Novel Pyrazolo[1,5- a ]Pyridine Integrated 1,2,3–Triazoles as Potent Antimicrobial Targets: Efficient Synthesis, ADMET Profiling, DFT, and Molecular Docking Insights

A novel series of 1,2,3-triazole-pyrazolo[1,5-a]pyridine based on targeting antibacterial and antifungal activity was rationally designed by integrating key pharmacophores into a single molecule. The target compounds (5a–5k) were efficiently prepared via a multistep synthetic route involving the condensation of pyrazolo[1,5-a]pyridine-acetyl chloride intermediate with corresponding amines, and their structures were confirmed through 1H-NMR,13C-NMR, and HRMS spectrometry. In vitro antimicrobial assessment against Klebsiella pneumoniae and Micrococcus luteus revealed that compounds 5d, 5 g, and 5k exhibited significant antibacterial activity at low minimum inhibitory concentrations (MIC, 3.85 ± 1.67 to 6.25 ± 1.33 µM), with favorable selectivity indices highlighting preferential toward microorganisms. Compounds 5f, 5 g, and 5k exhibited most promising antifungal activity, with MIC values ranging from 4.68 ± 1.03 to 5.2 ± 0.77 µM against Candida glabrata when compared with ketoconazole (KTZ) (MIC = 6.24 ± 0.56 µM). Molecular docking studies demonstrated good binding interactions between the synthesized compounds and the target proteins-dehydrogenase of Micrococcus luteus (PDB 6KQ9), and sterol 14α-demethylase (CYP51) from Candida albicans (PDB 5FSA) offering valuable insights into their binding mechanisms. Further, to confirm the formation of a novel linkage, the electronic and structural properties of the lead-most-active compound 5a and 5k were studied by DFT calculations on the Gaussian 09 software package. Moreover, drug-likeness and potential bioavailability were assessed by using in silico ADME-toxicity analysis to evaluate the pharmacokinetic features. The key findings of the in vitro antimicrobial and molecular docking results, as well as the analysis, demonstrated that the synthesized compounds have potential antimicrobial potency and can be further optimized to serve as lead compounds.