RESUMO
Multicomponent diversity-oriented synthesis (DOS) of conformationally anchored structural peptidomimetics like 2,5-diketopiperazines (2,5-DKP) containing heterocyclic bioisosteres of the amide bond, such as 1,2,3-triazoles and 1,5-disubstituted tetrazoles (1,5-DS-T) is described. Structural peptidomimetics are synthesized from similar available starting materials, via a strategy based on isocyanide-based multicomponent reactions (IMCRs): Ugi-4CR and Ugi-Azide (UA), followed by a one-pot process: SN 2/intramolecular alkyne-azide cycloaddition (IAAC). The sequential aligning of two powerful synthetic tools (IMCR and IAAC) has parallelly contributed to generate anchored conformation and complexity in target molecules, which are considered structural peptidomimetics of 2,5-DKP. Herein, the 1,2,3-triazole ring plays a key role in the preference for the boat conformation. Furthermore, the use of UA reaction generates scaffold diversity at the N-1 α-carbon of the pyrazinone ring, replacing a linear amide bond with a heterocyclic bioisostere such as 1,5-DS-T leading to the synthesis of novel tricyclic peptidomimetics. The DFT calculations confirmed the boat conformation of the synthesized molecules.
RESUMO
Zygomycetes are ubiquitous saprophytes in natural environments which transform organic matter. Some zygomycetes of gender Mucor have attracted interest in health sector. Due to its ability as opportunistic microorganisms infecting immuno-compromised people and to the few available pharmacological treatments, the mucormycosis is receiving worldwide attention. Concerning to the pharmacological treatments, some triazole-based compounds such as fluconazole are extensively used. Nevertheless, we focused in the quinolines since they are broadly used models for the design and development of new synthetic antifungal agents. In this study, the fungistatic activity on M. circinelloides of various 2-aryl-4-aryloxyquinoline-based compounds was discovered, and in some cases, it resulted better than reference compound fluconazole. These quinoline derivatives were synthesized via the Csp2-O bond formation using diaryliodonium(III) salts chemistry. A QSAR study was carried out to quantitatively correlate the chemical structure of the tested compounds with their biological activity. Also, a docking study to identify a plausible action target of our more active quinolines was carried out. The results highlighted an increased activity with the fluorine- and nitro-containing derivatives. In light of the few mucormycosis pharmacological treatments, herein we present some non-described molecules with excellent in vitro activities and potential use in the mucormycosis treatment.
Assuntos
Mucormicose , Quinolinas , Fluconazol , Humanos , Mucor , Mucormicose/tratamento farmacológico , Mucormicose/microbiologia , Relação Quantitativa Estrutura-Atividade , Quinolinas/farmacologia , Quinolinas/uso terapêuticoRESUMO
A novel strategy via the triple process (multicomponent reactions (MCR)-domino)/tandem was developed for the synthesis of restricted and constrained bis-1,2,3-triazole-linked pyrrolo[3,4-b]pyridine peptidomimetics dimers in overall yields of 20-55%. This strategy allows the construction of six heterocycles in two stages of the reaction.
Assuntos
Química Click/métodos , Reação de Cicloadição/métodos , Dimerização , Peptidomiméticos/síntese química , Cromatografia em Camada Fina , Cianetos/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Piridinas , Espectrometria de Massas por Ionização por Electrospray , Especificidade por Substrato , TriazóisRESUMO
In the presence of a catalytic amount of Pd(OAc)2 and XantPhos, the three-component reaction of ynones, imines, and aryl iodides affords fully substituted alkylidene-furan-3(2H)-ones via a sequence of the Mannich reaction followed by chemo- and regioselective oxypalladation and reductive elimination. One carbon-oxygen and two carbon-carbon bonds are generated to afford the heterocycle in good to excellent yield.
RESUMO
The Ugi reaction of 2-nitrobenzoic acid derivatives has been used for a diversity oriented synthesis of complex isoindolinones via a SNAr reaction involving the peptidyl position. When the cyclization is triggered by strong bases such as potassium tert-butylate, the SNAr reaction is followed by a deamidification/oxidation sequence leading to 2-hydroxyisoindolinones. The latter may be further transformed into polycyclic fused isoindolinones via Pictet-Spengler type cyclization or O-alkylation/metathesis sequences.
RESUMO
6-Triazolylmethyl-pyrrolo[3,4-b]pyridin-5-one tris-heterocycles were synthesized in 43-57% overall yields. The two-stage synthesis involved a cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) followed by a copper-assisted alkyne-azide [3+2] cycloaddition (CuAAC). This efficient and convergent strategy proceeded via complex terminal alkynes functionalized with a fused bis-heterocycle at the α-position. The final products are ideal candidates for SAR studies as they possess two privileged scaffolds in medicinal chemistry: 4-substituted or 1,4-substituted 1H-1,2,3-triazoles and pyrrolo[3,4-b]pyridin-5-ones.
