Scaffold Hybrid of the Natural Product Tanshinone I with Piperidine for the Discovery of a Potent NLRP3 Inflammasome Inhibitor

Abstract

Natural products provide inspiration and have proven to be the most valuable source for drug discovery. Herein, we report a scaffold hybrid strategy of Tanshinone I for the discovery of NLRP3 inflammasome inhibitors. 36 compounds were designed and synthesized, and the cheminformatic analyses showed that these compounds occupy a unique chemical space. The biological evaluation identified compounds 5j, 12a, and 12d as NLRP3 inflammasome inhibitors with significant potency, selectivity, and drug-likeness. Mechanistic studies revealed that these Tanshinone I derivatives could inhibit the degradation of the protein NLRP3 and block the oligomerization of NLRP3-induced apoptosis-associated speck-like proteins, thus inhibiting NLRP3 inflammasome activation. In addition, the water solubility, in vitro metabolic stability, and oral bioavailability of these compounds were also greatly improved compared to Tanshinone I. Therefore, this protocol provides a new structural evolution of Tanshinone I and a new class of potent NLRP3 inflammasome inhibitors.

Hit-to-Lead Optimization of the Natural Product Oridonin as Novel NLRP3 Inflammasome Inhibitors with Potent Anti-Inflammation Activity

“…7, 151.7, 130.5, 124.8, 120.8, 101.4, 77.4, 71.7, 68.6, 65.3, 62.8, 58.3, 57.6, 52.4, 42.5, 41.1, 38.4, 37.2, 35.3, 33.3, 32.4, 30.8 4.6.9. 3-(((4aR,5S,6S,9S,11aS,11bR)-5,14-Dihydroxy-4,4-dimethyl-8-methylene-7-oxo -3,4,4a,5,7,8,9,10,11,11a-decahydro-6H-6,11b-(epoxymethano)-6a,9-methanocyclohepta [a]naphthalen-6yl)oxy)-N,N-dipropylpropanamide (41). White solid, yield 78%, HPLC purity: 97.4%; 1 13 C NMR (101 MHz, CDCl 3 ) δ 206.…”

“…Among these analogues, compound 1 with sulfonamide, significantly suppressed the activation of NLRP3 inflammation in the dextran sulfate sodium (DSS)-induced colitis mouse model. 39 Additionally, compounds with varied scaffolds, including NIC-0102, 40 the tanshinone I derivative, 41 and OLT1177, 27 have been characterized as NLRP3 inflammasome inhibitors in distinct in vitro models. However, with the exception of sulfonylurea-containing compounds, the inhibitory activity of majority of NLRP3 inflammasome inhibitors was at the micromolar or submicromolar level, and thus, it is imperative to develop more effective compounds bearing unique scaffolds for enriching NLRP3 inflammasome inhibitors.…”

Recent Advances in the Green Synthesis of Active N-Heterocycles and Their Biological Activities

“…Various natural-product-derived N-heterocyclic FDA-approved drugs are available on the market. Some are under phase III clinical trial whereas several others have shown promising bioactivity to take is forward in the process of drug discovery [32][33][34]. A few such natural-product-derived N-heterocyclic compounds are displayed in Figure 1, whereas the synthetically prepared drug molecules Pharmaceuticals 2023, 16, 873 2 of 34 are represented in Figure 2.…”

Discovery of Triazinone Derivatives as Novel, Specific, and Direct NLRP3 Inflammasome Inhibitors for the Treatment of DSS-Induced Ulcerative Colitis

“…24 Among them, ZYIL-1 revealed rapid clinical improvement in CAPS patients with confirmed NLRP3 mutation during a Phase II proof-of-concept trial for CAPS-related flare-up (NCT05186051). 25 Additionally, there are several reported NLRP3 inhibitors in the literature, including INF39 (6), 26 Itaconate (7), 27 Oridonin (8), 28 Tanshinone I derivatives (9), 29 CY-09 (10), 30 Tranilast (11), 31 compounds 12, 32 13, 33 as well as YQ128 (14). 34 Oridonin blocked NLRP3 inflammasome activation by forming a covalent bond with cysteine 279 of the NLRP3-NACHT domain.…”