Structure-activity relationships and molecular docking studies of chromene and chromene based azo chromophores: A novel series of potent antimicrobial and anticancer agents

Abstract

The design of novel materials with significant biological properties is a main target in drug design research. Chromene compounds represent an interesting medicinal scaffold in drug replacement systems. This report illustrates a successful synthesis and characterization of two novel series of chromene compounds using multi-component reactions. The synthesis of the first example of azo chromophores containing chromene moieties has also been established using the same methodology. The antimicrobial activity of the new molecules has been tested against seven human pathogens including two Gm+ve, two Gm-ve bacteria, and four fungi, and the results of the inhibition zones with minimum inhibitory concentrations were reported as compared to reference drugs. All the designed compounds showed significant potent antimicrobial activities, among of them, four potent compounds 4b, 4c, 13e, and 13i showed promising MIC from 0.007 to 3.9 µg/mL. In addition, antiproliferative analysis against three target cell lines was examined for the novel compounds. Compounds 4a, 4b, 4c, and 7c possessed significant antiproliferative activity against three cell lines with an IC₅₀ of 0.3 to 2 µg/mL. Apoptotic analysis was performed for the most potent compounds via caspase enzyme activity assays as a potential mechanism for their antiproliferative effects. Finally, the computational 2D QSAR and docking simulations were accomplished for structure-activity relationship analyses.

Keywords: 2D QSAR and docking simulations; antitumor activity; biological applications; chromene azo dyes; chromene compounds.

Table 1. Well diffusion assay for antimicrobial activity of synthetic compounds (Inhibition Zone (IZ) diameter in mm) (5 mg/mL in DMSO)

Table 2. Antimicrobial activity of synthetic compounds (Minimum inhibitory concentration, MIC, µg/mL)

Table 3. Cytotoxicity of target Benzo Chromene compounds against three different cancer cell lines

Table 4. Cytotoxicity of target azo dyes and azo based chromene compounds against three different cancer cell lines

Table 5. DNA Gyrase data for some selected chromene and azo based chromene compounds

Table 6. QSAR models with all details including equations, descriptors space, and correlation parameters

Table 7. Molecular descriptor values of the QSAR models

Table 8. Correlation matrix of descriptor values

Figure 1. Target scaffold with corresponding novel series compounds appearing the mapping of physicochemical properties to biological activity

Figure 2. Synthesis of two series of chromene derivatives

Figure 3. 2,7-amino-4-aryl-3-cyano-4H-chromene (8a-d) and 2-amino-4-aryl-7-hydroxy-3-cyano-4H-chromene (9a-d)series

Figure 4. Synthesis of azo chromene dyes 13a-k

Figure 5. Heat map of inhibition zone data for the tested compounds against bacterial and fungal strains. The values are color-coded and color bars mark the matrix positions of compounds in a particular bacteria type.

Figure 6. Heat map of MIC data for the tested active compounds against bacterial and fungal strains. The values are color-coded and color bars mark the matrix positions of compounds in a particular bacteria type.

Figure 7. In vitro cytotoxic activity. The IC₅₀ values of target compounds compared to reference drug are color-coded according to the following scheme: green 0.5-10, black 11-14, and red 15-24. Color bars mark the matrix positions of compounds in a particular cell line.

Figure 8. In vitro analysis of caspases activity for representative target compounds

Figure 9. Bar chart summarizing the effect of compounds on acute neuronal toxicity. These graphs show the acute toxicity of target compounds against neuronal cells. A) The reported toxicity of target drugs within 24 h by concentration of 10 µM, B) The reported toxicity of target drugs within 24 h by concentration of 100 µM, C) The reported toxicity of compounds within 48 h (10 µM). The data represent mean with standard error values.

Figure 10. UV-vis study for metal chelation with target compound 4c

Figure 11. Heat map of correlation matrix of descriptor values

Figure 12. Histogram distribution of target compounds according to Q_VSA_HYD values

Figure 13. QSAR plot of correlation of the observed against predicted IC₅₀ of A) HCT-116, B) HepG-2, C) MCF-7 cell lines

Figure 14. Molecular interactions of the target compounds 4a, 4b, 4c, 7c, and reference ligand with active site of target protein caspase-3 enzyme

Figure 15. Molecular interactions of the target compounds 4a, 4b, 4c, 7c, and reference ligand with active site of target protein EGFR enzyme