Design, synthesis and in silico molecular docking evaluation of novel 1,2,3-triazole derivatives as potent antimicrobial agents

Abstract

Chalcone and triazole scaffolds have demonstrated a crucial role in the advancement of science and technology. Due to their significance, research has proceeded on the design and development of novel benzooxepine connected to 1,2,3-triazolyl chalcone structures. The new chalcone derivatives produced by benzooxepine triazole methyl ketone 2 and different aromatic carbonyl compounds 3 are discussed in this paper. All prepared compounds have well-established structures to a variety of spectral approaches, including mass analysis, ¹H NMR, ¹³C NMR, and IR. Among the tested compounds, hybrids 4c, 4d, 4i, and 4k exhibited exceptional antibacterial susceptibilities with MIC range of 3.59-10.30 μM against the tested S. aureus strain. Compounds 4c, 4d displayed superior antifungal activity against F. oxysporum with MIC 3.25, 4.89 μM, when compared to fluconazole (MIC = 3.83 μM) respectively. On the other hand, analogues 4d, 4f, and 4k demonstrated equivalent antitubercular action against H₃₇Rv strain with MIC range of 2.16-4.90 μM. The capacity of ligand 4f to form a stable compound on the active site of CYP51 from M. tuberculosis (1EA1) was confirmed by docking studies using amino acids Leu321(A), Pro77(A), Phe83(A), Lys74(A), Tyr76(A), Ala73(A), Arg96(A), Thr80(A), Met79(A), His259(A), and Gln72(A). Additionally, the chalcone‒1,2,3‒triazole hybrids ADME (absorption, distribution, metabolism, and excretion), characteristics of molecules, estimations of toxicity, and bioactivity parameters were assessed.

Keywords: 1,2,3-Triazoles; ADMETlab2.0; Benzooxepines; Biological evaluations; Chalcones; Docking interactions.

Graphical abstract

Fig. 1

Commercial chemical structures of the reported anti-TB active molecules and 1,2,3-triazoles.

Scheme 1

Design strategy of benzooxepine‒1,2,3‒triazoles linked to chalcones.

Fig. 2

List of 1,2,3–triazole benzooxepine chalcone derivatives.

Fig. 3

Antitubercular activity profile of final chalcone bearing 1,2,3‒triazole derivatives.

Fig. 4

2D-, 3D-docking conformations of the most active 1,2,3-triazole ligands (4d, 4f, and 4k) against CYP51 from M. tuberculosis [PDB: 1EA1].

Fig. 5

Ligplot docking poses of most active 1,2,3‒triazolylchalcone derivatives (4d, 4f, and 4k) within the active site of CYP51 from M. tuberculosis.

Fig. 6

Druglike ness modelscores of final triazoles 4b, 4c, and 4j.

Fig. 7

Bioavailability radar and the BOILED-Egg model of synthesised molecules 4b, 4c, 4d, 4f, and 4i.

Fig. 8

Molecules 4d, 4f and 4k are optimized at B3LYP/6-31g (d,p) level of theory in the gas phase.

Fig. 9

The frontier molecular orbital (FMO) single point energy calculation carried out at B3LYP/6-31g (d,p)//B3LYP/6-31g (d,p) level of theory in the gas phase (4d).