Synthesis, biological evaluation, pharmacological profiling, and molecular docking studies of 4-Aminocoumarin based phenyliodonium derivatives as potent therapeutic agents

Abstract

4-Aminocoumarins are significant in organic synthesis as key building blocks for various heterocyclic structures with pharmacological importance. This study focuses on synthesizing phenyliodonium derivatives of 4-aminocoumarins (T1-T6) and evaluating their broad-spectrum biological properties, including antibacterial, antifungal, antiviral, antioxidant, cytotoxicity, and wound-healing properties. The compounds synthesized were structurally confirmed through UV-Vis, GC-MS, ¹H-NMR, ¹³C-NMR, FT-IR, melting point, and CHNS analysis. The in vitro antibacterial and antifungal activities of these compounds were assessed against eight bacterial strains and five plant fungal pathogens. The antiviral property was evaluated by measuring the reduction in cytopathic effects of Dengue virus type-2 in BHK-21 cells. Cytotoxicity testing on human epidermal keratinocyte cells using the MTT assay at concentrations ranging from 1 to 100 µg/mL revealed that none of the compounds exhibited significant cytotoxic effects. Additionally, ADME/Toxicity, molecular docking, antioxidant, and wound-healing studies were examined, further supporting the therapeutic potential of these compounds. Most of the synthesized phenyliodonium derivatives demonstrated broad-spectrum antibacterial and antifungal activities. Among them, Compound T6 exhibited the most potent antimicrobial activity, as indicated by its MIC₉₀ and MBC values, demonstrating superior efficacy compared to ciprofloxacin. The antiviral test against Dengue virus type-2 showed minimal effects with a cytopathic effect reduction of 10-13% at non-toxic concentrations. These compounds exhibited broad-spectrum antimicrobial activity coupled with minimal cytotoxicity, highlighting their potential as promising candidates for developing novel therapeutic agents.

Keywords: ADME/Toxicity; Antimicrobial; Coumarin derivatives; Molecular docking; Scratch wound assay; Synthesis.

Fig. 1

Bioavailability radar plot for 4-AC (a), 4-A-3-PIC T (b), 3-PIC-4-I (c), 3-I-4-PAC (d), 4-PAC (e), 4-DPA 3-IC (f).

Fig. 2

3-D and 2-D molecular interaction diagram for Bacterial (a), Viral (b), and Fungal (c) target proteins with AC derivatives.

Fig. 3

Graphical representation of MIC₉₀ of AC derivatives against Acinetobacter baumannii (a), Escherichia coli (b), Bacillus subtilis (c), Klebsiella pneumoniae (d), Proteus mirabilis (e), Salmonella typhimurium (f), Pseudomonas aeruginosa (g), Staphylococcus aureus (h).

Fig. 4

Graphical representation of the antifungal activity of AC derivatives against plant fungal pathogens (a) A.niger, (b) F.oxysporum, (c) F.solani, and (d) P.chrysogenum.

Fig. 5

Morphological changes of DENV2 infected BHK-21 cells (a) and (b) HaCaT cell lines after treatment with AC derivatives.

Fig. 6

Scratch wound healing performance of HaCaT cells (a) Cell control, DMSO control, positive control (5-FU, < IC50), and positive control (5-FU, IC50), (b) Treated with 4-AC, 4-A-3-PIC T, 3-PIC-4-I, 3-I-4-PAC, 4-PAC, and 4-DPA-3-IC at 10 µg/mL.

Scheme 1

Synthesis of 4-AC.

Scheme 2

Synthesis of 4-A-3-PIC T.

Scheme 3

Synthesis of 3-PIC-4-I.

Scheme 4

Synthesis of 3-I-4-PAC.

Scheme 5

Synthesis of 4-PAC.

Scheme 6

Synthesis of 4-DPA-3-IC.