Synthesis, biological evaluation and computational studies of acrylohydrazide derivatives as potential Staphylococcus aureus NorA efflux pump inhibitors.

The NorA efflux pump decreases the intracellular concentration of fluoroquinolones (ciprofloxacin, norfloxacin) by effluxing them from Staphylococcus aureus cells. The synthesis of novel acrylohydrazide derivatives was achieved using well-known reactions and were characterized by various spectroscopy techniques. The synthesized 50 compounds were evaluated for the NorA efflux pump inhibition activity against S. aureus SA-1199B (norA++) and K1758 (norA-) strains. The study provided two most active compounds viz. 19 and 52. Compound 19 was found to be most active in potentiating effect of norfloxacin and also it showed enhanced uptake, efflux inhibition in ethidium bromide assay. Further compound 19 also enhanced post antibiotic effect and reduced mutation prevention concentration of norfloxacin. The homology modeling study was performed to elucidate three-dimensional structure of NorA. Docking studies of potent molecules were done to find the binding affinity and interaction with active site residues. Further, all the tested compounds exhibited good ADME and drug-likeness properties in- silico. Based on the in-silico studies and detailed in vitro studies, acrylohydrazides derivatives may be considered as potential NorA EPI candidates.

Identification of specific features of inhibition of PKCßII and its potential lead by shape-based virtual screening and molecular docking studies.

Protein kinase C ßII (PKCßII) is preferentially expressed during hyperglycemic state resulting in diabetic complications, particularly, diabetic cardiomyopathy. An effective inhibition of PKCßII is a potential option to directly treat the diabetic cardiomyopathy; however, till date no efficient drug targeting PKCßII is available and all the reported PKCßII ligands are maleimide derivatives. The purpose of the present work is to study the importance of the maleimide moiety in PKCßII inhibition and the effects that follow after replacing the maleimide with similar moiety on PKCßII inhibition. For this, an in-house database of maleimide analogues was prepared and shape based screening of commercial databases viz. Specs2009, NCI2003 was performed, followed by filtration using virtual filters. The binding features of reported PKCßII inhibitors, and high scoring hits were analyzed with the help of molecular docking studies. The features identified from the above studies were used for the rational design of new PKCßII inhibitors. The molecular dynamics simulation and ligand-receptor binding affinity studies of the designed molecules has been reported. The toxicity of all the shortlisted and designed molecules was predicted.