STRUCTURAL STUDIES OF ANALGESICS AND THEIR INTERACTIONS .12. STRUCTURE AND INTERACTIONS OF ANTI-INFLAMMATORY FENAMATES - A CONCERTED CRYSTALLOGRAPHIC AND THEORETICAL CONFORMATIONAL STUDY
STRUCTURAL STUDIES OF ANALGESICS AND THEIR INTERACTIONS .12. STRUCTURE AND INTERACTIONS OF ANTI-INFLAMMATORY FENAMATES - A CONCERTED CRYSTALLOGRAPHIC AND THEORETICAL CONFORMATIONAL STUDY
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DOI：
10.1107/s0108768188001107
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发表时间：
1988-08-01
影响因子：
1.9
通讯作者：
VIJAYAN, M
中科院分区：
文献类型：
--
作者：
DHANARAJ, V;VIJAYAN, M
本文报道了芳基（苯基）基上不同取代基的邻氨基苯甲酸或2-氨基烟酸n -芳基化衍生物的理论构象分析。这些镇痛药被认为是通过抑制前列腺素的生物合成来起作用的，分析使用半经验电位函数进行。结果和现有的晶体学观察已经严格审查了他们的相关性药物作用方面。对这些药物及其配合物的晶体学研究表明，氨基甲酸酯分子具有一个显著的不变特征，即含羧基的六元环与羧基和桥接亚胺基共面，共面性通过共振相互作用和亚胺基与羧基之间的内部氢键来稳定。理论分析的结果为观测到的不变共平面性提供了构象理论依据。第二个六元环在分子的大部分具有疏水性，在甲氧胺酸、甲氧胺酸和氟胺酸中具有有限的构象灵活性。这些酸的构象能图的比较表明，当它们与相关酶结合时，它们都可以呈现相同的构象。本研究提供了尼氟酸活性差异的结构解释，它可以假设整个分子几乎是平面的构象。羧基的主要作用似乎是为分子间相互作用提供一个位点，除了帮助稳定不变的共面特征和在分子的一端提供亲水性。因此，雌胺类提供了构象依赖的分子不对称的一个很好的例子。
A theoretical conformational analysis of fenamates, which are N-arylated derivatives of anthranilic acid or 2-aminonicotinic acid with different substituents on the aryl (phenyl) group, is reported. The analysis of these analgesics, which are believed to act through the inhibition of prostaglandin biosynthesis, was carried out using semi-empirical potential functions. The results and available crystallographic observations have been critically examined in terms of their relevance to drug action. Crystallographic studies of these drugs and their complexes have revealed that the fenamate molecules share a striking invariant feature, namely, the six-membered ring bearing the carboxyl group is coplanar with the carboxyl group and the bridging imino group, the coplanarity being stabilized by resonance interactions and an internal hydrogen bond between the imino and carboxyl groups. The results of the theoretical analysis provide a conformational rationale for the observed invariant coplanarity. The second six-membered ring, which provides hydrophobicity in a substantial part of the molecule, has limited conformational flexibility in meclofenamic, mefenamic and flufenamic acids. Comparison of the conformational energy maps of these acids shows that they could all assume the same conformation when bound to the relevant enzyme. The present study provides a structural explanation for the difference in the activity of niflumic acid, which can assume a conformation in which the whole molecule is nearly planar. The main role of the carboxyl group appears to be to provide a site for intermolecular interactions in addition to helping in stabilizing the invariant coplanar feature and providing hydrophilicity at one end of the molecule. The fenamates thus provide a good example of conformation-dependent molecular asymmetry.