A VARIETY of some novel substituted nicotines were synthesized and characterized by spectroscopic means where nicotinic acid hydrazide (6a) and/or (6b) are used as a key intermediate in the synthesis of hydrazones (8a-l) and (10a-f) by the reaction with different aromatic aldehydes (7a-f) and isatines (9a-e), respectively. Moreover, nicotinic acid hydrazide reacted with pentane-2,4-dione (11), 2-ethoxymethylene-malononitrile (13) and thiosemicarbazone (15) generating pyrazoles (12), (14) and 1,2,4-triazole (16), respectively. The newly synthesized compounds were tested against nine microbial strains. Some of these compounds showed a significant activity against several of the microorganisms. Compounds (8d), (10b) and (10c) were determined to be the most active compounds. Compound (8d) showed activity against S. aureus, B. subtilis and A. flavus with IZ = 2.4, 3.2 and 2.6 mm, respectively when compared with reference drugs (Amoxicillin, IZ = 2.3, 3.5 and Griseofulvin, IZ = 2.4 mm). Additionally, compound (10b) showed potent activity against P. aeruginosa and P. expansum with IZ = 2.6 and 2.8, respectively when compared with reference drugs (Amoxicillin, IZ = 2.2 mm and Griseofulvin, IZ = 2.8 mm), respectively, while (10c) showed the same activity as Griseofulvin against P. expansum with IZ = 2.8 mm. The biological activity (SAR) of the evaluated compounds and the relationship between the functional group variations are discussed.