RESUMO
In the present work, four new compounds based on the privileged structure acridone were efficiently synthesized following simple operational techniques and biologically tested on proliferative skeletal muscle cells (C2C12) and rhabdomyosarcoma cells (RD) showing no significant changes in the number of dead or viable cells at 1 µM during 24 or 48 h of treatment. Of relevance, acridone derivatives 3a-3d at 0.5 µM for 24 h effectively inhibited Akt activation in C2C12, while at 1 µM only compounds 3a and 3b have effect. RD cells showed a different response pattern. These cells treated with 3a (0.5 µM), 3b (0.5 µM) or 3d (0.5 or 1 µM) for 24 h shown significant Akt inhibition. In addition, 3a-3d assayed at 1 µM for 48 h were highly successful in inhibiting Akt phosphorylation. Finally, based on molecular docking and molecular dynamics simulations, we rationalize the experimental results mentioned above and propose that 3-phosphoinositide-dependent kinase-1 (PDK1) could be one of the molecular targets of this new series of 1, 3-dihydroxyacridone derivatives. Biological and in silico studies revealed that 3b could be considered as the most promising prototype for the development of new antitumor agents.
Assuntos
Antineoplásicos , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-akt/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Acridonas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Fibras Musculares Esqueléticas , Estrutura Molecular , Proliferação de CélulasRESUMO
AIM: The increase in the number of fungal infections worldwide, coupled with the limitations of current antifungal chemotherapy, demand the development of safe and effective new antifungals. Here, we presented the synthesis of a novel acridone (M14) and its antifungal properties against Candida and dermatophytes species. METHODS AND RESULTS: A series of 17 acridones was designed, synthesized and tested for its antifungal activity. The minimum inhibitory concentration (MIC) was determined by the broth microdilution method. Only the acridone M14 showed growth-inhibitory activity against reference strains and clinical isolates of Candida and dermatophytes, with MIC range of 7·81-31·25 µg ml-1 . Moreover, M14 exhibited fungicidal activity and prevented biofilm formation by C. albicans as well as reduced the viability of preformed biofilms, even at sub-MICs. The confocal laser scanning microscopy analysis revealed that C. albicans hyphal growth was completely inhibited in the presence of M14. Similarly, there was a severe inhibition on hyphal growth of Trichophyton rubrum. We also found that M14 has relatively low toxicity to human fibroblasts. CONCLUSIONS: The new acridone M14 has antifungal properties against Candida spp. and dermatophytes, and antibiofilm activity against C. albicans. In addition, M14 is relatively selective to fungal cells compared to human normal cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Because of its in vitro antifungal activity, anti-Candida biofilm effect and moderate cytotoxicity towards normal human cell, M14 may serve as a valuable lead compound to develop a new antifungal agent.
Assuntos
Acridonas/farmacologia , Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Acridonas/síntese química , Antifúngicos/síntese química , Biofilmes/crescimento & desenvolvimento , Candida/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Sobrevivência Celular , Humanos , Hifas/efeitos dos fármacos , Hifas/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Trichophyton/efeitos dos fármacos , Trichophyton/crescimento & desenvolvimentoRESUMO
In natural product studies, the purification of metabolites is an important challenge. To accelerate this step, alternatives such as integrated analytical tools should be employed. Based on this, the chemical study of Swinglea glutinosa (Rutaceae) was performed using two rapid dereplication strategies: Target Analysis (Bruker Daltonics®, Bremen, Germany) MS data analysis combined with MS/MS data obtained from the GNPS platform. Through UHPLC-HRMS data, the first approach allowed, from crude fractions, a quick and visual identification of compounds already reported in the Swinglea genus. Aside from this, by grouping compounds according to their fragmentation patterns, the second approach enabled the detection of eight molecular families, which presented matches for acridonic alkaloids, phenylacrylamides, and flavonoids. Unrelated compounds for S. glutinosa have been isolated and characterized by NMR experiments, Lansamide I, Lansiumamide B, Lansiumamide C, and N-(2-phenylethyl)cinnamamide.