Síntese de mono e diésteres, cetoésteres e 2-selenoacetanilidas derivados de ftalimida: atividade antimicrobiana, sinergismo, mecanismo de ação e ecotoxicidade

Abstract

Phthalimide stands out as a promising block in the synthesis of new drug candidates. Its results show several pharmacological activities, including antimicrobial, antitumor, antiinflammatory, among others. Thus, this study describes the description of four families of compounds, including potassium phthalimide (3a-e) and potassium phthaloylglycinate (4a-e), which were produced from 4-chlorobutyl benzoate precursors. Potassium phthaloylglycinate derivatives with 4-substituted 2-bromoacetophenones (6f-j) and phthaloylglycine derivatives with 2-selenoacetanilide (9k-n), in addition to phthaloylglycine monoesters (11o-u) and tetrachlorophthaloylglycine (12o-u) were also used to evaluate the impact of electrode and electrowithdrawing groups, as well as hydrocarbon spacers, on the antimicrobial properties. In total, thirty-three final compounds were synthesized, eighteen of which were new, using simplified synthetic routes and a reduced number of steps. The compounds were subjected to in vitro antimicrobial evaluation, where compounds 3a-c and 4a-d showed activity against the three bacterial strains and the four yeast strains with values ranging from 128 to 1024 μg mL-1. Compound 3b (monoester with 4-methyl substitute) derived from potassium phthalimide, showed protection against all strains of bacteria and yeasts tested, with MIC = 128 μg mL-1, lower than the standard drug for fungi (fluconazole). Thus, compound 3b was investigated in order to know its mechanism of action, where it associated with ergosterol led to an increase in MIC from 128 to 1024 μg mL-1. Compound 3b was also tested in association with chloramphenicol for the strain of Peseudomonas aeruginosa with the ICIF value = 0.5 μg mL-1 decreasing the synergism. Compound 9k (2-selenoacetanilide with phthaloylglycine) showed very significant activity against strains of Candida gattii and Aspergillus niger with MIC = 2.5 and 10 μg mL-1, respectively, and MIC of 80 and 40 μg mL-1 for Klebsiella pneumoniae and Salmonella typhimurium, respectively. Compounds 11r, 12p, 12s and 12t showed activity against strains of bacteria and fungi with MIC value = 512 and 1024 μg mL-1, where, with the increase of the carbonic extension, the impact increased. The selenide compound was obtained with sufficient crystallization quality to be diffracted and a crystallographic study was carried out, where it presented a monoclinic system. An in silico study was conducted with the most promising compounds, all of which met the Lipinski criteria, indicating good oral bioavailability in a possible application, in addition to showing low toxicity. Thus, the most promising compounds (3b, 3c, 4a and 4c) were evaluated for toxicity on Artemia salina, being classified as moderately toxic and non-toxic.