Cocrystallization Studies Extending from Small Molecules to Proteins: a) Cocrystals, Salts and Eutectics, b) Chemical, Structural and Biological Evaluation of Anthrapyrazolones as Inhibitors of JNK proteins

Abstract

In summary, we have designed and synthesized three halogenated derivatives of 1,9- pyrazoloanthrone. The involvement of halogen bonding provides highly directional interactions in the binding pocket and hence demonstrates improved inhibitory activity. Among the three halogenated derivatives of 1,9-pyrazoloanthrone, R3 exhibits the most specific inhibition of JNKs activity at significantly lower concentrations (1M) compared to R1, R2 and SP600125 with no off-target effects on other kinases such as p38 and ERK1/2. Further, R3 being a potent and specific inhibitor of JNKs, regulates LPStriggered expressions of chemokines in macrophages. R3 appears as the best designed inhibitor and hence may facilitate the development of novel therapeutics to treat JNKs associated disorders. Therefore, current study proposes R3 as a better alternative for SP600125 to inhibit JNKs activity and may act as a promising tool to comprehend the physiological role of JNKs for therapeutic benefits