17 research outputs found
Studies on the Interaction of Isocyanides with Imines: Reaction Scope and Mechanistic Variations
The interaction of imines with isocyanides has been studied. The main product results from a sequential process involving the attack of two units of isocyanide, under Lewis acid catalysis, upon the carbon-nitrogen double bond of the imine to form the 4-membered ring system. The scope of the reaction regarding the imine and isocyanide ranges has been determined, and also some mechanistic variations and structural features have been described
Charting the Chemical Reaction Space around a Multicomponent Combination: Controlled Access to a Diverse Set of Biologically Relevant Scaffolds
Heterocycle-Based Multicomponent Reactions in Drug Discovery: From Hit Finding to Rational Design
In the context of the structural complexity necessary for a molecule to selectively display a therapeutical action and the requirements for suitable pharmacokinetics, a robust synthetic approach is essential. Typically, thousands of relatively similar compounds should be prepared along the drug discovery process. In this respect, heterocycle‐based multicomponent reactions offer advantages over traditional stepwise sequences in terms of synthetic economy, as well as the fast access to chemsets to study the structure activity relationships, the fine tuning of properties, and the preparation of larger amounts for preclinical phases. In this account, we briefly summarize the scientific methodology backing the research line followed by the group. We comment on the main results, clustered according to the targets and, finally, in the conclusion section, we offer a general appraisal of the situation and some perspectives regarding future directions in academic and private research
New trimethoprim-like molecules: bacteriological evaluation and insights into their action
This work reports a detailed characterization of the antimicrobial profile of two trimethoprim-like molecules (compounds 1a and 1b) identified in previous studies. Both molecules displayed remarkable antimicrobial activity, particularly when combined with sulfamethoxazole. In disk difusion assays on Petri dish, compounds 1a and 1b showed synergistic effects with colistin. Specifically, in combinations with low concentrations of colistin very large increases in the activities of compounds 1a and 1b were determined, as demonstrated by alterations in the kinetics of bacterial growth despite only slight changes in the fractional inhibitory concentration index. The effect of colistin may be to increase the rate of antibiotic entry while reducing efflux pump activity. Compounds 1a and 1b were susceptible to extrusion by efflux pumps, whereas the inhibitor phenylalanine arginyl ß-naphthylamide (PAßN) exerted effects similar to those of colistin. The interactions between the target enzyme (dihydrofolate reductase), the coenzyme nicotinamide adenine dinucleotide phosphate (NADPH), and the studied molecules were explored using enzymology tools and computational chemistry. A model based on docking results is reported
A Bivalent Activatable Fluorescent Probe for Screening and Intravital Imaging of Chemotherapy‐Induced Cancer Cell Death
The detection and quantification of apoptotic cells is a key process in cancer research, particularly during the screening of anticancer therapeutics and in mechanistic studies using preclinical models. Intravital optical imaging enables high-resolution visualisation of cellular events in live organisms; however, there are few fluorescent probes that can reliably provide functional readouts in situ without interference from tissue autofluorescence. Here we report the design and optimisation of the fluorogenic probe Apotracker Red for real-time detection of cancer cell death. The strong fluorogenic behaviour, high selectivity, and excellent stability of Apotracker Red make it a reliable optical reporter for the characterisation of the effects of anticancer drugs in cells in vitro and for direct imaging of chemotherapy-induced apoptosis in vivo in mouse models of breast cancer
Tetrasubstituted Imidazolium Salts as Potent Antiparasitic Agents against African and American Trypanosomiases.
