Clean Synthesis of N-4-Alkylamino-7-chloroquinoline Cyclic Imides: Influence of Lipophilicity on Antibacterial and Ecotoxicological Properties.

Motivated by the promising antimicrobial and ecotoxicological effects of 4-alkylamino-7-chloroquinoline and N-alkylphthalimide derivatives, these privileged nuclei were linked to investigate how lipophilicity influences antibacterial activity and ecotoxicity. For this purpose, seven 4-alkylamino-7-chloroquinolines (2a-g) were prepared, of which four were used as precursors (2a-d) and reacted with different anhydrides. Using a clean synthetic approach, 4-alkylamino-7-chloroquinoline-succinimides (3a-d) and -phthalimides (5a-d) were obtained in yields of 60%-99% after only filtration with distilled water. In vitro assays were performed to determine the minimum inhibitory/bactericidal concentration (MIC/MBC) against Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus mutans. Lipophilicity (log P) and toxicity were predicted using the pkCSM program. In vitro toxicity tests on Artemia salina larvae were used as an indicator of ecotoxicity. 4-Alkylamino-7-chloroquinolines (2b, 2f, 2g) revealed a moderate MIC of 156.25 µg·mL-1 against Gram-(-) and Gram-(+) bacteria, whose predicted toxicity does not pose a potential risk to human health. Results indicate a correlation between increased lipophilicity and higher ecotoxicity, where less lipophilic compounds were less toxic to A. salina (LC50 133.01-777.50 µg·mL-1) than 4-alkylamino-7-chloroquinoline-phthalimides, suggesting further investigation of their cytotoxicity.