Discovery of naphthyl‐N‐acylhydrazone p38α MAPK inhibitors with in vivo anti‐inflammatory and anti‐TNF‐α activity

Abstract

Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen-activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti-inflammatory profile of new naphthyl-N-acylhydrazone derivatives using animal models. Although all tested compounds (3a-d) have been characterized as p38α MAPK inhibitors and have showed in vivo anti-inflammatory action, LASSBio-1824 (3b) presented the best performance as p38α MAPK inhibitor, with IC = 4.45 μm, and also demonstrated to be the most promising anti-inflammatory prototype, with good in vivo anti-TNF-α profile after oral administration.

Synthesis, in vitro and in vivo biological evaluation, COX-1/2 inhibition and molecular docking study of indole-N-acylhydrazone derivatives

“…2). Freitas et al (2018) 26 found similar results in theirs studies with new naphthyl-N-acylhydrazone derivatives. These authors showed high anti-inflammatory profile promoted by compound associated with low TNF-α production.…”

Two-Stage Strategy for Development of Proteolysis Targeting Chimeras and its Application for Estrogen Receptor Degraders

“…Mechanistic investigations showed the ability of our degraders to work through a mechanism similar to other PROTACs (Figure ) with a DC 50 in the low nanomolar range and almost complete degradation within 6 h (Figure ), making it a valuable chemical probe for ERα. Although the acylhydrazone moiety has been identified in various bioactive compounds, − including compounds with in vivo activity, , it is well-known that hydrolysis can occur under acidic conditions. In order to increase the stability and drug-likeness of the degraders, we modified the linkage to an amide containing the same number of atoms within the linker in the second stage and confirmed that the biological activity was retained (Figures and ).…”

The p38 MAPK Inhibitors and Their Role in Inflammatory Diseases

“…The ability of this compound to inhibit other kinases, as off-targets, was not described by the authors. [51] Tariq et al (2018) synthesized a new series of N-[3-(substituted-4H-1,2,4-triazol-4-yl)]-benzo[d]thiazol-2-amines (4 a-n) and subjected to in vitro evaluation for anti-inflammatory activity and p38α MAPK inhibition. Compound 4 f, which has a type I mode of inhibition, was found to be the most active with an IC50 of 0.036 � 0.12 μM and showed the maximum anti-inflammatory activity when compared to the standard drug diclofenac sodium.…”