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1.
J Org Chem ; 89(3): 1836-1845, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38226655

RESUMO

A regioselective visible-light-mediated denitrogenative alkene insertion of 1,2,3-benzotriazin-4(3H)-ones was developed to access 3-substituted isoindolinones, an important structural motif present in many biologically active molecules and natural products. Notably, divergent reactivity was achieved by switching from reported nickel catalysis (where C3-substituted 3,4-dihydroisoquinolin-1(2H)-ones form) to photocatalysis, where photocatalytic denitrogenation and a subsequent nitrogen-mediated hydrogen atom shift lead to exclusive 3-substituted isoindolinone formation. The developed photocatalytic reaction is compatible with activated terminal alkenes and cyclic α,ß-unsaturated esters and ketones, with wide functional group tolerance for N-substitution of the 1,2,3-benzotriazin-4(3H)-ones. The utility of this procedure is highlighted by a gram-scale synthesis and postsynthetic amidation. To understand the origin of this unique product selectivity, experimental and computational mechanistic studies were performed.

2.
Anal Chem ; 95(42): 15472-15476, 2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-37830912

RESUMO

An experimental platform is reported that allows for the online characterization of photochemical reactions by coupling a continuous flow photoreactor, equipped with LED light irradiation and a dual-tipped ESI source, directly to a mass spectrometer with electrospray ionization. The capabilities of this platform are demonstrated with two classes of photoreactions: (1) the photopolymerization of methyl methacrylate and (2) photocatalyzed alkyne insertion into a 1,2,3-benzotriazinone. The online technique provides rapid information to inform the underlying photochemical mechanism and evaluate the overall photochemistry.

3.
Chem Biol Drug Des ; 100(1): 41-50, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35359031

RESUMO

This paper reports a series of nine hybrid compounds of 7-substituted 4-aminoquinoline and cinnamic acid as antiplasmodial agents. 1 H NMR and 13 C NMR spectroscopic analysis and mass spectrometry studies were used to confirm the structures. The synthesized compounds were moderately active, with IC50 values ranging from 1.8 to 16 µM against the Pf3D7 chloroquine-sensitive strain in vitro. Compound C11 was shown to be the most potent in this investigation, with an IC50 value of 1.8 µM. Molecular docking studies revealed that compounds C14 and C17, with binding energies (ΔG0) of -7.19 and -7.72 kcal/mol and inhibition constants (Ki ) of 5.36 and 2.20 µM, respectively, were the best inhibitor candidates. The results of the Frontier molecular orbitals revealed that compounds possessed a small HOMO-LUMO energy gap. The HOMO-LUMO energy distributions indicated that the cinnamic acid regions favored the LUMO distribution, while the quinoline regions favored the HOMO energy. The investigation of absorption, distribution, metabolism, excretion, and toxicity based on in silico ADME tools predicted that the compounds have a good drug-like character.


Assuntos
Antimaláricos , Aminoquinolinas , Antimaláricos/química , Cinamatos , Simulação de Acoplamento Molecular , Plasmodium falciparum/metabolismo , Relação Estrutura-Atividade
4.
Arch Pharm (Weinheim) ; 354(7): e2000331, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33710656

RESUMO

A rationally designed series of 2-(N-cyclicamino)quinolines coupled with methyl (E)-3-(2/3/4-aminophenyl)acrylates was synthesized and subjected to in vitro screening bioassays for potential antiplasmodial and antitrypanosomal activities against a chloroquine-sensitive (3D7) strain of Plasmodium falciparum and nagana Trypanosoma brucei brucei 427, respectively. Substituent effects on activity were evaluated; meta-acrylate 24 and the ortho-acrylate 29 exhibited the highest antiplasmodial (IC50 = 1.4 µM) and antitrypanosomal (IC50 = 10.4 µM) activities, respectively. The activity against HeLa cells showed that the synthesized analogs are not cytotoxic at the maximum tested concentration. The ADME (absorption, distribution, metabolism, and excretion) drug-like properties of the synthesized compounds were predicted through the SwissADME software.


Assuntos
Acrilatos/farmacologia , Antimaláricos/farmacologia , Quinolinas/farmacologia , Tripanossomicidas/farmacologia , Acrilatos/síntese química , Acrilatos/química , Antimaláricos/síntese química , Antimaláricos/química , Células HeLa , Humanos , Concentração Inibidora 50 , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma brucei brucei/efeitos dos fármacos
5.
Bioorg Med Chem Lett ; 38: 127855, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33609655

RESUMO

Several classes of antimalarial drugs are currently available, although issues of toxicity and the emergence of drug resistant malaria parasites have reduced their overall therapeutic efficiency. Quinoline based antiplasmodial drugs have unequivocally been long-established and continue to inspire the design of new antimalarial agents. Herein, a series of mono- and bisquinoline methanamine derivatives were synthesised through sequential steps; Vilsmeier-Haack, reductive amination, and nucleophilic substitution, and obtained in low to excellent yields. The resulting compounds were investigated for in vitro antiplasmodial activity against the 3D7 chloroquine-sensitive strain of Plasmodium falciparum, and compounds 40 and 59 emerged as the most promising with IC50 values of 0.23 and 0.93 µM, respectively. The most promising compounds were also evaluated in silico by molecular docking protocols for binding affinity to the {001} fast-growing face of a hemozoin crystal model.


Assuntos
Antimaláricos/farmacologia , Desenho de Fármacos , Metilaminas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Metilaminas/síntese química , Metilaminas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
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