurs antagonistes aient été développés pour le traitement de maladies neurodégénératives, ceux-ci présentent un manque d’efficacité corrélée à de faibles propriétés pharmacocinétiques. Ainsi, à partir d’études de modélisation moléculaire, deux nouvelles familles d’antagonistes présentant un noyau central benzoxazole ou quinazoline ont été conçus, synthétisés et évalués pharmacologiquement. Trois composés ont été sélectionnés et font actuellement l’objet d’études pharmacologiques complémentaires sur modèles animaux. / Alzheimer’s disease (AD) is the most prevalent form of dementia in the aged population. So far, there is no way to halt or slow-down AD. Therefore, there is a constant need of developing novel therapeutic strategies.In recent years, adenosine A2A receptor (A2AR) has attracted a growing interest since it has been proved that this receptor is over-expressed during AD. Also, epidemiological studies showed that people consuming regularly caffeine-based beverages over a lifetime are substantially less likely to develop this disease. Indeed, A2AR antagonists improve memory performance as it reduces β-amyloid deposits and Tau-phosphorylation.Though several antagonists have been developed for the treatment of neurodegenerative diseases, current research efforts are focus on developing new antagonists with relevant ADME properties and a better efficacy. Based on a molecular modeling-guided design, we synthesised new A2AR antagonists with benzoxazole and quinazoline as central scaffold. Three molecules were selected and will be subject to evaluation on animal’s model.

Fluoroquinolones are a class of antibiotics used clinically to treat a wide array of bacterial infections. These therapeutics act by targeting a bacterial enzyme required for cell viability, bacterial type-II topoisomerases. Fluoroquinolones act by forming a ternary complex with bacterial type II topoisomerases and cleaved DNA; religation of DNA is subsequently blocked, therefore leading to bacterial cell death. In ternary complex the keto-acid moiety of the fluoroquinolone is complexed with a divalent magnesium ion, forming a drug-magnesium-water bridge to a serine and an aspartate (or glutamate) residue on helix-4 of the topoisomerase enzyme. A major issue with fluoroquinolones is the rise in bacterial resistance. Resistance arises through substitutions of the serine or aspartate/glutamate residue, therefore preventing formation of the magnesium-water bridge and dramatically diminishing the overall antibiotic activity of the fluoroquinolone. Quinazoline-2,4-diones are structurally similar to fluoroquinolones; diones also form a ternary complex similar to fluoroquinolones, however, these complexes are less active due to lack of a potent magnesium-water bridge interaction in helix-4. While quinazoline-2,4-diones are therefore less potent antibiotics, their non-reliance on the magnesium water bridge generally affords equipotent activity with wild-type and fluoroquinolone-resistant strains of bacteria. The first objective of this work was to probe the helix-4 interaction of the bacterial type-II topoisomerase by quinazoline-2,4-dione modification, specifically at the N3 and C4 positions of the quinazoline-2,4-dione scaffold to afford potentially new binding contacts. These modified quinazoline-2,4-diones will provide deeper understanding of the helix-4 interaction and potentially afford potent novel quinazoline-2,4-dione scaffolds, against both wild-type and resistant bacteria, for iterative drug design. Metabolism is one of the primary sources of detoxification, inactivation, and clearance of drugs from the body and is a critical consideration for all early stage therapeutic development. Clinically used fluoroquinolones, i.e. Moxifloxacin and Ciprofloxacin, historically are metabolically stable, and are not known to be metabolized by Phase I and/or Phase II drug metabolizing enzymes. However, major modifications to the Moxifloxacin and Ciprofloxacin scaffolds, due to the development of next generation antibiotics, may display different metabolic stability profiles. Moreover, metabolism of quinazoline-2,4-diones, developed for fluoroquinolone-resistant bacteria, is not extensively studied and may be subject to different metabolic liabilities that may render the quinazoline-2,4-dione an ineffective potential antibiotic. The second objective of this work was to determine the in vitro Phase I and Phase II metabolic stabilities of fluoroquinolone and quinazoline-2,4-dione scaffolds to determine any structural features that render the potential therapeutic a metabolic liability. The results from these two objectives have led to the discovery of a novel bacterial type-II topoisomerase catalytic inhibitor and the acquisition of initial metabolic stability data of fluoroquinolone and quinazoline-2,4-dione scaffolds. These findings further promote research into quinazoline-2,4-diones as bacterial topoisomerase targets, and provide metabolic considerations for both fluoroquinolone and quinazoline-2,4-dione therapeutic development, which is severely underrepresented in the field of quinolone antibiotics.