RESUMO
A new, efficient, green, endogenous water-triggered, solvent- and catalyst-free ultrasound-assisted one-pot Groebke-Blackburn-Bienaymé reaction/SNAr/ring-chain azido-tautomerization strategy to synthesize bound-type fused bis-heterocycles imidazo or benzo[d]imidazo[2,1-b]thiazoles and 1,5-disubstituted tetrazole (1,5-DsT) containing quinoline moiety is described, which allows synthesis of two types of fused heterocycles in one step under mild green conditions. Antibacterial and antiamebic activities of selected newly synthesized compounds were carried out against three bacterial species: Gram-positive bacterium Staphylococcus aureus ATCC 6538 and Gram-negative bacteria Pseudomonas aeruginosa ATCC 13384 and Escherichia coli O55 and against one amebic species: Entamoeba histolytica.
RESUMO
A rapid and efficient synthesis of a series of (±)-nuevamine, (±)-lennoxamine and magallanesine aza analogues is described. The synthetic strategy involves Ugi-3CR and two further condensation processes, aza-Diels-Alder cycloaddition and the Pomeranz-Fritsch reaction. The variation of the chain-size in aldehyde moieties provided structural diversity in only two operational reaction steps.
Assuntos
Dioxanos/síntese química , Alcaloides Indólicos/síntese química , Dioxanos/química , Alcaloides Indólicos/química , Estrutura Molecular , EstereoisomerismoRESUMO
A series of 18 3-tetrazolyl-tetrazolo[1,5-a]quinolines were synthesized in 21-90% yields via a novel one-pot Ugi-azide/SNAr/ring-chain azido-tautomerization process. We report also the synthesis of 10 3-imidazo[1,2-a]pyridin-tetrazolo[1,5-a]quinolines in 28-94% yields via a novel one-pot Groebke-Blackburn-Bienaymé/SNAr/ring-chain azido-tautomerization process. Both synthetic strategies involve the use of microwaves or ultrasound, and catalyst-free conditions. Finally, we show the synthesis of the tetrazolo[1,5-a]quinoline-3-carbaldehyde and tetrazolo[1,5-a]quinoline-3-dimethyl acetal at room temperature in methanol as solvent.
RESUMO
Trimethylsilyl chloride is an efficient activating agent for azines in isocyanide-based reactions, which then proceed through a key insertion of the isocyanide into a N-Si bond. The reaction is initiated by Nâ activation of the azine, followed by nucleophilic attack of an isocyanide in a Reissert-type process. Finally, a second equivalent of the same or a different isocyanide inserts into the N-Si bond leading to the final adduct. The use of distinct nucleophiles leads to a variety of α-substituted dihydroazines after a selective cascade process. Based on computational studies, a mechanistic hypothesis for the course of these reactions was proposed. The resulting products exhibit significant activity against Trypanosomaâ brucei and T.â cruzi, featuring favorable drug-like properties and safety profiles.
Assuntos
Antiparasitários/farmacologia , Cianetos/química , Hidrazinas/química , Nitrogênio/química , Silício/química , Trypanosoma cruzi/efeitos dos fármacos , Antiparasitários/síntese química , Antiparasitários/química , Estrutura Molecular , Testes de Sensibilidade ParasitáriaRESUMO
A series of nine new 3-acetamide-azepino[4,5-b]indol-4-ones were synthesized in two steps: (i) multicomponent reaction (Ugi-4CR/SN2) and (ii) free radical-mediated cyclization. These compounds, along with their tetrazole-based analogs, were studied in vitro to assess their binding with the 5-hydroxytryptamine type 6 receptor (5-Ht6R). The 3-acetamide-azepino[4,5-b]indol-4-ones displayed moderate affinity, whereas the 3-tetrazolylmethyl-azepino[4,5-b]indol-4-ones affinity values are lower. However, one of the 3-acetamide-azepino[4,5-b]indol-4-ones exhibited a hit value of Ki (211.2nM) to the 5-Ht6R. Minimal-energy structures of one cis-amide and its tetrazole-based analog (calculated by means of the Density Functional Theory) were analyzed to assess some interesting bioisosterism aspects. Interactions and binding energies between all products and the 5-Ht6R were calculated through in silico molecular couplings. Finally, a QSAR model was proposed using the results of the in vitro assays.
Assuntos
Radicais Livres/química , Indóis/síntese química , Receptores de Serotonina/metabolismo , Ciclização , Técnicas In Vitro , Indóis/metabolismo , Indóis/farmacologia , Ligantes , Simulação de Acoplamento MolecularRESUMO
A series of fifteen 2-tetrazolylmethyl-isoindolin-1-one linked-type bis-heterocycles were synthesized in 10-76% yields under mild conditions via a one-pot Ugi-azide/(N-acylation/exo-Diels-Alder)/dehydration process from furan-2-ylmethanamine, aldehydes, isocyanides, azidotrimethylsilane, and maleic anhydride. Density functional theory calculations were performed using the polarizable continuum model (toluene)-M06-2X-D3/6-311+G(d)//M06-2X-D3/6-31G(d) level of theory to obtain the full energy profile when investigating over eight possible pathways. An anthracene-containing analogue displayed a distribution of its highest occupied molecular orbital-lowest unoccupied molecular orbital throughout both cyclic moieties.
