RESUMO
Seven polycharged species, incorporating 1, 2, 3, 4 and 6 guanidine arms organized around a benzene core were synthesized and assayed as anti-mycobacterial agents against Mycobacterium tuberculosis. They display MIC values comprised between 25 and 12.5 µM (close to ethambutol EMB) for the mono- and the hexa-substituted derivatives, and 0.8 µM (close to isoniazid and streptomycin) for the tri-substituted derivative. The three bi- and the tetra-substituted analogs displayed MIC values of ca. 6.5-3.0 µM. The latter were also evaluated against the isoniazid-resistant MYC5165 strain, resulting in highly interesting micromolar or sub-micromolar MIC, ca. 4-125 times more active than isoniazid. These preliminary results are attractive for the development of new anti-TB agents.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Guanidina/análogos & derivados , Guanidina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Humanos , Modelos Moleculares , Tuberculose/tratamento farmacológicoRESUMO
A new family of poly-guanidinium species with a benzene core as the organising agent has been developed. Their antibacterial properties have been evaluated against reference Gram positive and Gram negative bacteria, and their cytotoxicity against eukaryotic cells. Most of these compounds exhibited Minimum Inhibitory Concentrations in the micromolar range.
Assuntos
Antibacterianos/farmacologia , Derivados de Benzeno/farmacologia , Citotoxinas/toxicidade , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Guanidina/análogos & derivados , Guanidina/farmacologia , Éteres Fenílicos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/toxicidade , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/química , Relação Dose-Resposta a Droga , Guanidina/síntese química , Guanidina/química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Éteres Fenílicos/síntese química , Éteres Fenílicos/química , Relação Estrutura-AtividadeRESUMO
Various polycharged calix[4]arenes were assayed as anti-mycobacterial agents against Mycobacterium tuberculosis, H(37)Rv strain. The sulfonate, carboxylate and phosphonate anionic species displayed no activity. Cationic derivatives integrating four aminoethyl groups at the upper rim and two 6,6'-dimethyl-2,2'-bipyridyl- or 4,4'-dimethyl-2,2'-bithiazolyl subunits at the lower rim were also found inactive against M. tuberculosis, while the unsubstituded and the 5,5'-dimethyl-2,2'-bipyridyl-analogues exhibited MIC values of 3.2 and 0.8µM respectively. Introduction of guanidinoethyl groups at the upper rim resulted, except for the 6,6'-dimethyl-2,2'-bipyridyl-derivative, in high anti-mycobacterial activities for the unsubstituted, the 5,5'-dimethyl-2,2'-bipyridyl- and the 4,4'-dimethyl-2,2'-bithiazolyl analogues, with MIC values of 0.8, 0.8 and 1.6µM, respectively, similar to those of current commercial anti-tuberculosis agents. The five more active substances were also evaluated against the isoniazid-resistant strain MYC5165, resulting in highly interesting micromolar or sub-micromolar MIC and IC(50), ca. 4-125 times more active than isoniazid. These preliminary results are attractive for the development of new anti-TB agents.