Pyrazole appended hetero-hybrids: Bioisosteric design, synthesis, in silico and in vitro antibacterial and anti-inflammatory evaluations

Abstract

In the present investigation, we adopted bioisosteric based design and synthesis of pyrazole appended "New Molecular Hybrids" to develop antibacterial agents that are efficient against multidrug resistant bacteria. Structure of the compounds were well characterized with the aid of spectroscopic and analytical techniques and, the selected derivatives were further confirmed through the single crystal X-ray analysis. Following an in-silico evaluation of the compounds' effectiveness through docking studies and ADMET calculations, we conducted an in vitro antibacterial assessment and found that 6c was the most effective, having an MIC of 5 µg/mL against P. aeruginosa and M. smegmatis, which was superior to standard drug ampicillin (15.6 and 6.25 µg/mL, respectively). SAR studies of compound 6c on protein 1kzn indicate that it has a binding energy of -8.64 kcal mol−1 via various noncovalent interactions. The anti-inflammatory potential screening revealed that, 6b was the most potent with an IC50 of 9.3 µg/mL, which is moderately active in comparison to standard aspirin (5.03 µg/mL). Thus, based on SAR studies, ADMET calculations, and in vitro studies, the new hybrids appear to be promising hits for the antibacterial and anti-inflammatory drug discovery endeavours.