Synthesis, biological evaluation and molecular modeling studies of novel 1,2,3-triazole-linked menadione-furan derivatives as P2X7 inhibitors

Santos, Juliana P S Dos; Ribeiro, Ruan Stevan de Almeida; Faria, Juliana Vieira; Bello, Murilo Lamim; Lima, Carolina G. S.; Pauli, Fernanda P.; Borges, Amanda A; Rocha, David R. da; Moraes, Matheus G. de; Forezi, Luana da S. M.; Ferreira, Vı́tor F.; Faria, Robson Xavier; Silva, Fernando de Carvalho da

doi:10.1007/s10863-022-09947-2

Cited by 8 publications

(4 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In medicinal chemistry, the biological potency of a lead molecule changes with modifications to the pharmacophoric moieties. The versatility of quinone chemistry in drug development is extensive (Borba‐Santos et al, 2022; Di Marco et al, 2021; Dos Santos et al, 2022; Mahalapbutr et al, 2022). Our recent studies have demonstrated the in vitro and in silico anticancer activities of brominated PQ analogs against MCF7 breast cancer cells via cell cycle arrest and oxidative stress induction (Jannuzzi et al, 2022).…”

Section: Resultsmentioning

confidence: 99%

“…1,4‐Quinone moiety has occupied a unique role in the design and discovery of biologically active molecules with remarkable medicinal activity (Borba‐Santos et al, 2022; Dahlem Junior et al, 2022; Dos Santos et al, 2022; Mahalapbutr et al, 2022; Wellington, 2015). 1,4‐Quinone moiety is an attractive building block for pharmaceutical research because it is present in the structures of versatile potent drugs (Basset et al, 2017; Gupta et al, 2021; Okeke et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Cytotoxic activity of quinolinequinones in cancer: In vitro studies, molecular docking, and ADME/PK profiling

et al. 2023

View full text Add to dashboard Cite

Lead molecules containing 1,4‐quinone moiety are intriguing novel compounds that can be utilized to treat cancer owing to their antiproliferative activities. Nine previously reported quinolinequinones (AQQ1‐9) were studied to better understand their inhibitory profile to produce potent and possibly safe lead molecules. The National Cancer Institute (NCI) of Bethesda chose all quinolinequinones (AQQ1‐9) based on the NCI Developmental Therapeutics Program and tested them against a panel of 60 cancer cell lines. At a single dose and five further doses, AQQ7 significantly inhibited the proliferation of all leukemia cell lines and some breast cancer cell lines. We investigated the in vitro cytotoxic activities of the most promising compounds, AQQ2 and AQQ7, in MCF7 and T‐47D breast cancer cells, DU‐145 prostate cancer cells, HCT‐116 and COLO 205 colon cancer cell lines, and HaCaT human keratinocytes using the MTT assay. AQQ7 showed particularly high cytotoxicity against MCF7 cells. Further analysis showed that AQQ7 exhibits anticancer activity through the induction of apoptosis without causing cell cycle arrest or oxidative stress. Molecular docking simulations for AQQ2 and AQQ7 were conducted against the COX, PTEN, and EGFR proteins, which are commonly overexpressed in breast, cervical, and prostate cancers. The in vitro ADME and in vivo PK profiling of these compounds have also been reported.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Cytotoxic activity of quinolinequinones in cancer: In vitro studies, molecular docking, and ADME/PK profiling

et al. 2023

View full text Add to dashboard Cite

show abstract

“…In recent years, our research group has focused on the identification of novel and more selective chemotypes of P2X7 receptor inhibitors. In particular, we reported several natural and synthetic compounds with potent antagonist activity toward P2X7R and ATP-induced inflammatory responses [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Recently, we reported the synthesis and biological evaluation of a group of naphthoquinones sulfonamide and sulfonate ester derivatives against Chikungunya virus (CHIKV).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation and Molecular Modeling Studies of Naphthoquinone Sulfonamides and Sulfonate Ester Derivatives as P2X7 Inhibitors

et al. 2023

View full text Add to dashboard Cite

ATP acts in the extracellular environment as an important signal, activating a family of receptors called purinergic receptors. In recent years, interest in the potential therapeutics of purinergic components, including agonists and antagonists of receptors, has increased. Currently, many observations have indicated that ATP acts as an important mediator of inflammatory responses and, when found in high concentrations in the extracellular space, is related to the activation of the P2X7 purinergic receptor. In this sense, the search for new inhibitors for this receptor has attracted a great deal of attention in recent years. Sulfonamide derivatives have been reported to be potent inhibitors of P2X receptors. In this study, ten naphthoquinone sulfonamide derivatives and five naphthoquinone sulfonate ester derivatives were tested for their inhibitory activity on the P2X7 receptor expressed in peritoneal macrophages. Some compounds showed promising results, displaying IC50 values lower than that of A740003. Molecular docking and dynamic studies also indicated that the active compounds bind to an allosteric site on P2X7R. The binding free energy indicates that sulfonamides have an affinity for the P2X7 receptor similar to A740003. Therefore, the compounds studied herein present potential P2X7R inhibition.

show abstract

“…In this study, we designed a series of amide-based 1,2,3-triazole derivatives as potential P2X7R antagonists by linking the amide group with halopyridine via a triazole linker. Our initial design rationale stemmed from the widespread application of triazole as a pharmacophore in P2X7R antagonists design − (compounds 1 – 4 in Figure ). Moreover, the benzamidomethyl scaffold, initially reported by AstraZeneca in the 2000s, is widely employed among P2X7R antagonists , (compounds 5 – 8 in Figure ), and the amide structure within this scaffold plays a crucial role as a key linker for preserving the compound’s activity.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury

Zhang,

Su,

Yang

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

Sepsis-associated acute kidney injury (AKI) is a serious clinical problem, without effective drugs. Abnormal activation of the purinergic P2X7 receptor (P2X7R) in septic kidneys makes its antagonist a promising therapeutic approach. Herein, a series of novel P2X7R antagonists were designed, synthesized, and structurally optimized. Based on in vitro potency in human/mouse P2X7R using HEK293 cells, hepatic microsomal stability, and pharmacokinetic and preliminary in vivo assessments, compound 14a was identified by respective human and mouse P2X7R IC 50 values of 64.7 and 10.1 nM, together with favorable pharmacokinetic properties. Importantly, 14a dose-dependently alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)-and cecal ligation/perforation (CLP)-induced septic AKI mice with a good safety profile. Mechanistically, 14a could suppress NLRP3 inflammasome activation to inhibit the expression of cleaved caspase-1, gasdermin D, IL-1β, and IL-18 in the injured kidneys of septic mice. Collectively, these results highlighted that P2X7R antagonist 14a exerted a therapeutic potential against septic AKI.

show abstract

Synthesis, biological evaluation and molecular modeling studies of novel 1,2,3-triazole-linked menadione-furan derivatives as P2X7 inhibitors

Cited by 8 publications

References 74 publications

Cytotoxic activity of quinolinequinones in cancer: In vitro studies, molecular docking, and ADME/PK profiling

Cytotoxic activity of quinolinequinones in cancer: In vitro studies, molecular docking, and ADME/PK profiling

Synthesis, Biological Evaluation and Molecular Modeling Studies of Naphthoquinone Sulfonamides and Sulfonate Ester Derivatives as P2X7 Inhibitors

Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury

Contact Info

Product

Resources

About