N-[4-[2,3-Dihydro-1-(2-methylbenzoyl)-1H-indol-5-yl]-5-methyl-2-thiazolyl]-1,3-benzodioxole-5-acetamide
[CAS# 846557-71-9]

Identification

• Classification: Organic raw materials >> Amino compound >> Amide compound
• Name: N-[4-[2,3-Dihydro-1-(2-methylbenzoyl)-1H-indol-5-yl]-5-methyl-2-thiazolyl]-1,3-benzodioxole-5-acetamide
• Synonyms: 2-(Benzo[d][1,3]dioxol-5-yl)-N-(5-methyl-4-(1-(2-methylbenzoyl)indolin-5-yl)thiazol-2-yl)acetamide
• Molecular Formula: C₂₉H₂₅N₃O₄S
• Molecular Weight: 511.59
• CAS Registry Number: 846557-71-9
• SMILES: CC1=CC=CC=C1C(=O)N2CCC3=C2C=CC(=C3)C4=C(SC(=N4)NC(=O)CC5=CC6=C(C=C5)OCO6)C

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Solubility: Soluble 50 mM in DMSO (Expl.)
• Index of refraction: 1.693 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P305+P351+P338

Discovery and Applications

N-[4-[2,3-Dihydro-1-(2-methylbenzoyl)-1H-indol-5-yl]-5-methyl-2-thiazolyl]-1,3-benzodioxole-5-acetamide is a synthetic compound known for its biological activity as a selective inhibitor of cyclooxygenase-2 (COX-2), an enzyme involved in the inflammatory response. This compound belongs to a class of nonsteroidal anti-inflammatory drugs (NSAIDs) designed to reduce pain and inflammation by specifically targeting the COX-2 isoform, while sparing COX-1, which plays a key role in protecting the gastrointestinal lining and maintaining renal function.

The compound was developed as part of the medicinal chemistry efforts to identify new COX-2 inhibitors with improved safety profiles compared to traditional NSAIDs. Traditional NSAIDs often inhibit both COX-1 and COX-2 enzymes, leading to gastrointestinal side effects such as ulcers and bleeding. By selectively inhibiting COX-2, compounds such as N-[4-[2,3-dihydro-1-(2-methylbenzoyl)-1H-indol-5-yl]-5-methyl-2-thiazolyl]-1,3-benzodioxole-5-acetamide aim to provide anti-inflammatory and analgesic effects while minimizing adverse effects on the gastrointestinal tract.

The discovery of this compound involved structure-activity relationship (SAR) studies, which allowed researchers to optimize molecular features necessary for COX-2 selectivity and potency. The indole core, methylbenzoyl group, and thiazolyl ring contribute to binding affinity and selectivity through interactions with specific residues in the COX-2 active site. The benzodioxole-acetamide moiety enhances pharmacokinetic properties and contributes to overall molecular stability.

In preclinical studies, the compound demonstrated strong inhibition of prostaglandin synthesis mediated by COX-2 without significantly affecting COX-1 activity. This selective inhibition has been associated with anti-inflammatory, analgesic, and antipyretic effects in animal models. Additionally, its favorable pharmacodynamic and pharmacokinetic properties made it a candidate for further investigation as a therapeutic agent.

Although it shows promising biological activity, development of such selective COX-2 inhibitors has been accompanied by safety assessments due to concerns over cardiovascular risks. Several COX-2 selective inhibitors have been associated with an increased risk of heart attack and stroke when used chronically or at high doses. As a result, regulatory agencies closely evaluate such compounds to determine acceptable risk-benefit ratios for therapeutic use.

In pharmaceutical research, N-[4-[2,3-dihydro-1-(2-methylbenzoyl)-1H-indol-5-yl]-5-methyl-2-thiazolyl]-1,3-benzodioxole-5-acetamide is used as a reference compound for studying the COX-2 inhibition mechanism and for the design of newer anti-inflammatory agents. It serves as a lead compound for further chemical modifications aimed at improving efficacy, selectivity, and safety.

Beyond inflammation, COX-2 inhibitors are being investigated for potential roles in cancer chemoprevention, neurodegenerative disease modulation, and other chronic conditions where COX-2 is upregulated. However, such applications require comprehensive evaluation through clinical studies to confirm long-term safety and effectiveness.

In summary, N-[4-[2,3-dihydro-1-(2-methylbenzoyl)-1H-indol-5-yl]-5-methyl-2-thiazolyl]-1,3-benzodioxole-5-acetamide is a synthetically derived COX-2 selective inhibitor with well-established anti-inflammatory properties. It exemplifies the targeted drug design strategies used in modern medicinal chemistry and contributes to the ongoing development of safer and more effective anti-inflammatory therapeutics.

References

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DOI: 10.1021/acschembio.6b00651

2023. Synergistic Effects of Tranylcypromine and NRF2 Inhibitor: A Repurposing Strategy for Effective Cancer Therapy. ChemMedChem, 18(22).
DOI: 10.1002/cmdc.202300282

2024. The Effects of ML385 on Head and Neck Squamous Cell Carcinoma: Implications for NRF2 Inhibition as a Therapeutic Strategy. International Journal of Molecular Sciences, 25(13).
DOI: 10.3390/ijms25137011