Comprehensive Structure-activity Relationship Research Articles

Hybrids of 3-Hydroxypyridin-4(1H)-ones and Long-Chain 4-Aminoquinolines as Potent Biofilm Inhibitors of Pseudomonas aeruginosa Potentiate Tobramycin and Polymyxin B Activity.

The biofilm formation of Pseudomonas aeruginosa involves multiple complex regulatory pathways; thus, blocking a single pathway is unlikely to achieve the desired antibiofilm efficacy. Herein, a series of hybrids of 3-hydroxypyridin-4(1H)-ones and long-chain 4-aminoquinolines were synthesized as biofilm inhibitors against P. aeruginosa based on a multipathway antibiofilm strategy. Comprehensive structure-activity relationship studies identified compound 30b as the most valuable antagonist, which significantly inhibited P. aeruginosa biofilm formation (IC50 = 5.8 μM) and various virulence phenotypes. Mechanistic studies revealed that 30b not only targets the three quorum sensing systems but also strongly induces iron deficiency signals in P. aeruginosa. Furthermore, 30b demonstrated a favorable in vitro and in vivo safety profile. Moreover, 30b specifically enhanced the antibacterial activity of tobramycin and polymyxin B in in vitro and in vivo combination therapy. Overall, these results highlight the potential of 30b as a novel anti-infective candidate for treating P. aeruginosa infections.

Structural Optimization of Oxaprozin for Selective Inverse Nurr1 Agonism.

Nuclear receptor related 1 (Nurr1, NR4A2) is a ligand-sensing transcription factor with neuroprotective and anti-inflammatory roles widely distributed in the CNS. Pharmacological Nurr1 modulation is considered a promising experimental strategy in Parkinson's and Alzheimer's disease but target validation is incomplete. While significant progress has been made in Nurr1 agonist development, inverse agonists blocking the receptor's constitutive activity are lacking. Here we report comprehensive structure-activity relationship elucidation of oxaprozin which acts as moderately potent and nonselective inverse Nurr1 agonist and RXR agonist. We identified structural determinants selectively driving RXR agonism or inverse Nurr1 agonism of the scaffold enabling the development of selective inverse Nurr1 agonists with enhanced potency and strong efficacy.

Discovery and Optimization of Tetrahydroisoquinoline Derivatives To Enhance Lysosome Biogenesis as Preclinical Candidates for the Treatment of Alzheimer's Disease.

More than 55 million individuals are suffering from Alzheimer's disease (AD), while the effective therapeutic strategies remain elusive. Our previous study identified a lysosome-enhancing lead compound LH2-051 with a tetrahydroisoquinoline scaffold through a novel dopamine transporter-cyclin-dependent kinase 9-transcription factor EB (DAT-CDK9-TFEB) regulation mechanism to promote TFEB activation and lysosome biogenesis. Here, we launched a comprehensive structure-activity relationship study for LH2-051, and 47 new derivatives were designed and synthesized, in which several compounds exhibited remarkable lysosome-enhancing activities. Notably, compounds 37 and 45 exhibited more favorable TFEB activation and lysosome biogenesis capabilities, good safety profiles, and excellent pharmacokinetic profiles with high brain penetration. Further investigations demonstrated that both compounds significantly enhance the clearance of Aβ aggregates and ameliorate the impairment of learning, memory, and cognition in APP/PS1 mice. Overall, these results indicated that compounds 37 and 45 are promising preclinical drug candidates for the treatment of AD.

Design, synthesis, and biological evaluation of first-in-class FABP1 inhibitors for the treatment of NASH

The fatty acid-binding protein 1 (FABP1) is a fatty acid transporter protein that is considered as an emerging target for metabolic diseases. Despite forceful evidence that the inhibition of FABP1 is essential for ameliorating NASH, pharmacological control and validation of FABP1 are hindered by a lack of relevant inhibitors as pharmacological tool. Therefore, the development of effective FABP1 inhibitors is a current focus of research. Herein, we firstly reported the comprehensive structure-activity relationship (SAR) study of novel FABP1 inhibitors derived from high throughput screening of our in-house library, which resulting in the identification of the optimal compound 44 (IC50 = 4.46 ± 0.54 μM). Molecular docking studies revealed that 44 forms stable hydrogen bonds with amino acids around the active pocket of FABP1. Moreover, 44 alleviated the typical histological features of fatty liver in NASH mice, including steatosis, lobular inflammation, ballooning and fibrosis. Additionally, 44 has been demonstrated to have lipid metabolism regulating, anti-oxidative stress and hepatoprotective properties. This study might be provided a promising insight into the field of NASH and inspiration for the development of FABP1 inhibitors.