RESUMO
In vitro studies to fourteen previously synthesized chromone-tetrazoles and four novel fluorine-containing analogs were conducted against pathogenic protozoan (Entamoeba histolytica), pathogenic bacteria (Pseudomonas aeruginosa, and Staphylococcus aureus), and human fungal pathogens (Sporothrix schenckii, Candida albicans, and Candida tropicalis), which have become in a serious health problem, mainly in tropical countries.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antiprotozoários/farmacologia , Cromonas/farmacologia , Tetrazóis/farmacologia , Antibacterianos/síntese química , Antifúngicos/síntese química , Antiprotozoários/síntese química , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Candida tropicalis/efeitos dos fármacos , Candida tropicalis/crescimento & desenvolvimento , Candida tropicalis/patogenicidade , Cromonas/síntese química , Entamoeba histolytica/efeitos dos fármacos , Entamoeba histolytica/crescimento & desenvolvimento , Entamoeba histolytica/patogenicidade , Flúor/química , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/patogenicidade , Sporothrix/efeitos dos fármacos , Sporothrix/crescimento & desenvolvimento , Sporothrix/patogenicidade , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/patogenicidade , Tetrazóis/síntese químicaRESUMO
Based on in vitro studies of twelve newly-synthesized 1-acetamide-5-methoxy-2-oxindoles as 5-Ht7 receptor ligands, Structure Affinity Relationship (SAR) and Quantitative Structure Affinity Relationship model (QSAR) are provided. Also, a ligand-based pharmacophore model is proposed through molecular docking techniques and Nucleus Independent Chemical Shift DFT calculations (NICS).
Assuntos
Acetamidas/farmacologia , Indóis/farmacologia , Simulação de Acoplamento Molecular , Receptores de Serotonina/metabolismo , Acetamidas/síntese química , Acetamidas/química , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Ligantes , Estrutura Molecular , Teoria Quântica , Relação Estrutura-AtividadeRESUMO
A series of five novel bis-1,5-disubstituted-1H-tetrazoles (bis-1,5-DS-1H-T) were quickly prepared by a catalyst-free Ugi-azide repetitive process from easily accessible starting materials in excellent yields, either at room temperature (88%-95%) or using mild MW-heating conditions (80%-91%). These molecules may have a wide range of applications, such as chelating agents, organocatalysts and luminescent materials, and mainly as bioactive compounds.
Assuntos
Azidas/química , Química Orgânica/métodos , Tetrazóis/síntese química , Catálise , Cátions , Ligantes , Tetrazóis/química , Tetrazóis/farmacologiaRESUMO
The synthesis of novel 3-tetrazolylmethyl-4H-chromen-4-ones via an Ugi-azide multicomponent reaction and their biological evaluation against Entamoeba histolytica, Giardia lamblia and Trichomona vaginalis are described. Reported yields are moderate to good and biological results show that these compounds could be considered as candidates to anti-parasitic drugs, especially against G. lamblia.
Assuntos
Anti-Infecciosos/síntese química , Antiprotozoários/farmacologia , Azidas/química , Benzopiranos/química , Entamoeba histolytica/efeitos dos fármacos , Giardia lamblia/efeitos dos fármacos , Trichomonas vaginalis/efeitos dos fármacos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Benzopiranos/síntese química , Benzopiranos/farmacologia , Cristalografia por Raios X , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
A series of nine novel 3-tetrazolylmethyl-azepino[4,5-b]indol-4-ones were prepared in moderate to good overall yields in only two reaction steps. The first step consisted of a one-pot sequential process of an Ugi-azide multicomponent reaction, N-acylation and SN2 to give the xanthates. The second step was an intramolecular cyclization under free radical conditions. Also, their binding modes have been modelled using docking techniques.
Assuntos
Azepinas/síntese química , Azidas/química , Indóis/síntese química , Acilação , Azepinas/química , Ciclização , Radicais Livres/síntese química , Radicais Livres/química , Indóis/química , Modelos Moleculares , Estrutura MolecularRESUMO
Flavones were directly alkylated at the C-3 position in moderate yields using a xanthate-based oxidative radical addition procedure. This methodology is a suitable synthetic tool for the direct substitution of the vinylic and unactivated C-H bond of the C ring of the flavone by an alkyl functionality under neutral conditions.
Assuntos
Alquilantes/química , Flavonas/síntese química , Tionas/química , Alquilação , Cristalografia por Raios X , Radicais Livres/química , Micro-Ondas , Estrutura Molecular , OxirreduçãoRESUMO
Oxidative cleavage and cyclization cascades of N-aryl peptides have been achieved under palladium catalysis with air as the sole stoichiometric oxidant.