A synergistic investigation of azo-thiazole derivatives incorporating thiazole moieties: a comprehensive exploration of their synthesis, characterization, computational insights, solvatochromism, and multimodal biological activity assessment

Abstract

In the present study, a novel series of azo-thiazole derivatives (3a-c) containing a thiazole moiety was successfully synthesized. The structure of these derivatives was examined by spectroscopic techniques, including ¹H NMR, ¹³C NMR, FT-IR, and HRMS. Further, the novel synthesized compounds were evaluated for their in vitro biological activities, such as antibacterial and anti-inflammatory activities, and an in silico study was performed. The antibacterial results demonstrated that compounds 3a and 3c (MIC = 10 μg mL^-1) have a notable potency against Staphylococcus aureus compared to azithromycin (MIC = 40 μg mL^-1). Alternatively, compound 3b displayed a four-fold higher potency (24 recovery days, 1.83 mg day^-1) than Hamazine (28 recovery days, 4.14 mg day^-1) in promoting burn wound healing, and it also exhibited a comparable inhibitory activity against screened bacterial pathogens compared to the reference drug. Docking on 1KZN, considering the excellent impact of compounds on the crystal structure of E. coli1KZN, a 24 kDa domain, in complex with clorobiocin, indicated the close binding of compounds 3a-c with the active site of the 1KZN protein, which is consistent with their observed biological activity. Additionally, we conducted molecular dynamics simulations on the docked complexes of compounds 3a-c with 1KZN retrieved from the PDB to assess their stability and molecular interactions. Furthermore, we assessed their electrochemical characteristics via DFT calculations. Employing PASS and pkCSM platforms, we gained insights into controlling the bioactivity and physicochemical features of these compounds, highlighting their potential as new active agents.

Scheme 1. A schematic of the synthesis of compounds 3a–c.

Fig. 1. The UV-vis spectra of the synthesized molecules recorded in different solvents (a) 3, (b) 3a, (c) 3b and (d) 3c.

Fig. 2. The UV-vis spectra of compounds 3 and 3a–c recorded in (a) DMSO and (b) DMF solvents.

Fig. 3. A schematic diagram of the solvation effect on the n–π* transitions.

Fig. 4. The antimicrobial effects of compounds 3 and 3a–c were evaluated using the disc diffusion technique at a concentration of 1000 μg mL⁻¹.

Fig. 5. Variations in the healing advancement of burns on day 1 (A), 3 (B), 12 (C), 14 (D), 17 (E), and 26 (F).

Fig. 6. FMO orbitals and the energy gap between the HOMO and LUMO states in compounds 3a–c.

Fig. 7. The molecular electrostatic potential surface of compounds 3a–c.

Fig. 8. Explored binding modes in the active site of 1KZN and hydrogen bonds with antibacterial compounds (3a–c). Shown in 2D (left) and 3D (right).

Fig. 9. The globular structure of 1KZN after binding with 3a: (a) deformability, (b) the B-factor, (c) the Eigen score, and (d) the covariance matrix.

Fig. 10. MD simulation trajectories over 100 ns: (a) the C-alpha atom RMSD, (b) C-alpha atom RMSF, (c) complex gyration radius, (d) solvent accessible surface area of the docked complex indicating the protein area change, (e) complex hydrogen bonds, and (f) binding energy.