Discovery of a Potent, Selective, and Cell-Active SPIN1 Inhibitor.

The methyl-lysine reader protein SPIN1 plays important roles in various human diseases. However, targeting methyl-lysine reader proteins has been challenging. Very few cellularly active SPIN1 inhibitors have been developed. We previously reported that our G9a/GLP inhibitor UNC0638 weakly inhibited SPIN1. Here, we present our comprehensive structure-activity relationship study that led to the discovery of compound 11, a dual SPIN1 and G9a/GLP inhibitor, and compound 18 (MS8535), a SPIN1 selective inhibitor. We solved the cocrystal structure of SPIN1 in complex with 11, confirming that 11 occupied one of the three Tudor domains. Importantly, 18 displayed high selectivity for SPIN1 over 38 epigenetic targets, including G9a/GLP, and concentration dependently disrupted the interactions of SPIN1 and H3 in cells. Furthermore, 18 was bioavailable in mice. We also developed 19 (MS8535N), which was inactive against SPIN1, as a negative control of 18. Collectively, these compounds are useful chemical tools to study biological functions of SPIN1.

Abstract 1809: Discovery of novel AXL and MER inhibitors as potential anticancer and immunomodulatory drugs

Abstract In cancer progression, abnormal AXL expression can promote tumor growth, metastasis, and chemotherapy resistance, while MER can identify apoptotic cancer cells and induce immune suppression in the tumor microenvironment. Combining AXL and MER inhibitors could generate a synergistic effect, enhancing antitumor responses, and further suppressing resistance formed by monotherapy with AXL selective or MER selective inhibitors. According to the explicit function of AXL and MER, the development of dual AXL and MER inhibitors may provide tremendous advantages to cancer patients. Drawing on our experience in the discovery of an anti-EGFR and anti-HER2 clinical candidate, we introduced several AXL-active and MER-active pharmacophores into DBPR112. Furthermore, we modified the scaffold and the solubilizing groups to improve the drug-like properties. Our comprehensive structure-activity relationship study led to the discovery of several potent dual AXL and MER inhibitors. Among approximately 200 synthesized compounds, BPR5K230 demonstrated strong inhibitory activities against AXL and MER, along with favorable oral bioavailability (F% = 55%) and promising in vivo antitumor effects in various mouse xenograft models, including MDA-MB-231, 4T1, and MC-38 tumor models. BPR5K230 effectively addressed sorafenib resistance in the Hepa 1-6 model and exhibited significant synergistic antitumor effects when combined with an anti-PD-L1 antibody in the EMT-6 model. As a result, BPR5K230 represents a promising dual AXL/MER kinase inhibitor, and further preclinical evaluation is underway for its development as a potential anticancer and immune-modulating drug. Citation Format: Hsing-Pang Hsieh, Mu-Chun Li, Wan-Ching Yen, Su-Ying Wu, Teng-Kuang Yeh, Ching-Chuan Kuo, Shau-Hua Ueng, Han-Chung Wu. Discovery of novel AXL and MER inhibitors as potential anticancer and immunomodulatory drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1809.

