Scholarlink

Abstract <p>A series of (E)<i>-N-</i>(1-(cyclohexylamino)-3-methyl-1-oxopent-3-en-2-yl)-6-fluoro<i>-N-</i>phenyl chromane-2-carboxamide derivatives were synthesized using the Ugi multicomponent reaction. The reaction sequence involved the formation of imine intermediates from anilines and an aldehyde, followed by protonation using 6-fluorochromane-2-carboxylic acid and subsequent reaction with an isocyanide, generating nitrilium intermediates. These underwent nucleophilic attack by a carbonate anion, leading to <i>O</i>-imine intermediates, which further proceeded through a Mumm rearrangement to yield the final compounds. Optimization studies identified methanol as the most effective solvent, achieving a 62–78% yield in 24 h target carboxoamides, compared to lower yields and longer reaction times with ethanol, dichloromethane, toluene, and dimethylformamide. Physicochemical properties of the derivatives were evaluated using principal component analysis (PCA) and radar charts, revealing consistent drug-likeness across the series, with variations in lipophilicity (LIPO) and polarity (POLAR) influencing their pharmacokinetic profiles. ADME studies further assessed their drug-likeness, showing moderate permeability and solubility (TPSA = 58.64–104.46), varying lipophilicity (log<i>P =</i> 4.32–6.72), and low aqueous solubility (negative ESOL log<i>S</i> values). Most compounds exhibited high gastrointestinal absorption but limited blood–brain barrier permeability, with P-glycoprotein interactions and CYP2D6/CYP3A4 inhibition indicating potential metabolic challenges. Lipinski violations (0–2) and synthetic accessibility scores (4.61–4.90) suggest moderate drug development feasibility. These findings highlight the potential of the derivatives as therapeutic candidates, with 2-fluorophenyl substituted carboxoamide showing a balanced physicochemical profile for further optimization<i>.</i></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Synthesis, Physicochemical Profiling, and ADME Analysis of (E)-N-(1-(Cyclohexylamino)-3-methyl-1-oxopent-3-en-2-yl)-6-fluoro-N-phenylchromane-2-carboxamide Derivatives

  • 期刊论文

  • 发表日期：

    2025年6月1日

查看全文
  • Jyoti Gohel,
  • Dharmesh Katariya,
  • Amita Vyas,
  • Ranjan Khunt

摘要

Abstract

A series of (E)-N-(1-(cyclohexylamino)-3-methyl-1-oxopent-3-en-2-yl)-6-fluoro-N-phenyl chromane-2-carboxamide derivatives were synthesized using the Ugi multicomponent reaction. The reaction sequence involved the formation of imine intermediates from anilines and an aldehyde, followed by protonation using 6-fluorochromane-2-carboxylic acid and subsequent reaction with an isocyanide, generating nitrilium intermediates. These underwent nucleophilic attack by a carbonate anion, leading to O-imine intermediates, which further proceeded through a Mumm rearrangement to yield the final compounds. Optimization studies identified methanol as the most effective solvent, achieving a 62–78% yield in 24 h target carboxoamides, compared to lower yields and longer reaction times with ethanol, dichloromethane, toluene, and dimethylformamide. Physicochemical properties of the derivatives were evaluated using principal component analysis (PCA) and radar charts, revealing consistent drug-likeness across the series, with variations in lipophilicity (LIPO) and polarity (POLAR) influencing their pharmacokinetic profiles. ADME studies further assessed their drug-likeness, showing moderate permeability and solubility (TPSA = 58.64–104.46), varying lipophilicity (logP = 4.32–6.72), and low aqueous solubility (negative ESOL logS values). Most compounds exhibited high gastrointestinal absorption but limited blood–brain barrier permeability, with P-glycoprotein interactions and CYP2D6/CYP3A4 inhibition indicating potential metabolic challenges. Lipinski violations (0–2) and synthetic accessibility scores (4.61–4.90) suggest moderate drug development feasibility. These findings highlight the potential of the derivatives as therapeutic candidates, with 2-fluorophenyl substituted carboxoamide showing a balanced physicochemical profile for further optimization.