Synthesis of New Derivatives of Leaf-Eating Ant Toxic Gland Pheromone Compounds and Investigation of their Biological Properties


Mahdi Mohammadi
Saadullah Khadimzada
Hassanali Moradi
Ghulam Reza Raesi


Background: The anti-mycobacterial characteristics of 2-pyrazinoic acid esters have been discovered through recent research. Research has demonstrated that the pyrazine ring and the alkyl part of these compounds interact with the enzyme phytynetase, which in turn inhibits the interaction between NADPH and mycobacterial fatty acids synthase, the enzyme responsible for synthesizing the fatty acids required for the cell wall of mycobacteria.
Materials and Methods: Targeted pyrazinoic acid molecules have been synthesized, their structure verified by spectroscopic data, and their anti-mycobacterial activity against Mycobacterium TB H37Rv at a dose of 10 micrograms per milliliter assessed in order to test this theory. Significant anti-mycobacterial capabilities were shown by several compounds, including 3c, 3J, and 3M, which inhibited mycobacterial growth by 45.7%, 45.4%, and 51%, respectively.
Findings: The results showed that the compounds exhibited little toxicity and did not inhibit macrophage cell proliferation. Pyrazinamide had significant antibacterial and antifungal activity, despite its lack of fatal action against non-tubercular mycobacteria and both Gram-positive and Gram-negative bacteria. Compound 3B, for example, exhibited excellent antibacterial properties against Gram-positive bacteria, such as S. aureus, with a minimum inhibitory concentration (MIC) of 125 micrograms per milliliter. Conversely, the compounds showed equally potent antibacterial properties against Gram-negative bacteria. Interestingly, compared to Gram-positive bacteria, the ester produced from maltol exhibited greater antibacterial efficacy against Gram-negative bacteria. Compounds synthesized with biodegradable groups also exhibited time-dependent toxicity against K562 leukemia cancer cells in MTT measurements, with compounds 3e and 3J displaying IC50 values of 25 micromolars.
Conclusion: After synthesizing pyrazinoic acid monoterpene esters, spectral data was used to confirm their structures. When their biological characteristics were assessed, toxicity studies against K562 leukemia cells produced encouraging results. Through the use of Thio Ester-mediated activation of 2-pyrazinoic acid by 2, 2-dibenzothiazole disulfide and triphenylphosphine, 6-aminopenicillanic acid (6-APA) was coupled with pyrazinoic acid.


Pyrazine, Pyrazinoic Acid, Pheromone Compounds, Anti-mycobacterial


How to Cite
Mohammadi, M., Khadimzada, S., Moradi, H., & Raesi, G. R. (2023). Synthesis of New Derivatives of Leaf-Eating Ant Toxic Gland Pheromone Compounds and Investigation of their Biological Properties. NUIJB, 2(04), 173–184. Retrieved from


  1. Beckers, R., Goss, S., Deneubourg, J. L., & Pasteels, J. M. (1989). Colony size, communication and ant foraging strategy. Psyche: A Journal of Entomology, 96, 239-256.
  2. Blum, M. S. (1996). Semiochemical parsimony in the Arthropoda. Annual review of entomology, 41(1), 353-374.
  3. Bohman, B., Phillips, R. D., Menz, M. H., Berntsson, B. W., Flematti, G. R., Barrow, R. A., ... & Peakall, R. (2014). Discovery of pyrazines as pollinator sex pheromones and orchid semiochemicals: implications for the evolution of sexual deception. New Phytologist, 203(3), 939-952.
  4. Casanova, D., Alemany, P., & Alvarez, S. (2010). Symmetry measures of the electron density. Journal of computational chemistry, 31(13), 2389-2404.
  5. David Morgan, E. (2009). Trail pheromones of ants. Physiological entomology, 34(1), 1-17.
  6. Dembitsky, V. M., Gloriozova, T. A., & Poroikov, V. V. (2005). Novel antitumor agents: marine sponge alkaloids, their synthetic analogs and derivatives. Mini reviews in medicinal chemistry, 5(3), 319-336.
  7. Juréen, P., Werngren, J., Toro, J. C., & Hoffner, S. (2008). Pyrazinamide resistance and pncA gene mutations in Mycobacterium tuberculosis. Antimicrobial agents and chemotherapy, 52(5), 1852-1854.
  8. Karlson, P., & Lüscher, M. (1959). ‘Pheromones’: a new term for a class of biologically active substances. Nature, 183(4653), 55-56.
  9. Ke, N., Wang, X., Xu, X., & Abassi, Y. A. (2011). The xCELLigence system for real-time and label-free monitoring of cell viability. Mammalian Cell Viability: Methods and Protocols, 33-43.
  10. Kleerebezem, M., & Quadri, L. E. (2001). Peptide pheromone-dependent regulation of antimicrobial peptide production in Gram-positive bacteria: a case of multicellular behavior. Peptides, 22(10), 1579-1596.
  11. Smith, M. B. and J. March. (2002). March's advanced organic chemistry: reactions, mechanisms, and structure: John Wiley & Sons.
  12. Mahboub, R., & Memmou, F. (2015). Antioxidant activity and kinetics studies of eugenol and 6-bromoeugenol. Natural Product Research, 29(10), 966-971.
  13. Mo, H., & Elson, C. E. (2004). Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention. Experimental biology and medicine, 229(7), 567-585.
  14. Ngo, S. C., Zimhony, O., Chung, W. J., Sayahi, H., Jacobs Jr, W. R., & Welch, J. T. (2007). Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs. Antimicrobial agents and chemotherapy, 51(7), 2430-2435.
  15. Rajini, K. S., Aparna, P., Sasikala, C., & Ramana, C. V. (2011). Microbial metabolism of pyrazines. Critical reviews in microbiology, 37(2), 99-112.
  16. Seitz, L. E., Suling, W. J., & Reynolds, R. C. (2002). Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives. Journal of medicinal chemistry, 45(25), 5604-5606.
  17. Wang, T., Hanzelka, B., Muh, U., & Bemis, G. (2011). U.S. Patent Application No. 12/855,263.
  18. Wang, Y., Wu, J. I. C., Li, Q., & Schleyer, P. V. R. (2010). Aromaticity and relative stabilities of azines. Organic Letters, 12(21), 4824-4827.
  19. Zhu, J. Y., Yang, Y., Han, H., Betzi, S., Olesen, S. H., Marsilio, F., & Schönbrunn, E. (2012). Functional consequence of covalent reaction of phosphoenolpyruvate with UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA). Journal of Biological Chemistry, 287(16), 12657-12667.
  20. Zimhony, O., Vilcheze, C., Arai, M., Welch, J. T., & Jacobs Jr, W. R. (2007). Pyrazinoic acid and its n-propyl ester inhibit fatty acid synthase type I in replicating tubercle bacilli. Antimicrobial agents and chemotherapy, 51(2), 752-754.