RESUMO
A facile one-pot synthesis of C-ring substituted angular luotonins has been realized via a methanesulfonic acid mediated aza-Nazarov-Friedlander condensation sequence on quinazolinonyl enones. Topoisomerase I (topo-I) inhibition studies revealed that the angular luotonin library (7a-7l) and their regioisomeric analogs (linear luotonins, 8a-8l) are weak negative modulators, compared to camptothecin. These results would fare well for the design of topo-I-inert luotonins for non-oncological applications such as anti-fungal and insecticide lead developments. Surprisingly, the tricyclic vasicinones (9h, 9i, and 9j) showed better topo-I inhibition compared to pentacyclic C-aryl luotonins providing a novel pharmacophore for further explorations.
Assuntos
Alcaloides/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Desenho de Fármacos , Pirróis/farmacologia , Quinonas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Alcaloides/síntese química , Alcaloides/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Quinonas/síntese química , Quinonas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/químicaRESUMO
Synthesis of novel 4(3H)-quinazolinonyl aminopyrimidine derivatives has been achieved via quinazolinonyl enones which in turn were obtained from 2-acyl-4(3H)-quinazolinone. They have been assayed for biofilm inhibition against Gram-positive (methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative bacteria (Acinetobacter baumannii). The analogues with 2,4,6-trimethoxy phenyl, 4-methylthio phenyl, and 3-bromo phenyl substituents (5h, 5j & 5k) have been shown to inhibit biofilm formation efficiently in MRSA with IC50 values of 20.7-22.4 µM). The analogues 5h and 5j have demonstrated low toxicity in human cells in vitro and can be investigated further as leads.
Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Pirimidinas/farmacologia , Quinazolinonas/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/fisiologia , Antibacterianos/síntese química , Antibacterianos/toxicidade , Linhagem Celular , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/toxicidade , Quinazolinonas/síntese química , Quinazolinonas/toxicidade , Relação Estrutura-AtividadeRESUMO
A facile synthesis of C-ring substituted luotonins and vasicinones has been realized via a super-acid-mediated aza-Nazarov cyclization of quinazolinonyl enones. The regioselectivity of the cyclization is highly dependent on proton availability in the reaction medium.