Imidazolium salts are privileged compounds in organic chemistry, and have valuable biological properties. Recent studies show that symmetric imidazolium salts with bulky moieties can display antiparasitic activity against T. cruzi. After developing a facile methodology for the synthesis of tetrasubstituted imidazolium salts from propargylamines and isocyanides, we screened a small library of these adducts against the causative agents of African and American trypanosomiases. These compounds display nanomolar activity against T. brucei and low (or sub) micromolar activity against T. cruzi, with excellent selectivity indexes and favorable molecular properties, thereby emerging as promising hits for the treatment of Chagas disease and sleeping sickness
Development of New Multicomponent Processes based on Unexplored Chemistry of Isocyanides: Access to Heterocyclic Scaffolds and Applications
[eng] 1. It was observed that the interaction of imines and isocyanides in the presence of a Lewis acid can lead to a variety of scaffolds including α-aminoamides, α-aminoamidines, indoles and diiminoazetidines. The reaction conditions were optimized to yield the later as the main product. Screening the scope of amines, aldehydes and isocyanides led to a small library of azetidine adducts. Also, a few spiro-azetidine adducts were prepared using isatine ketimines. A unified mechanism was proposed to explain the structural diversity that the process offers. In case of the main azetidine adduct, the process goes through consecutive insertion of two isocyanides followed by a 4-exo-dig cyclization. The structural elucidation of the azetidine compounds confirms the unexpected syn nature of the formed imine bonds.
2. It was shown that N-insertion of isocyanides to N-substituted propargylamines in the presence of HCl yields 1,3,4,5-tetrasubstituted imidazoliums salts. As the propargylamines arise from A3 reactions, the scope of the process in terms of aldehydes, amines, alkynes, and isocyanides was studied. The described conditions do not apply for aliphatic amines as opposed to the Zhu reaction [1] who used a different activation method (dual metallic catalysis). However, mild reaction conditions allow the incorporation of tert-Bu isocyanide, avoiding undesired elimination, as in Zhu conditions. Furthermore, the A3 reaction was successfully combined with the new reaction to obtain the imidazolium salts in a one pot process. We also explored the properties of the MCR adducts: As a proof of concept, an adduct was used as an NHC ligand for to catalyze a standard Suzuki coupling. Interestingly, some of the obtained compounds displayed potent antiparasitic activity against Trypanosoma brucei and T. cruzi at nanomolar level.
3. A TMSCl- catalyzed Reissert type MCR was studied. The process features insertion of isocyanide to N-Si bond as the mechanistical key step. Computational and experimental methods were applied to study this novel interaction of isocyanides and N-Si bonds. The reaction yields aminoimidazolium salts from the incorporation of two isocyanide units into azines. The new activation mode offers significantly wider scope. Regioselective incorporation of two distinct isocyanides was successfully performed. Furthermore, some obtained adducts demonstrated potent antiparasitic properties against Trypanosoma Brucei and Cruzi.
[1] S. Tong, Q. Wang, M.-X. Wang, J. Zhu, Angew. Chem. Int. Ed. 2015, 54, 1293–1297.
The paper of Zhu group was published when the project was in the course of manuscript writing.
4. The application of multiple Groebcke-Bienaymé-Blackburn reactions on di- and triaminoazines leads to the formation of a variety of new N-fused heterocyclic scaffolds (aminoimidazopyridines) with several diversity points. The selective reactivity mode of diaminopyrimidine provides controlled synthesis of non-symmetrical adducts. The scope of reaction was studied (analyzing the range of the aldehyde, isocyanide and aminoazine components) and post- modifications were applied to further diversify the rich structural outcome of the process. Adducts arising from melamine were structurally enlarged, exploiting cross-coupling reactions to achieve nanosized tripodal structures. The synthesized adducts displayed interesting pH and environment sensitive fluorescent properties. Interestingly, a novel borylated BODYPY-type adduct was successfully synthesized and used for staining lysosomes in mammal cells Moreover, some adducts demonstrated potent antiviral activity against Adenovirus. Furthermore, selected compounds they showed selective affinity to G-quadruplex DNA sequences, suggesting potential applications in medicinal and biological chemistry.[spa] • La interacción de iminas e isocianuros en presencia de un ácido de Lewis puede conducir a una variedad de tipos estructurales incluyendo diiminoazetidinas. La selección del alcance de la reacción dio lugar a una pequeña biblioteca de aductos de azetidina. También, se prepararon unos pocos aductos de espiro-azetidina usando isatinas. Se propuso un mecanismo unificado para explicar la diversidad estructural que ofrece el proceso.
