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Arch Pharm (Weinheim) ; : e1900294, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31894862


A series of (3-benzyl-5-hydroxyphenyl)carbamates were evaluated as new antibacterial agents. Several compounds showed potent inhibitory activity against sensitive and drug-resistant Gram-positive bacteria. The compounds are ineffective against all tested Gram-negative bacteria. The structure of the ester group exerted a profound effect on antibacterial activity. 4,4-Dimethylcyclohexanyl carbamate 6h exhibited the most potent inhibitory activity against the standard and clinically isolated Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecalis (minimum inhibitory concentration = 4-8 µg/ml) strains. The preliminary experimental evidence indicated that these carbamates target the bacterial cell wall and share a similar mechanism of action with vancomycin.

Molecules ; 24(10)2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31137832


A series of 3-amino-5-benzylphenol derivatives were designed and synthesized. Among them, (3-benzyl-5-hydroxyphenyl)carbamates were found to exert good inhibitory activity against M. tuberculosis H37Ra, H37Rv and clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.625-6.25 µg/mL). The privileged compounds 3i and 3l showed moderate cytotoxicity against cell line A549. Compound 3l also exhibited potent in vivo inhibitory activity on a mouse infection model via the oral administration. The results demonstrated 3-hydroxyphenylcarbamates as a class of new antitubercular agents with good potential.

Antituberculosos/farmacologia , Carbamatos/farmacologia , Descoberta de Drogas , Células A549 , Animais , Antituberculosos/química , Carbamatos/química , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Resultado do Tratamento , Tuberculose/tratamento farmacológico
Molecules ; 24(6)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934578


Inspired by the potent inhibition activity of the c-Met (mesenchymal-epithelial transition factor) inhibitor Tepotinib, a series of new Tepotinib derivatives were synthesized and evaluated for their ability to act as antiproliferative agents to find the leading compounds with good activity and limited side effects. Among them, compound 31e exhibited potent antiproliferative activity (IC50 (50% inhibitory concentration) = 0.026 µΜ) against hepatic carcinoma 97H (human liver cancer cell) cells and, importantly, had very low inhibitory activity against normal cells. A mechanism study demonstrated that 31e induced G1 phase (First growth phase or G indicating gap) arrest, inhibited the phosphorylation of c-Met and its downstream signaling component, Akt (Protein Kinase B), and also inhibited the migration of hepatic carcinoma 97H cells.

Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
Arch Pharm (Weinheim) ; 352(4): e1800277, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30698293


A series of novel 3-amidophenols with 5-heteroatomic substitutions were designed and synthesized. Several compounds showed potent antitubercular activity against Mycobacterium tuberculosis H37Ra (MIC = 0.25-5 µg/mL). Compounds 12j and 14i also displayed good inhibitory activity against M. tuberculosis H37Rv and two clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.39-3.12 µg/mL). The privileged compound 14i showed certain oral efficacy on a mouse infection model. The compounds are non-cytotoxic against L-O2 hepatocytes and RAW264.7 macrophagocytes. They did not exert inhibitory activity against representative Gram-positive and Gram-negative bacteria.

Amidas/farmacologia , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Fenóis/farmacologia , Tuberculose/tratamento farmacológico , Administração Oral , Amidas/síntese química , Amidas/química , Animais , Antituberculosos/síntese química , Antituberculosos/química , Linhagem Celular , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Fenóis/síntese química , Fenóis/química , Células RAW 264.7 , Relação Estrutura-Atividade , Tuberculose/microbiologia
Medchemcomm ; 9(8): 1293-1304, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30151083


A series of m-amidophenol derivatives (6a-6l, 7a-7q, 9a, 9b, 12a-12c, 14 and 15) were designed and synthesized. Their antitubercular activities were evaluated in vitro against M. tuberculosis strains H37Ra and H37Rv and clinically isolated multidrug-resistant M. tuberculosis strains. Ten compounds displayed minimal inhibitory concentrations (MICs) against M. tuberculosis H37Ra below 2.5 µg mL-1 and 6g was the most active compound (MIC = 0.625 µg mL-1). Compounds 6g and 7a also showed potent inhibitory activity against M. tuberculosis H37Rv (MIC = 0.39 µg mL-1) and several clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.39-3.125 µg mL-1). The compounds did not show inhibitory activity against normal Gram-positive and Gram-negative bacteria. They exhibited low cytotoxicity against HepG2 and RAW264.7 cell lines. The results demonstrated m-amidophenol as an attractive scaffold for the development of new antitubercular agents.