Synthesis and screening of cyclic diketone indanedione derivatives as future scaffolds for neutrophil elastase inhibition.

Human neutrophil elastase (HNE) and proteinase 3 (Pr3) released from neutrophils at inflammatory sites are the major causes of pathogens in chronic obstructive pulmonary disease (COPD) and various lung tissue derangements, among which cystic fibrosis and blockade of airway passages are chronic. These proteolytic mediatory agents combined with induced oxidative reactions sustain pathogenicity. Cyclic diketone indane-1,3-dione derivatives were designed, and toxicity evaluation predictions were performed in silico. Benzimidazole and hydrazide derivatives of indanedione were synthesized and characterized. Synthesized compounds were run using neutrophil elastase inhibition assay protocols. The compounds exhibit considerable inhibition of neutrophil elastase enzymes.

A novel family of small molecule HIF-1 alpha stabilizers for the treatment of diabetic wounds; an integrated in silico, in vitro, and in vivo strategy.

Hypoxia-inducible factor-1 alpha (HIF-1α) is a crucial regulator of wound healing, which includes epithelialization, angiogenesis, granulation, tissue development, and wound contraction. Even though diabetic wounds are hypoxic, HIF-1α levels are decreased during healing. Diabetic wound healing necessitates the modulation of hypoxia-induced responses by VHL-HIF-1α protein-protein inhibition. Our proposed hypothesis is to increase HIF-1α levels by inhibiting VHL and HIF-1α interactions by novel small bioactive molecules, accelerating diabetic wound healing. A three features (two aromatic rings and one hydrogen bond acceptor) pharmacophore hypothesis was generated from the existing HIF-1α modulators. Virtual screening was done based on the generated pharmacophore, and a library consisting of the top 20 out of 3728 compounds was selected using ZINCPharmer. Of the top 20 molecules, the pyrazole moiety was identified as the top "HIT". Five analogues of pyrazole were designed, and Scifinder ascertained the novelty. The designed compounds were synthesized and characterized by IR, Mass, and NMR. Preliminarily, we have carried out a scratch wound assay using 3T3L1 cell lines. All the synthesized compounds showed significant wound healing activity. Further, to validate the in vitro assay, the compound CI, which showed effective in vitro results was used for in vivo study. Using the diabetes mouse model, comprising streptozotocin-induced (STZ) diabetic mice and scratch wound assay, we demonstrated that inhibiting the VHL and HIF-1α connection is a promising strategy for treating diabetic ulcers. Molecules CI and CP were found to have substantial in silico, in vitro, and in vivo outcomes.