Design and Enzyme-Targeted Assessment of 1,2,4-Triazole-1,8-Naphthalimide Hybrids in Drug Discovery

Abstract

This study reports the design, synthesis, and biological evaluation of novel hybrid 1,2,4-triazole-1,8-naphthalimide derivatives using both classical and environmentally friendly synthetic routes. The synthetic strategy involved a multistep process starting with the preparation of triazolylthioacetic acid esters, followed by electrophilic cyclization-employing both conventional bromine and a green, bromine-free method-and culminating in amidation reactions to yield the target compounds. Structural modifications, including the incorporation of pyridinyl and benzoate moieties, were introduced to enhance biological activity. The compounds were evaluated for antimicrobial and anti-inflammatory activities. In antimicrobial assays, several derivatives demonstrated selective activity, with Compound 5f showing the strongest broad-spectrum antibacterial effects, particularly against Bacillus cereus and Lactobacillus plantarum, and Compound 3e displaying notable dual-action activity against both bacterial and fungal strains. These observations underscore the influence of specific functional groups on microbial targeting and membrane penetration. Anti-inflammatory potential was assessed via IL-6 inhibition using ELISA. Significant reductions in IL-6 levels were observed for Compounds 3a, 3c, 3e, 4, 5c, 5f, and 5g, indicating promising activity, with Compounds 5c and 3a reducing IL-6 levels to 7 pg/mL. The complementary molecular docking studies revealed strong binding affinities for Compound 5f across multiple bacterial enzymes, suggesting effective interactions through hydrogen bonding, electrostatic, and hydrophobic forces and supporting its potential to target iron-regulated pathways and fosfomycin resistance mechanisms. Overall, the integrative approach combining synthetic chemistry, biological assays, and computational modeling highlights the potential of these hybrid 1,2,4-triazole derivatives as candidates for further development as antimicrobial and anti-inflammatory agents.

Figure 1

Schematic representation of hybrid 1,2,4-triazole–1,8-naphthalimide compounds, illustrating their origins and key biological properties.

Scheme 1

Synthesis of alkylated triazole derivatives 3a–3e via alkylation of Compound 1.

Scheme 2

Electrophilic bromocyclization of Compound 3b leading to the formation of Salt 4.

Scheme 3

Synthesis of amides 5a–5g from ester 3c via aminolysis.

Figure 2

Visualization of molecular docking results showing the interactions between Compound 5f and the IsdG protein from Bacillus cereus (PDB ID: 8AVI) in both (a) 3D and (b) 2D views.

Figure 3

Visualization of molecular docking results showing the interactions between Compound 5f and the FosB enzyme from Bacillus cereus (PDB ID: 8DTD) in both (a) 3D and (b) 2D views.

Figure 4

Visualization of molecular docking results showing the interactions between Compound 5f and the putative cell surface hydrolase from Lactobacillus plantarum (PDB ID: 3LP5) in both (a) 3D and (b) 2D views.

Figure 5

Visualization of molecular docking results showing the interactions between Compound 5f and the esterase LpEst1 from Lactobacillus plantarum (PDB ID: 4C87) in both (a) 3D and (b) 2D views.

Figure 6

Visualization of molecular docking results showing the interactions between Compound 3e and the IsdG protein from Bacillus cereus (PDB ID: 8AVI) in both (a) 3D and (b) 2D views.

Figure 7

Visualization of molecular docking results showing the interactions between Compound 3e and the FosB enzyme from Bacillus cereus (PDB ID: 8DTD) in both (a) 3D and (b) 2D views.

Figure 8

Visualization of molecular docking results showing the interactions between Compound 3e and the dihydrofolate reductase from Staphylococcus aureus (PDB ID: 1DHI) in both (a) 3D and (b) 2D views.

Figure 9

Visualization of molecular docking results showing the interactions between Compound 3e and the enzyme Sortase A from Staphylococcus aureus (PDB ID: 1T2P) in both (a) 3D and (b) 2D views.

Figure 10

Visualization of molecular docking results showing the interactions between Compound 3e and Cel7A from Geotrichum candidum (PDB ID: 4ZZT) in both (a) 3D and (b) 2D views.

Figure 11

Visualization of molecular docking results showing the interactions between Compound 3e and the Chitin Synthase 2 from Geotrichum candidum (PDB ID: 7STO) in both (a) 3D and (b) 2D views.