A novel antimicrobial peptide with broad-spectrum and exceptional stability derived from the natural peptide Brevicidine

The global issue of antibiotic resistance is increasingly severe, highlighting the urgent necessity for the development of new antibiotics. Brevicidine, a natural cyclic lipopeptide, exhibits remarkable antimicrobial activity against Gram-negative bacteria. In this study, a comprehensive structure-activity relationship of Brevicidine was investigated through 20 newly synthesized cyclic lipopeptide analogs, resulting in the identification of an optimal linear analog 22. The sequence of analog 22 consisted of five d-amino acids and four non-natural amino acid 2,5-diaminovaleric acid (Orn) and conjugated with decanoic acid at N-terminal. Compared to Brevicidine, analog 22 was easier to synthesize, and exerted broad spectrum antimicrobial activity and excellent stability (t1/2 = 40.98 h). Additionally, analog 22 demonstrated a rapid bactericidal effect by permeating non-specifically through the bacterial membranes, thereby minimizing the likelihood of inducing resistance. Moreover, it exhibited remarkable efficacy in combating bacterial biofilms and reversing bacterial resistance to conventional antibiotics. Furthermore, it effectively suppressed the growth of bacteria in vital organs of mice infected with S. aureus ATCC 25923. In conclusion, analog 22 may represent a potential antimicrobial peptide for further optimization.

Design, Synthesis, and Biological Evaluation of 5-(5-Iodo-2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine (AF-353) Derivatives as Novel DHFR Inhibitors against Staphylococcus aureus.

The high lethality of Staphylococcus aureus infections and the emergence of antibiotic resistance make the development of new antibiotics urgent. Our previous work identified a hit compound h1 (AF-353) as a novel Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitor. Herein, we analyzed the antimicrobial profile of h1 and performed a comprehensive structure-activity relationship (SAR) assay based on h1. The representative compound j9 exhibited potent antibacterial activity against S. aureus without cross-resistance to other antimicrobial classes. Multiple genetic and biochemical approaches showed that j9 directly binds to SaDHFR, resulting in strong inhibition of its enzymatic activity (IC50 = 0.97 nM). Additionally, j9 had an acceptable in vivo safety profile and oral bioavailability (F = 40.7%) and also showed favorable efficacy in a mouse model of methicillin-resistant S. aureus (MRSA) skin infection. Collectively, these findings identified j9 as a novel SaDHFR inhibitor with the potential to combat drug-resistant S. aureus infections.

Sulfone-based human liver pyruvate kinase inhibitors – Design, synthesis and in vitro bioactivity

Non-alcoholic fatty liver disease (NAFLD) is a prevalent pathological condition characterised by the accumulation of fat in the liver. Almost one-third of the global population is affected by NAFLD, making it a significant health concern. However, despite its prevalence, there is currently no approved drug specifically designed for the treatment of NAFLD. To address this critical gap, researchers have been investigating potential targets for NAFLD drug development. One promising candidate is the liver isoform of pyruvate kinase (PKL). In recent studies, Urolithin C, an allosteric inhibitor of PKL, has emerged as a potential lead compound for therapeutic intervention. Building upon this knowledge, our team has conducted a comprehensive structure-activity relationship of Urolithin C. In this work, we have employed a scaffold-hopping approach, modifying the urolithin structure by replacing the urolithin carbonyl with a sulfone moiety. Our structure-activity relationship analysis has identified the sulfone group as particularly favourable for potent PKL inhibition. Additionally, we have found that the presence of catechol moieties on the two aromatic rings further improves the inhibitory activity. The most promising inhibitor from this new series displayed nanomolar inhibition, boasting an IC50 value of 0.07 μM. This level of potency rivals that of urolithin D and significantly surpasses the effectiveness of urolithin C by an order of magnitude. To better understand the molecular interactions underlying this inhibition, we obtained the crystal structure of one of the inhibitors complexed with PKL. This structural insight served as a valuable reference point, aiding us in the design of inhibitors.

Anti-Inflammatory Flavonoids from Agrimonia pilosa Ledeb: Focusing on Activity-Guided Isolation.

