Eco-friendly Regioselective Synthesis, Biological Evaluation of Some New 5-acylfunctionalized 2-(1H-pyrazol-1-yl)thiazoles as Potential Antimicrobial and Anthelmintic Agents

Abstract

The present study describes an eco-friendly NBS-assisted regioselective synthesis of new 5-acylfunctionalized 5-acylfunctionalized 2-(1H-pyrazol-1-yl)thiazoles by condensation of 3,5-dimethyl-1H-pyrazole-1-carbothioamide with unsymmetrical 1,3-diketones under solvent-free conditions. The structural elucidation of the newly synthesized compounds was accomplished using various spectroscopic techniques viz. FTIR, NMR and mass spectrometry. All the newly synthesized compounds were examined for their in vitro antimicrobial potential against both pathogenic gram positive and gram negative bacterial and fungal species as well as anthelmintic activity against Pheretima posthuma earthworms. The results of antimicrobial activity revealed that all tested compounds 3 a-j showed excellent antimicrobial potential particularly against S. aureus. It was also observed that compounds 3 e and 3 i (MIC=62.5 μg/mL) showed greater potency against E. coli, whereas compounds 3 a and 3 h (MIC=50 μg/mL and 62.5 μg/mL) demonstrated better activity against P. aeruginosa and compound 3 i (MIC=62.5 μg/mL) exhibited superior activity against S. pyogenus when compared to standard drug Ampicillin (MIC=100μg/mL). Compound 3 e and 3 j revealed remarkable antifungal and anthelmintic activities. To find out binding interactions of target compounds with target proteins and pharmacokinetic parameters of the compounds, in silico investigations involving molecular docking studies and ADMET predictions were also performed.

Keywords: 2-(1H-pyrazol-1-yl)thiazoles; Solvent-free; anthelmintic; antimicrobial; multinuclear 2D NMR; structure activity relationship.

Figure 1

Various isomeric structural variants of pyrazolyl‐thiazole.

Figure 2

Several pharmaceutically important 2‐(1H‐pyrazol‐1‐yl)thiazole skeletons.

Figure 3

Rationale for the design of the new 5‐acyl functionalized 2‐(1H‐pyrazol‐1‐yl)thiazoles.

Scheme 1

Possible regioisomers formed by reaction of 1 and 2.

Figure 4

NMR chemical shift values and 2D NMR correlations diagram for compounds 3 a.

Scheme 2

Plausible mechanism for regioselective synthesis of 5‐acylfunctionalized 2‐(1H‐pyrazol‐1‐yl)thiazoles 3 a–j.

Figure 5

Binding interactions of 3 e (a), 3 i (b) and Ampicillin (c) with E. coli (PDB ID: 2EX6); 3 a (d), 3 h (e), Ampicillin (f) with P. aeruginosa (PDB ID: 6P8U); 3 i (g), 3 j (h), Ampicillin (i) with S. aureus (PDB ID: 3HUN) and 3 i (j), Ampicillin (k) with S. pyogenes (PDB ID: 4CMQ).

Figure 6

Binding interactions of compounds 3 c (a), 3 e (b), 3 j (c) and Griseofulvin (d) with C. albicans (PDB ID: 5TZ1).

Figure 7

The blood brain barrier permeability (BBBP) and gastrointestinal absorption (GIA) properties of the compounds 3 a–j using Brain or Intestinal estimated permeation predictive method.

Figure 8

Structure‐activity relationship of 5‐acylfunctionalized 2‐(1H‐pyrazol‐1‐yl)thiazoles.