Novel Picolinic Acid-Derived Pyridine Carboxamides: Synthesis, Characterization and Evaluation of Cytotoxic and Antibacterial Activities

Abstract

Picolinic acid represents a versatile nitrogen-containing heteroaromatic scaffold with considerable potential for structural diversification and biological investigation. In the present study, a series of ten picolinic acid-derived pyridine carboxamide derivatives (VIa–VIj) was designed, synthesized, and evaluated for their in vitro cytotoxic and antibacterial activities. The target compounds were prepared through a multistep synthetic sequence involving conversion of picolinic acid to 4-chloropyridine-2-carbonyl chloride, formation of 4-chloro-N,N-disubstituted pyridine-2-carboxamide intermediates, synthesis of N-(4-nitrobenzylidene)benzene-1,2-diamine, and subsequent coupling to afford the final derivatives. The synthesized compounds were obtained in 62–75% yields, with melting points ranging from 197 to 239 °C. Structural characterization was supported by infrared spectroscopy, ^1H NMR spectroscopy, and molecular ion data. The cytotoxic activity was evaluated against MCF-7, HT-29, and A549 cancer cell lines using the MTT assay. Among the synthesized derivatives, VIh exhibited the most potent cytotoxic activity, with IC₅₀ values of 9.2, 8.4, and 16.6 µM against MCF-7, HT-29, and A549 cells, respectively, followed by VIg with IC₅₀ values of 11.4, 13.5, and 18.9 µM. Antibacterial activity was evaluated against Bacillus thermophilus, Staphylococcus aureus, Klebsiella pneumoniae, and Salmonella paratyphi A using the cup-plate method. VIh demonstrated the broadest antibacterial activity, producing inhibition zones of 13, 15, 11, and 14 mm, respectively, while VIg produced zones of 12, 10, 9, and 12 mm. Although the activity of the lead derivatives remained lower than that of the respective reference standards, the results demonstrate that structural modification of the picolinic acid-derived pyridine carboxamide scaffold can produce compounds with promising dual biological activity. Overall, VIg and VIh emerged as the most promising derivatives and may serve as useful lead structures for further optimization and mechanistic investigation.

Keywords: Antibacterial activity; Anticancer activity; Cytotoxicity; Heterocyclic compounds; Picolinic acid; Pyridine carboxamides.