N-formylpyrazolines and N-benzoylpyrazolines as novel inhibitors of mammalian cathepsin B and cathepsin H

• Title pyrazolines were synthesized and studied as inhibitors to cathepsin B and H.
• Synthesized compounds selectively inhibited cathepsin B and cathepsin H.
• Most inhibitory compound 1i exhibited Ki value of 1 × 10−9 M for cathepsin B.
• The inhibition is equivalent to specific inhibitor, leupeptin.
• The results are compared with the in silico studies.

Cathepsins, intracellular proteases, are known to be involved in a number of physiological processes ranging from degradation of extracellular proteins, prohormone processing, progressions of atherosclerosis, etc. High levels of cathepsins have been indicated in various pathological conditions like arthritis, cancer and other tissue degenerative disorders. One of the reasons attributed to these high levels is decrease in inhibitor concentration. Therefore, the work on the identification of small molecular weight compounds as inhibitors of cysteine proteases is of great therapeutic significance. Exploring this work in the same direction, we here present the synthesis of substituted N-formylpyrazolines and N-benzoylpyrazolines and study these as inhibitors to cysteine proteases. After a preliminary screening of the compounds as inhibitors to cysteine proteases in general, studies were carried out to study their inhibitory effects on cathepsin B and cathepsin H. SAR studies show that N-formylpyrazolines were better inhibitors than N-benzoylpyrazolines. The most potent inhibitors among the two series were nitro substituted compounds 1i and 2i with Ki values of ∼1.1 × 10−9 M and 19.5 × 10−8 M for cathepsin B and Ki values of ∼5.19 × 10−8 M and 9.8 × 10−7 M for cathepsin H, respectively. Docking experiments showing interaction between N-formylpyrazolines and N-benzoylpyrazolines with enzyme active sites structures also provided useful insights.

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