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CN-121627594-B - Double-target inhibitor and preparation method and application thereof

CN121627594BCN 121627594 BCN121627594 BCN 121627594BCN-121627594-B

Abstract

The invention discloses a double-target inhibitor and a preparation method and application thereof, and belongs to the technical field of medicines. The inhibitor is a novel PDE4/HDAC6 double-target inhibitor, and the chemical structure of the inhibitor comprises a specific general formula which comprises 31 specific compounds. The inhibitor can effectively inhibit PDE4 and HDAC6 activities simultaneously. In a sepsis model, the inhibitor shows remarkable anti-inflammatory effect, can down regulate inflammatory factors such as IL-6, TNF-alpha and the like, protect intestinal barriers and alleviate lung and other multi-organ injuries. The invention also provides a clear preparation method of the inhibitor. The double-target inhibitor provides a new drug candidate for the treatment of sepsis.

Inventors

  • PAN WEI
  • CHEN WENHUA
  • YAO HONGLIANG
  • LI GANG
  • GENG YAN
  • ZHANG YALI

Assignees

  • 五邑大学
  • 广东省科学院动物研究所

Dates

Publication Date
20260508
Application Date
20260202

Claims (9)

  1. 1. A PDE4/HDAC6 dual-target inhibitor, having the structural formula: wherein n is 1, 2, 3, 4, 5 or 6.
  2. 2. A method of preparing a PDE4/HDAC6 dual-target inhibitor according to claim 1, comprising the steps of: dissolving a first reactant in a first solvent, adding a condensing agent and N, N-diisopropylethylamine, stirring, adding a second reactant, and reacting at room temperature to obtain a first intermediate; dissolving the first intermediate in a second solvent, and then adding a hydrogen chloride-dioxane solution to obtain the double-target inhibitor; wherein the first reactant is: The second reactant is as follows: ; The first intermediate is: ; wherein n is 1, 2, 3, 4, 5 or 6.
  3. 3. The method of preparing a PDE4/HDAC6 dual-target inhibitor according to claim 2, wherein said method comprises The preparation method of (2) comprises the following steps: Dissolving a third reactant in a first solvent, adding a condensing agent and N, N-diisopropylethylamine, stirring, adding a fourth reactant, and reacting at room temperature to obtain a second intermediate; carrying out hydrolysis reaction on the second intermediate to obtain a target product; wherein the third reactant is: ; the fourth reactant is as follows: ; the second intermediate is: ; wherein n is 1, 2, 3, 4, 5 or 6.
  4. 4. The method of preparing a PDE4/HDAC6 dual-target inhibitor according to claim 3, wherein said third reactant The preparation method of (2) comprises the following steps: dissolving a fifth reactant in a first solvent, adding a condensing agent and N, N-diisopropylethylamine, stirring, adding a sixth reactant, and reacting at room temperature to obtain a third intermediate; Dissolving the third intermediate in a second solvent, and then adding hydrogen chloride-dioxane solution to obtain a target product; Wherein the fifth reactant is: ; The sixth reactant is: ; The third intermediate is: ; wherein n is 1, 2, 3, 4, 5 or 6.
  5. 5. The method for preparing the PDE4/HDAC6 dual target inhibitor according to claim 3, wherein the hydrolysis reaction is performed for 2-6 hours at 20-50 ℃.
  6. 6. The method of preparing a PDE4/HDAC6 dual-target inhibitor according to claim 2, wherein said condensing agent is 2- (7-azabenzotriazol) -tetramethylurea hexafluorophosphate.
  7. 7. The method of preparing a PDE4/HDAC6 dual-target inhibitor according to claim 2, wherein said first solvent is N, N-dimethylformamide and said second solvent is dichloromethane.
  8. 8. Use of a PDE4/HDAC6 dual-target inhibitor according to claim 1 in the manufacture of a medicament for the treatment and/or prophylaxis of sepsis.
  9. 9. A pharmaceutical composition for the treatment and/or prevention of sepsis, characterized in that it comprises as active principle a PDE4/HDAC6 dual-target inhibitor according to claim 1, together with at least one pharmaceutically acceptable adjuvant.