To elucidate the anti-inflammatory properties and constituents of Agrimonia pilosa Ledeb. (A. pilosa), a comprehensive investigation was conducted employing activity-guided isolation. The anti-inflammatory effects were evaluated through an in vitro nitric oxide (NO) assay on lipopolysaccharide (LPS)-treated RAW 264.7 macrophage cells. Seven bio-active compounds with anti-inflammatory properties were successfully isolated from the butanol fraction and identified as follows: quercetin-7-O-β-d-rhamnoside (1), apigenin-7-O-β-d-glucopyranoside (2), kaempferol-7-O-β-d-glucopyranoside (3), quercetin (4), kaempferol (5), apigenin (6), and apigenin-7-O-β-d-glucuronide-6″-butylester (7). All isolated compounds showed strong NO inhibitory activity with IC50 values ranging from 1.4 to 31 µM. Compound 6 demonstrated the most potent NO inhibition. Compound 7, a rare flavonoid, was discerned as a novel anti-inflammatory agent, ascertained through its inaugural demonstration of nitric oxide inhibition. Subsequently, a comprehensive structure-activity relationship (SAR) analysis was conducted employing eight flavonoids derived from A. pilosa. The outcomes elucidated that flavones exhibit superior NO inhibitory effects compared to flavonols, and the aglycone form manifests greater potency in NO inhibition than the glycone counterpart. These results highlight A. pilosa as a promising source of effective anti-inflammatory agents and indicate its potential as a health-beneficial dietary supplement and therapeutic material.

Novel anthraquinone amide derivatives as potential glyoxalase-I inhibitors.

This study aimed to identify novel Glyoxalase-I (Glo-I) inhibitors with potential anticancer properties, focusing on anthraquinone amide-based derivatives. We synthesized a series of these derivatives and conducted in silico docking studies to predict their binding interactions with Glo-I. In vitro assessments were performed to evaluate the anti-Glo-I activity of the synthesized compounds. A comprehensive structure-activity relationship (SAR) analysis identified key features responsible for specific binding affinities of anthraquinone amide-based derivatives to Glo-I. Additionally, a 100 ns molecular dynamics simulation assessed the stability of the most potent compound compared to a co-crystallized ligand. Compound MQ3 demonstrated a remarkable inhibitory effect against Glo-I, with an IC50 concentration of 1.45 µM. The inhibitory potency of MQ3 may be attributed to the catechol ring, amide functional group, and anthraquinone moiety, collectively contributing to a strong binding affinity with Glo-I. Anthraquinone amide-based derivatives exhibit substantial potential as Glo-I inhibitors with prospective anticancer activity. The exceptional inhibitory efficacy of compound MQ3 indicates its potential as an effective anticancer agent. These findings underscore the significance of anthraquinone amide-based derivatives as a novel class of compounds for cancer therapy, supporting further research and advancements in targeting the Glo-I enzyme to combat cancer.

Design, Synthesis and Characterization of Deoxycholic Acid-chalcone Conjugates as Antioxidant Agents

Abstract: The present article reports the synthesis, characterization, and antioxidant activity of the chalcone-deoxycholic acid conjugates. The structures of the synthesised bile acidchalcone conjugates have been determined using 1H and 13C NMR spectroscopy. According to the results of the DPPH experiment, compounds 5e (3, 4, 5-methoxy; IC50; 15.04 μg /ml) and 5f (4-hydroxy group; IC50; 11.73 μg /ml) had higher antioxidant activity than the control compound ascorbic acid (IC50; 20.72 μg /ml). The best conjugate was found to be 5f in the DPPH test (IC50: 11.73 μg /ml; 4-hydroxy group), while the best conjugate in the ABTS assay was found to be 5g (IC50: 67.97 μg /ml; pyridine group). It is straightforward to synthesize a huge library of bile acid-derived compounds and employ them in comprehensive structure-activity relationship investigations to identify the compounds with the best antioxidant activity.

Multifaceted approach toward mapping out the anticancer properties of small molecules via invitro evaluation on melanoma and nonmelanoma skin cancer cells, and in silico target fishing.

