1. Academic Validation
  2. Design, synthesis and anti-necroptosis activity of fused heterocyclic MLKL inhibitors

Design, synthesis and anti-necroptosis activity of fused heterocyclic MLKL inhibitors

  • Bioorg Med Chem. 2024 Mar 1:102:117659. doi: 10.1016/j.bmc.2024.117659.
Yining Tang 1 Chunlin Zhuang 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
  • 2 School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: zclnathan@163.com.
Abstract

Necroptosis is an important form of programmed cell death (PCD), which is mediated by a death receptor and independent of the Caspase proteolytic Enzyme. Mixed Lineage Kinase domain-like (MLKL) is the final effector of Necroptosis, playing an irreplaceable role in the execution of Necroptosis. However, the studies on MLKL inhibitors are in their infancy. Necrosulfonamide (NSA) is an early-discovered covalent MLKL inhibitor, possessing medium anti-necroptosis activity and a structure-activity relationship (SAR) not widely disclosed. In this study, with the covalent motif maintained, we aim to improve the activity by introducing the terminal fused heterocycles and meanwhile revealing the SAR on the part. As a result, compounds 9 and 14 showed the best activity (EC50 = 148.4 and 595.9 nM) against Necroptosis among the analogues by covalently binding to MLKL. The SAR was also concluded to guide further structural optimization in this field.

Keywords

Inhibitors; MLKL; Necroptosis; SAR.

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