Side Chain Effects on the Lipophilicity-antimicrobial-toxicity Correlation of Greener 4-Alkoxy/Amino-7-Chloroquinolines.

Background: More robust 4-substituted 7-chloroquinolines have been investigated for their diverse properties. However, there is still no systematic study that correlates the effects of the side chain at the 4-position of chloroquine and hydroxychloroquine derivatives with their lipophilicity, antimicrobial and toxicity properties.

Objective: To this end, a cleaner and facile approach was planned to obtain nineteen 4- substituted 7-chloroquinolines, whose influence of the substituent group and side chain extension at the 4-position on their properties was studied.

Methods: 4-Alkoxy/amino-7-chloroquinolines were prepared by a nucleophilic aromatic substitution (SNAr) reaction between 4,7-dichloroquinoline and alcohols/amines, evaluated for their in silico ADMET test, in vitro antimicrobial activity against Gram-(+) and Gram-(-) bacteria, and Candida albicans fungus, and in vitro toxicity on Artemia salina larvae.

Results: 4-Alkoxy/amino-7-chloroquinolines were obtained in yields ranging from 81 to 100%. The best results showed antimicrobial activity against Pseudomonas aeruginosa for 4-amino-7-chloroquinolines 6-8, with halos greater than 20 mm, and against C. albicans for 4-amino-7-chloroquinolines 1-3, with halos close to 30 mm. A correspondence between Minnow toxicity prediction and in vitro toxicity on A. salina larvae was observed, where compounds 3 and 14, with R = Pent, were both predicted to have high acute toxicity (log LC50 < -0.3) and classified as highly toxic (LC50 < 100 μg mL-1). It seems that increased lipophilicity in the side chain is harmful to A. salina larvae.

Conclusion: Considering the results for compounds 1-3 and 6-8 with greater activity against C. albicans and P. aeruginosa, respectively, especially for 4-amino-7-chloroquinolines 6 and 7, which are slightly toxic on A. salina larvae (LC50 500-1000 μg mL-1), their antimicrobial studies deserve to be continued by the determination of Minimum Inhibitory Concentration (MIC) values.