• La inserción de isonitrilos en el enlace N-H de propargilaminas N-sustituidas en presencia de HCl proporcionó sales de imidazolio 1,3,4,5-tetrasustituidas. Como las propargilaminas proceden de reacciones de A3, se estudió el alcance del procedimiento en términos de aldehídos, aminas, alquinos e isocianuros. La reacción de A3 se combinó con la nueva reacción para obtener las sales de imidazolio en un proceso de una sola etapa. También se exploraron las propiedades de los aductos MCR: Como una prueba de concepto, un aducto se utilizó como un ligando NHC para catalizar un acoplamiento estándar de Suzuki. Algunos de los compuestos obtenidos mostraron una potente actividad antiparasitaria contra T. brucei y T. cruzi a nivel nanomolar.
• Se estudió una MCR de tipo Reissert catalizada por TMSCl. El procedimiento presenta la inserción de isocianuro en enlace N-Si como paso clave. Se aplicaron métodos computacionales y experimentales para estudiar esta nueva interacción de isocianuros y enlaces N-Si. La reacción produce sales de aminoimidazolio a partir de la incorporación de dos isocianuros en azinas. El nuevo modo de activación ofrece un alcance mucho más amplio. Se realizó incorporación regioselectiva de dos isocianuros distintos. Algunos aductos demostraron potentes propiedades antiparasitarias contra Trypanosoma Brucei y Cruzi.
• La aplicación de múltiples reacciones de GBB sobre poliaminoazinas dio lugar a la formación de nuevos tipos estructurales heterocíclicos N-fusionados con varios puntos de diversidad. El modo regioselectivo sobre diaminopirimidinas proporciona una síntesis controlada de aductos no simétricos. Se estudió el alcance de la reacción y se aplicaron modificaciones posteriores para diversificar aún más el resultado estructural del proceso. Los aductos de melamina se aumentaron de tamaño, explotando reacciones de acoplamiento cruzado para conseguir estructuras tridimensionales nanométricas. Los aductos sintetizados mostraron interesantes propiedades fluorescentes sensibles al pH y al medio ambiente. Se sintetizó un nuevo aducto de tipo BODYPY borilado y se usó para teñir lisosomas en células de mamífero. Además, algunos aductos demostraron una potente actividad antiviral contra Adenovirus humanos. Los compuestos seleccionados mostraron afinidad selectiva a las secuencias de ADN de G- quadruplex, lo que sugiere aplicaciones potenciales en química medicinal y biológica
Selectivity in multiple multicomponent reactions: types and synthetic applications
Multiple multicomponent reactions reach an unparalleled level of connectivity, leading to highly complex adducts. Usually, only one type of transformation involving the same set of reactants takes place. However, in some occasions this is not the case. Selectivity issues then arise, and different scenarios are analyzed. The structural pattern of the reactants, the reaction design and the experimental conditions are the critical factors dictating selectivity in these processes
Multicomponent Reactions upon the Known Drug Trimethoprim as a Source of Novel Antimicrobial Agents
Novel antibiotic compounds have been prepared through a selective multicomponent reaction upon the known drug Trimethoprim. The Groebke-Blackburn-Bienaymé reaction involving this α-aminoazine, with a range of aldehydes and isocyanides afforded the desired adducts in one-step. The analogs display meaningful structural features of the initial drug together with relevant modifications at several points, keeping antibiotic potency and showing satisfactory antimicrobial profile (good activity levels and reduced growth rates), especially against methicillin-resistant Staphylococcus aureus. The new products may open new possibilities to fight bacterial infections
Studies on the interaction of isocyanides with imines: reaction scope and mechanistic variations
The interaction of imines with isocyanides has been studied. The main product results from a sequential process involving the attack of two units of isocyanide, under Lewis acid catalysis, upon the carbon–nitrogen double bond of the imine to form the 4-membered ring system. The scope of the reaction regarding the imine and isocyanide ranges has been determined, and also some mechanistic variations and structural features have been described