Cucurbituril-resisted acylation of the anti-tuberculosis drug isoniazidvia a supramolecular strategy

Abstract

A chemical investigation reveals that the resistance to acylation of an anti-tuberculosis drug, isoniazid is a consequent result of the inclusion or exclusion of cucurbit[n]urils (n = 6 or 7). The (1)H NMR spectra analysis shows that the different interaction models of the isoniazid with the two cucurbiturils are dependent on the cavity size of the hosts. Quantum chemistry calculations with density functional theory method indicate that the interaction of the isoniazid with both cucurbiturils is through thermodynamic stabilization in both the gas phase and aqueous solution through hydrogen bonding on the portal carbonyls of the cucurbiturils. Electronic absorption titration spectra suggest the hosts and guest interact in a ratio of 1 : 1 with moderate binding constants. Acylation kinetics of isoniazid with various acylating agents in the presence of the cucurbiturils revealed that resistance is only dependent on the host-isoniazid ratio, and independent on the size of the cucurbiturils and the species of acylating agents.

Cucurbit[7]uril: an emerging candidate for pharmaceutical excipients

“…Similarly, in another of our recent studies, the host–guest complex of CB[7] and the antituberculosis drug CFZ retained the drug's antimycobacterial activity in vitro to Mycobacterium smegmatis . On the other hand, tuberculosis patients who are fast acetylators usually have resistance to the antituberculosis drug isoniazid (INH) owing to the fact that N ‐acetylation of INH deactivates this drug . However, CB[7] stabilized INH by slowing down N ‐acetylation, with the initial reaction rate decreased by a factor of 10 –2 in the presence of 0.8 equivalents of CB[7], thus potentially maintaining the efficacy of this drug in patients with the fast‐acetylator phenotype and mitigating drug resistance .…”

“…On the other hand, tuberculosis patients who are fast acetylators usually have resistance to the antituberculosis drug isoniazid (INH) owing to the fact that N ‐acetylation of INH deactivates this drug . However, CB[7] stabilized INH by slowing down N ‐acetylation, with the initial reaction rate decreased by a factor of 10 –2 in the presence of 0.8 equivalents of CB[7], thus potentially maintaining the efficacy of this drug in patients with the fast‐acetylator phenotype and mitigating drug resistance . Most recently, we showed that the anticancer agent nitidine chloride (NC) formed a 1:1 complex with CB[7], and this complex enhanced the therapeutic efficacy of NC to breast cancer cell line MCF‐7 more than twofold (IC 50 was decreased from 7.28 ± 0.36 to 2.94 ± 0.15 μM) .…”

Supramolecular catalysis of esterification by hemicucurbiturils under mild conditions

“…Q[6]-catalytic 1,3-dipole addition has contributed to the synthesis of a few pseudo-polyrotaxanes with a Q [6] block [14]. Photochemical dimerization of olefins and coumarins via stereoselective catalysis by Q [8] has also been developed [15,16]. Other organic reactions catalyzed via encapsulation include Knoevenagel condensation of benzaldehyde with diethyl malonate in ionic liquids [17] and IBX oxidation of alcohols in aqueous solution [18,19].…”

Supramolecular Catalysis of Cucurbit[8]uril on Photocycloaddition of 1,ω-Bi(2-aminopyridinium)alkylates

“…Subsequently, the photocycloaddition reactions of the substrates have been carried out in the presence of Q [8], and the dependence of the supramolecular catalytic active on the construction of substrate was observed. Keywords 1,ω-bi(2-aminopyridinium)alkylates; cucurbituril; photocycloaddition; host-guest interaction; supramolecular catalysis [6,7] ; 利用瓜环与药物分子的包结, 可对多种药 物的降解代谢进行稳定, 减小其毒性 [8,9] ; 利用瓜环与金 属离子的配位化合物, 可设计、 构建新型的金属-有机框 架材料(MOF) [10,11] ; 而瓜环的超分子催化作用是瓜环化 合物发现以来, 最早研究的性质之一 [12] . 在近三十年的 瓜环化学发展过程中, 瓜环催化始终是重要的研究内 容 [13] .…”

“…Keywords 1,ω-bi(2-aminopyridinium)alkylates; cucurbituril; photocycloaddition; host-guest interaction; supramolecular catalysis [6,7] ; 利用瓜环与药物分子的包结, 可对多种药 物的降解代谢进行稳定, 减小其毒性 [8,9] ; 利用瓜环与金 属离子的配位化合物, 可设计、 构建新型的金属-有机框 架材料(MOF) [10,11] ; 而瓜环的超分子催化作用是瓜环化 合物发现以来, 最早研究的性质之一 [12] . 在近三十年的 瓜环化学发展过程中, 瓜环催化始终是重要的研究内 容 [13] . [19,20] , 通过瓜环与底物的主客体相互作用,…”