Fluoroquinolones, broad-spectrum bactericidal antibiotics, exert their effects by inhibiting type II topoisomerases through the formation of a fluoroquinolone-DNA-topoisomerase ternary complex. Recently, newer, structurally unique fluoroquinolones have been shown to kill bacteria by promoting chromosomal fragmentation in the presence and absence of protein synthesis, thus allowing fluoroquinolones to potentially be used in the treatment of microorganisms that go into a dormant state. There is a need to further understand the structure activity relationships (SAR) of fluoroquinolones to develop new antibiotics that can kill dormant bacteria and are active against current resistant strains. The hypothesis that structurally unique fluoroquinolones interact with the DNA- fluoroquinolone-topoisomerase ternary complex in a unique way that leads to different killing pathways is the basis of this work. The first approach to understand SAR for fluoroquinolones to kill non-growing bacteria was to evaluate the effect of modifications at the C-8 and C-5 positions on lethality. Novel, synthetically-derived and commercially-available fluoroquinolones were evaluated for ability to kill Escherichia coli in the presence and absence of chloramphenicol, a known protein synthesis inhibitor used to simulate non-growing bacteria. The second study was to understand SAR of fluoroquinolone-class agents necessary to maintain antibacterial activity against common fluoroquinolone resistance-causing bacterial mutations on topoisomerase IV. A panel of novel fluoroquinolones, 2,4-quinazoline diones, and fluoroquinolone-like analogues with unique substitution combinations at C-8 and C-7 was synthesized and evaluated for ability to poison wild-type and mutant Bacillus anthracis topoisomerase IV. The third study to understand the contribution of SAR of fluoroquinolone-class agents to novel killing mechanisms was to evaluate the binding interaction of fluoroquinolones to double-stranded and nicked DNA. Binding affinities of fluoroquinolones to DNA were determined; fluoroquinolones were found to bind different DNA types with varied affinities. The ability of a series of C-8 and C-7 modified fluoroquinolones to stabilize or destabilize DNA was assessed. The results of these studies also add broadly to the understanding of SAR associated with fluoroquinolone-class antibiotics for killing in the presence and absence of protein synthesis, maintaining activity in the presence of resistance-causing mutations in the target enzymes, and increasing binding interactions with different types of DNA.

The development of novel selective 5-HT6 and 5-HT7 receptor antagonists is an ever-growing area of interest among medicinal chemists. The potential of developing a therapeutic agent useful as an antipsychotic or antidepressant, as well as the possibility to develop a drug for Alzheimer’s disease and obesity has led to an increase in synthesis of possible lead compounds. The synthesis of unfused biheteroaryl derivatives is described within. The derivatives have been evaluated for binding affinity at 5-HT2A, 5-HT6 and 5-HT7 receptors. The most potent 5-HT6 receptor antagonists include a benzene ring, a hydrophobic group and a protonated nitrogen atom. The most potent and selective compound synthesized is 1-[3-butyl-5-(thienyl)phenyl]-4-methylpiperazine. The binding site of the 5-HT7 receptor is similar to that of the 5-HT6 receptor and the most selective and potent 5-HT7 receptor antagonist also contains a potonated nitrogen atom and a hydrophobic group. The difference in selectivity between the 5-HT6 and 5-HT7 receptor antagonists is the aromatic ring. The most potent 5-HT7 receptor antagonist synthesized contains a pyridine ring instead of benzene, as in the 5-HT6 receptor antagonist. The most potent and selective 5-HT7 receptor antagonist is 1-[4-(3-furyl)-6-methylpyridin-2-yl]-4-methylpiperazine. The need to increase selectivity for both 5-HT6 and 5-HT7 receptors has led to the synthesis of flexible-chain linked derivatives and the results are described within.

Tetrahydroisoquinoline alkaloids are a class of structurally complex natural products and a huge number of its natural product widely exist in nature which, from the discovery has been more than a century, it compounds with high anti-tumor activity, antibacterial and other physical activity, but also because of its special structure, with low oncentration of biological activity, but these alkaloids are not sold in the market mainly due to a less natural extraction, chemical synthesis method and multi-step, low yield. Therefore, we constructed a combination of tetrahydroisoquinoline alkaloids and the pyrazino [2,1-b] quinazoline-3,6-diones structure of the new compounds, which have the quinazolinone compounds which is the drug synthesis and drug activity on the bond, is also a kind of unique and widely used drug structure, and causes a lot of scientists and drug research interest and discussion, as we develop the motivation.