Melanoma and nonmelanoma skin cancers are among the most prevalent and most lethal forms of skin cancers. To identify new lead compounds with potential anticancer properties for further optimization, invitro assays combined with in-silico target fishing and docking have been used to identify and further map out the antiproliferative and potential mode of action of molecules from a small library of compounds previously prepared in our laboratory. From screening these compounds invitro against A375, SK-MEL-28, A431, and SCC-12 skin cancer cell lines, 35 displayed antiproliferative activities at the micromolar level, with the majority being primarily potent against the A431 and SCC-12 squamous carcinoma cell lines. The most active compounds 11 (A431: IC50 = 5.0 μM, SCC-12: IC50 = 2.9 μM, SKMEL-28: IC50 = 4.9 μM, A375: IC50 = 6.7 μM) and 13 (A431: IC50 = 5.0 μM, SCC-12: IC50 = 3.3 μM, SKMEL-28: IC50 = 13.8 μM, A375: IC50 = 17.1 μM), significantly and dose-dependently induced apoptosis of SCC-12 and SK-MEL-28 cells, as evidenced by the suppression of Bcl-2 and upregulation of Bax, cleaved caspase-3, caspase-9, and PARP protein expression levels. Both agents significantly reduced scratch wound healing, colony formation, and expression levels of deregulated cancer molecular targets including RSK/Akt/ERK1/2 and S6K1. In silico target prediction and docking studies using the SwissTargetPrediction web-based tool suggested that CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, might be prospective targets for the two most active compounds. Further validation of these targets by western blot analyses, revealed that ROCK/Fyn and its associated Hedgehog (Hh) pathways were downregulated or modulated by the two lead compounds. In aggregate, these results provide a strong framework for further validation of the observed activities and the development of a more comprehensive structure-activity relationship through the preparation and biological evaluation of analogs.

Synthesis and antifungal activity of 2,4-dihydroxy-5-methylphenyl ethanone derivatives against phytopathogenic fungi in vitro

In an endeavor to pinpoint the structural constituents vital for the biological activity of 2,4-dihydroxy-5-methylphenyl ethanone, a series of its ether derivatives was synthesized and examined for their antifungal activities against five notable phytopathogenic fungi. The bioassay revealed that compounds 2, 3a, 3g, 3j and 3k manifested a broad spectrum of antifungal efficacy. Notably, compound 3g was identified as especially potent, with IC50 values ranging from 16.52 to 37.52 μg/mL, outperforming the standard thiabendazole. The data underscore compound 3g as a prospective candidate for the development of an innovative antifungal agent. A comprehensive structure-activity relationship (SAR) study of the acetophenones was also conducted.

A potent and selective cis-amide inhibitor of ryanodine receptor 2 as a candidate for cardiac arrhythmia treatment

Ryanodine receptor 2 (RyR2) is a Ca2+ release channel mainly located on the sarcoplasmic reticulum (SR) membrane of heart muscle cells and regulates the concentration of Ca2+ in the cytosol. RyR2 overactivation causes potentially lethal cardiac arrhythmias, but no specific inhibitor is yet available. Herein we developed the first highly potent and selective RyR2 inhibitor, TMDJ-035, containing 3,5-difluoro substituents on the A ring and a 4-fluoro substituent on the B ring, based on a comprehensive structure-activity relationship (SAR) study of tetrazole compound 1. The SAR study also showed that the amide conformation is critical for inhibitory potency. Single-crystal X-ray diffraction analysis and variable-temperature 1H NMR revealed that TMDJ-035 strongly favors cis-amide configuration, while the inactive analogue TMDJ-011 with a secondary amide takes trans-amide configuration. Examination of the selectivity among RyRs indicated that TMDJ-035 displayed high selectivity for RyR2. TMDJ-035 suppressed abnormal Ca2+ waves and transients in isolated cardiomyocytes from RyR2-mutated mice. It appears to be a promising candidate drug for treating cardiac arrhythmias due to RyR2 overactivation, as well as a tool for studying the mechanism and dynamics of RyR2 channel gating.

Discovery of novel carboxylesterase 2 inhibitors for the treatment of delayed diarrhea and ulcerative colitis

