Design and synthesis of anti–inflammatory 1,2,3–triazolylpyrrolobenzodiazepinone derivatives and impact of molecular structure on COX–2 selective targeting

Kumar, Amit; Alam, Mohammad Sarwar; Hamid, Hinna; Chugh, Vaishali; Tikla, Tanvi; Kaul, Rajeev; Dhulap, Abhijeet; Sharma, Sunil K.

doi:10.1016/j.molstruc.2022.134151

Cited by 10 publications

(4 citation statements)

References 37 publications

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“…COX-2, a key enzyme that catalyzes the rate-limiting steps in the conversion of arachidonic acid to prostaglandins, plays a pivotal role in the inflammatory process. 140 Therapeutic utilization of selective COX-2 inhibitors has been considered an effective approach for treating inflammation with emasculated side effects. Notably, (−)-dispirocochlearoid B ( 131 ) was a more potent selective inhibitor against COX-2 (IC 50 : 386 nM) than other analogues.…”

Section: Pharmacological Activity Of Gmsmentioning

confidence: 99%

Structural diversity, hypothetical biosynthesis, chemical synthesis, and biological activity ofGanodermameroterpenoids

et al. 2023

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Section: Pharmacological Activity Of Gmsmentioning

confidence: 99%

Structural diversity, hypothetical biosynthesis, chemical synthesis, and biological activity ofGanodermameroterpenoids

et al. 2023

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“…Among these, 1,4-benzodiazepinone, which is a seven-membered lactam, presents a structural framework frequently observed in numerous natural substances. Derivatives of this compound can exhibit a wide range of biological activities and valuable pharmaceutical characteristics, indicating their promise as potential candidates for drug discovery ( Figure 1 ) [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Currently, this seven-membered structural framework is prevalent in numerous drug molecules with distinct bioactivities.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective [4+3]-Cycloaddition of 2-Amino-β-nitrostyrenes with Azaoxyallyl Cations to Access Functionalized 1,4-Benzodiazepin-3-ones

Kim,

Kim

2024

Molecules

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The 1,4-benzodiazepine structural framework is a fascinating element commonly found in biologically active and pharmaceutically relevant compounds. A highly efficient method for synthesizing 1,4-benzodiazepin-3-ones is described, involving a [4+3]-cycloaddition reaction between 2-amino-β-nitrostyrenes and α-bromohydroxamate, with Cs2CO3 used as a base. This process yielded the desired 1,4-benzodiazepines in good yields. Furthermore, an organocatalytic asymmetric [4+3]-cycloaddition was successfully accomplished using a bifunctional squaramide-based catalyst. This approach enabled the enantioselective synthesis of chiral 1,4-benzodiazepines with commendable yields and moderate enantioselectivities, reaching up to 80% yield and 72% ee.

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“…Thus, the critical role of iNOS and COX-2 enzymes and cytokines in the initiation and progression of inflammation is evident. Therefore, drugs capable of modulating these targets and associated with a low toxicity profile are essential as potential pharmacological agents for new anti-inflammatory therapies [14,15]. In this context, acylhydrazone derivatives stand out as a class of synthetic chemical structures with diverse bioactivity, among which the N-acylhydrazone function has shown relevant anti-inflammatory and analgesic responses [14].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Activity of N′-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide Derivative via sGC-NO/Cytokine Pathway

da Silva,

Apolinário,

Silva

et al. 2023

Pharmaceuticals

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The N-acylhydrazone function has been reported as a pharmacophore group of molecules with diverse pharmacological activities, including anti-inflammatory effects. Therefore, this study was designed to evaluate the anti-inflammatory potential of the compound N′-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide (JR19) in vivo. The study started with the carrageenan-induced peritonitis model, followed by an investigation of leukocyte migration using the subcutaneous air pouch test and an assessment of the antinociceptive profile using formalin-induced pain. A preliminary molecular docking study focusing on the crystallographic structures of NFκB, iNOS, and sGC was performed to determine the likely mechanism of action. The computational study revealed satisfactory interaction energies with the selected targets, and the same peritonitis model was used to validate the involvement of the nitric oxide pathway and cytokine expression in the peritoneal exudate of mice pretreated with L-NAME or methylene blue. In the peritonitis assay, JR19 (10 and 20 mg/kg) reduced leukocyte migration by 59% and 52%, respectively, compared to the vehicle group, with the 10 mg/kg dose used in subsequent assays. In the subcutaneous air pouch assay, the reduction in cell migration was 66%, and the response to intraplantar formalin was reduced by 39%, particularly during the inflammatory phase, suggesting that the compound lacks central analgesic activity. In addition, a reversal of the anti-inflammatory effect was observed in mice pretreated with L-NAME or methylene blue, indicating the involvement of iNOS and sGC in the anti-inflammatory response of JR19. The compound effectively and significantly decreased the levels of IL-6, TNF-α, IL-17, and IFN-γ, and this effect was reversed in animals pretreated with L-NAME, supporting a NO-dependent anti-inflammatory effect. In contrast, pretreatment with methylene blue only reversed the reduction in TNF-α levels. Therefore, these results demonstrate the pharmacological potential of the novel N-acylhydrazone derivative, which acts through the nitric oxide pathway and cytokine signaling, making it a strong candidate as an anti-inflammatory and immunomodulatory agent.

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Design and synthesis of anti–inflammatory 1,2,3–triazolylpyrrolobenzodiazepinone derivatives and impact of molecular structure on COX–2 selective targeting

Cited by 10 publications

References 37 publications

Structural diversity, hypothetical biosynthesis, chemical synthesis, and biological activity ofGanodermameroterpenoids

Structural diversity, hypothetical biosynthesis, chemical synthesis, and biological activity ofGanodermameroterpenoids

Stereoselective [4+3]-Cycloaddition of 2-Amino-β-nitrostyrenes with Azaoxyallyl Cations to Access Functionalized 1,4-Benzodiazepin-3-ones

Anti-Inflammatory Activity of N′-(3-(1H-indol-3-yl)benzylidene)-2-cyanoacetohydrazide Derivative via sGC-NO/Cytokine Pathway

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