Description

Double-target inhibitor and preparation method and application thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to a double-target inhibitor and a preparation method and application thereof. Background Sepsis is a systemic inflammatory response syndrome induced by infection, whose central pathophysiological mechanism is an immunoregulatory disorder, manifested by an imbalance of excessive inflammatory and compensatory anti-inflammatory responses, often accompanied by coagulation dysfunction and microcirculation disturbance, and eventually can progress to multiple organ dysfunction syndrome. In this pathological process, the intestine and lung serve as key target organs that are extremely vulnerable and closely related, and their injury and interaction have important effects on the progression of the disease. The core feature of sepsis intestinal injury is a severe disruption of intestinal barrier function. The systemic hemodynamic disturbance and local microthrombosis together lead to insufficient perfusion of intestinal mucosa and ischemic injury, and a large amount of follow-up pro-inflammatory cytokines (such as TNF-alpha and IL-1 beta) are released to directly induce apoptosis of intestinal epithelial cells, destroy intercellular tight connection and obviously increase permeability of the intestinal mucosa. This pathological change promotes translocation of the intestinal flora and its products (e.g., endotoxins) to the mesenteric lymphatic system and portal circulation, which exacerbates the systemic inflammatory cascade and may be a potential source of secondary infection. In addition, intestinal dyskinesia and immune surveillance dysfunction can further exacerbate the malignant cycle of the condition. Sepsis lung injury typically characterizes the pathology of acute respiratory distress syndrome. The pathogen-associated and damage-associated molecular patterns in the circulation activate the pulmonary vascular endothelial cells and alveolar epithelial cells, induce a large number of neutrophils to aggregate and infiltrate in the lung, and release proteases and active oxygen to destroy the alveolar-capillary membrane structure. This results in a significant increase in vascular permeability, protein-rich fluid exudes to the alveolar space, forming non-cardiac pulmonary edema, and simultaneously, impaired alveolar type II epithelial cell function results in reduced synthesis of surface active substances, leading to alveolar collapse and reduced lung compliance. Partial pulmonary dysfunction and pulmonary hypertension can also occur, ultimately leading to refractory hypoxia. There is a close pathophysiological link between intestinal injury and lung injury via the "intestinal-pulmonary axis". Bacteria and endotoxin translocation caused by intestinal barrier dysfunction can directly activate inherent immune cells in the lung through circulatory and lymphatic pathways to amplify lung inflammatory response, otherwise, systemic hypoxia and inflammatory mediator release caused by lung injury can further aggravate intestinal ischemia and barrier injury. This interaction between organs is a key mechanism for the worsening of sepsis condition and high mortality. Therefore, clinical control strategies need to be based on controlling systemic infection, and the protection of intestinal barrier function and early respiratory function support are considered. Disclosure of Invention Aiming at the technical problems, the invention provides a double-target inhibitor and a preparation method and application thereof. The invention designs and synthesizes 31 novel PDE4/HDAC6 double-target inhibitors aiming at PDE4 and HDAC6 targets. In order to achieve the above purpose, the present invention provides the following technical solutions: a dual-target inhibitor having a chemical structural formula selected from one of the following formulas: And ; Wherein X is selected from NH, S or O, R 1 is selected from NH 2 or H, and R 2 is selected fromOr H, L is selected fromN is 1,2, 3, 4, 5 or 6;m is 0 or 1, the dashed lines independently represent the presence or absence of a bond, and the connection position is represented. PDE4 is a hydrolase that regulates intracellular levels of the key anti-inflammatory messenger cAMP. In sepsis, PDE4 activity enhancement accelerates cAMP degradation, resulting in massive release of pro-inflammatory factors (e.g. TNF- α, IL-6), exacerbating inflammatory storms. PDE4 inhibitors can effectively inhibit immune cell overactivation by increasing cAMP level, and relieve vascular leakage, hypotension and lung, liver and other multi-organ injuries related to sepsis. HDAC6 is then primarily a protein-modifying enzyme in the cytoplasm, affecting cytoskeleton and signaling by deacetylation (e.g., modulating α -tubulin). In sepsis, HDAC6 promotes inducible nitric oxide synthase expression by activating pathways such as signal transduction and tra