Human carboxylesterase 2 (hCES2) is an enzyme that metabolizes irinotecan to SN-38, a toxic metabolite considered a significant source of side effects (lethal delayed diarrhea). The hCES2 inhibitors could block the hydrolysis of irinotecan in the intestine and thus reduce the exposure of intestinal SN-38, which may alleviate irinotecan-associated diarrhea. However, existing hCES2 inhibitors (except loperamide) are not used in clinical applications due to lack of validity or acceptable safety. Therefore, developing more effective and safer drugs for treating delayed diarrhea is urgently needed. This study identified a lead compound 1 with a novel scaffold by high-throughput screening in our in-house library. After a comprehensive structure–activity relationship study, the optimal compound 24 was discovered as an efficient and highly selective hCES2 inhibitor (hCES2: IC50 = 6.72 μM; hCES1: IC50 > 100 μM). Further enzyme kinetics study indicated that compound 24 is a reversible inhibitor of hCES2 with competitive inhibition mode (Ki = 6.28 μM). The cell experiments showed that compound 24 could reduce the level of hCES2 in living cells (IC50 = 6.54 μM). The modeling study suggested that compound 24 fitted very well with the binding pocket of hCES2 by forming multiple interactions. Notably, compound 24 can effectively treat irinotecan-induced delayed diarrhea and DSS-induced ulcerative colitis, and its safety has also been verified in subtoxic studies. Based on the overall pharmacological and preliminary safety profiles, compound 24 is worthy of further evaluation as a novel agent for irinotecan-induced delayed diarrhea.

A critical review of benzimidazole: Sky-high objectives towards the lead molecule to predict the future in medicinal chemistry

Out of several heterocyclic templates, the use of a Benzimidazole (BZ) scaffold is immensely observed. This fused heterocycle comprises two ring nitrogen atoms placed at 1st and 3rd position, in which the 1st nitrogen is connected to hydrogen that gets released to exhibit the acidic property. The use of BZ for the purpose of making clinically useful compounds was started in the year of 1944. BZ derivatives have been consistently used as effective chemotherapeutic agents to treat a diverse range of disorders. Apart from their clinical usefulness, BZ-based compounds also confer high safety, bio-availability, and stability. Out of several clinical conditions, cancer, and helminthiasis are a few where this template has been maximally utilized. The present review emphasizes chronologically the developments of BZ-based compounds in the entire scope of medicinal chemistry as antibacterial, anticancer, antifungal, anti-inflammatory, anti-HIV (human immunodeficiency virus), anticonvulsant, antioxidant, antidiabetic, antitubercular, antileishmanial, antimalarial, anti-histaminic. This review also covers patents on BZ of clinical importance till 2020. The primary objective of this review is to develop a comprehensive SAR (structure–activity relationship), which in turn assists the medicinal chemist to come up with novel ideas, while being implemented could produce novel compounds with enormous potential.

Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents

Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay.

Structural requirement of RARγ agonism through computational aspects

RARγ is a therapeutic target for many skin diseases and has potential in cancer treatment. In the current study, we put forward a comprehensive structure-activity relationship study of third and fourth generations of RARγ agonists, addressing multiple crystal structures of RARγ complexes and approved drugs. Adapalene and Trifarotene, through hybrid strategies including protein contacts Atlas analysis, molecular docking, dynamics simulations, MM-GBSA, ASM, and pharmacophore modeling. Our result revealed crucial amino acids Arg267, Ser278, Phe288, Phe230, Met272, Leu271, and Leu268 within the RARγ pocket, as well as pharmacophore features such as two hydrophobic groups, two aromatic rings, and negative ionic features, which are essential for the binding of RARγ agonists. Based on this study, the binding mechanism of RARγ agonists was elucidated, which will be helpful for the rational design of new RARγ agonists for skin diseases and cancer treatment. In this study, Schrödinger suite 2021-2 with OPLS_4 force field, Discovery Studio program 3.0, LigandScout 4.3, and PyMOL are utilized in the investigation.

Discovery of Sibiriline derivatives as novel receptor-interacting protein kinase 1 inhibitors

Receptor-interacting protein kinase 1 (RIPK1), a vital protein of the necroptosis pathway, plays a pivotal role in various inflammatory diseases. Sibiriline has been reported to be a potent ATP-competitive RIPK1 inhibitor, but its anti-necroptotic effects are limited. A series of structural analogues of Sibiriline were synthesized and evaluated for their anti-necroptotic activity. Comprehensive structure-activity relationship (SAR) was performed to left azaindole and right substituents of benzene of Sibiriline, respectively. The optimal compound KWCN-41, specifically inhibiting cell necroptosis but not apoptosis, protects cell survival by blocking the necroptotic pathway, which inhibits the phosphorylation of essential proteins of the necroptosis. It also prevented the development of inflammation and reduced the level of inflammatory factors in mice. KWCN-41 is expected to be a lead compound for further studies in inflammatory diseases.