The compounds 8-butyl(2),8-hexyl-(3),8-octyl-(4),8-decyl(5),8-dodecyl(6) and 8-hexadecyl(7) palmatine derivatives were synthesized and confirmed by UV, IR, CHN, 1H NMR, 13C NMR and MS spectra data. The series of the synthesized compounds has been tested for their antimicrobial activity in vitro to evaluate structure-activity relationships. Substitution of the H with alkyl groups at C-8-H led to significant changes in the antimicrobial activity. The antimicrobial activity of the substituted derivatives was up to 64 times higher than that of palmatine, especially against Gram-positive bacteria. Which increased as the aliphatic chain was elongated and then decreased gradually when the alkyl chain exceeded eight carbon atoms. 8-Octylpalmatin-e (4) displayed the highest antimicrobial activity of all compounds. The LD50 values of compounds (2-7) decreased as the aliphatic chain was elongated. Compound 7 showed the lowest toxicity.