Exploration of α-Pyridone-containing compounds as multitarget antifungals

There is an endless search for more reliable and effective antifungals. α-Pyridone-containing compounds can be thus considered as an important moiety for their development [1], possessing multitarget action. Thus, as part of our research on antifungal agents, an in-house collection of natural and synthetic α-pyridone-containing analogs (n = 68) were studied by molecular docking and molecular dynamics simulations within the active site of 65 fungal enzymes, along with broth microdilution test on Candida albicans and Fusarium oxysporum. Results indicated that tri and tetracyclic-containing α-pyridone analogs were found to exhibit the best docking scores and interaction profile with N-myristoyltransferase (NMT), lanosterol 14α-demethylase (LDM) and the respective Upc2 transcription factor as well as in vitro antifungal effect. Resulting docking scores were appropriately correlated with experimental inhibition against fungi using supervised statistics, and this antifungal dataset correlated very-well with molecular interaction fields provided by Comparative Molecular Field Analysis (r² > 0.9, q² > 0.7). 3-ethoxycarbonyl-1-(3,4-methylendioxybenzyl)-2-methyl-α-pyridone, a very antifungal compound (IC₅₀ < 0.1 μM), was found to interact with NMT, LDM and Upc2TF according to the in-silico performance. Computational protein:ligand interaction profiles exhibited a common receptor contact which contributes to the non-polar stabilization. The hits and structural requirements can be used in the further development of antifungals based on α-pyridone analogs, being an excellent starting point for future studies on structural optimization of this kind of analogs towards development of multitarget antifungal drugs

This work is a product derived by the Project IMP-CIAS-2924 financed by Vicerrectoría de Investigaciones at UMNG - Validity 2018.

• References

• 1 Hamama WS, Waly M, El-Hawary I, Zoorob HH. Developments in the Chemistry of 2-Pyridone. Synth Comm 2014; 44: 1730-1759