RESUMO
The mosquito Aedes aegypti is the vector agent responsible for the transmission of yellow fever and dengue fever viruses to over 80 million people in tropical and subtropical regions of the world. Exhaustive efforts have lead to a vaccine candidate with only 30% effectiveness against the dengue virus and failure to protect patients against the serotype 2. Hence, vector control remains the most viable route to dengue fever control programs. We have synthesized a class of 1,2,4-oxadiazole derivatives whose most biologically active compounds exhibit potent activity against Aedes aegypti larvae (ca. of 15 ppm) and low toxicity in mammals. Exposure to these larvicides results in larvae pigmentation in a manner correlated with the LC50 measurements. Structural comparisons of the 1,2,4-oxadiazole nucleus against known inhibitors of insect enzymes allowed the identification of 3-hydroxykynurenine transaminase as a potential target for these synthetic larvicides. Molecular docking calculations indicate that 1,2,4-oxadiazole compounds can bind to 3-hydroxykynurenine transaminase with similar conformation and binding energies as its crystallographic inhibitor 4-(2-aminophenyl)-4-oxobutanoic acid.
Assuntos
Aedes/efeitos dos fármacos , Aedes/enzimologia , Inseticidas , Oxidiazóis/química , Oxidiazóis/farmacologia , Transaminases/antagonistas & inibidores , Aedes/crescimento & desenvolvimento , Animais , Sítios de Ligação , Larva/efeitos dos fármacos , Larva/enzimologia , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Transaminases/metabolismoRESUMO
Ultrasound irradiation, an efficient and innocuous technique of reagent activation for synthesizing organic compounds, has been applied with success to transform seven carboxylic acids to fourteen secondary amides in good to excellent yields. The reaction has worked well either with aryl or alkyl carboxylic acids as well as with aromatic or aliphatic amines. This methodology is expeditious and reliable for preparing secondary carboxamides which in many cases are embedded in the C-5 side-chain of 1,2,4-oxadiazoles (14, 15, 17-27). The elemental analyses of new compounds (19-27) in conjunction with the spectral data of all synthesized amides gave an idea about their structures, while the crystallographic data of one of the compounds (26) supplied information concerning the configurational behavior of the amidic part and also the conformational aspect of the entire molecule in the crystalline state.
Assuntos
Amidas/síntese química , Nitrogênio/química , Ultrassom , Amidas/química , Carbonatos/química , Indicadores e Reagentes/química , Cinética , Potássio/químicaRESUMO
The convergent synthesis of an unusual (but simple) class of compounds 5a-g has been achieved by the copper-catalyzed [3+2] cycloaddition reaction of 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl azide 4 with propynyl 3-[3-(aryl)-1,2,4-oxadiazol-5-yl] propionates 3a-g. The formerly known azide 4 has been prepared according to the literature procedure; however, the synthesis of esters 3a-g is being reported for the first time. The infrared as well as (1)H NMR spectra of all new products are in agreement with their proposed structures. By carrying out the nOe experiment of one of the final compounds 5a, we have been able to establish that only the 1,4-regioisomers have been formed in the cycloaddition reaction. All final products presented weak cytotoxic activity, but 5e and 5g had somewhat better behaviour showing 22-25% cell growth inhibition against two cell strains: NCI-H(292) (lung carcinoma) and HEp-2 (larynx carcinoma).
Assuntos
Antineoplásicos/química , Antineoplásicos/toxicidade , Oxidiazóis/química , Oxidiazóis/toxicidade , Triazóis/química , Triazóis/toxicidade , Antineoplásicos/síntese química , Carbono/química , Carcinoma/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glicosilação , Humanos , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Oxidiazóis/síntese química , Oxigênio/química , Triazóis/síntese químicaRESUMO
A one-step, simple and straightforward synthesis of the title amides from the corresponding carboxylic acids, urea and imidazole under microwave irradiation is described.