Cornea Alexandra Cătălina, Marc Gabriel, Ionuț Ioana, Moldovan Cristina, Stana Anca, Oniga Smaranda Dafina, Pîrnău Adrian, Vlase Laurian, Oniga Ilioara, Oniga Ovidiu
Department of Pharmaceutical Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, RO-400012 Cluj-Napoca, Romania.
Department of Organic Chemistry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 41 Victor Babeș Street, RO-400012 Cluj-Napoca, Romania.
Molecules. 2025 Mar 17;30(6):1345. doi: 10.3390/molecules30061345.
Reactive oxygen species play a significant role in various pathological conditions, driving the need for novel, potent antioxidants. While polyphenols are known for their antioxidant properties, their limited stability and bioavailability present challenges for therapeutic applications. To address these limitations, a series of novel thiazolyl-polyphenolic compounds was synthesized via a multi-step synthetic route incorporating Hantzsch heterocyclization in the final step. The synthesized compounds - were structurally characterized using spectroscopic techniques, including NMR, MS, and IR. In silico thermodynamic calculations, including HOMO-LUMO gap and bond dissociation enthalpy (BDE) calculations, revealed a promising antioxidant profile for these compounds and indicated that the substitution in position 2 of the thiazole ring does not substantially influence the antioxidant activity conferred by the catechol moiety in position 4. The antioxidant capacity of the synthesized compounds was experimentally validated using a panel of six distinct assays: two radical scavenging assays (ABTS and DPPH) and four electron transfer-based assays (RP, TAC, FRAP, and CUPRAC). The in vitro evaluation demonstrated that compounds and exhibited significantly enhanced antioxidant activity compared to the established antioxidant standards, ascorbic acid and Trolox. These findings suggest that the strategic modifications in position 2 of the thiazole scaffold represent a promising direction for future research aimed at developing novel therapeutic agents with enhanced antioxidant properties. The present study is limited to the in vitro evaluation of compounds based on the N-methyl substituted thiazole scaffold, but future studies can include modifications such as changing the substituent on the thiazole nitrogen, the hydrazone linker or possible insertion of substituents in position 5 of thiazole ring of substituents with various electronic or physico-chemical properties.
活性氧在各种病理状况中发挥着重要作用，这推动了对新型高效抗氧化剂的需求。虽然多酚以其抗氧化特性而闻名，但其有限的稳定性和生物利用度给治疗应用带来了挑战。为了解决这些局限性，通过多步合成路线合成了一系列新型噻唑基多酚化合物，最后一步采用了汉茨希杂环化反应。使用包括核磁共振（NMR）、质谱（MS）和红外光谱（IR）在内的光谱技术对合成的化合物进行了结构表征。包括最高占据分子轨道-最低未占据分子轨道能隙（HOMO-LUMO gap）和键解离焓（BDE）计算在内的计算机热力学计算表明，这些化合物具有良好的抗氧化特性，并且表明噻唑环2位的取代对4位儿茶酚部分赋予的抗氧化活性没有实质性影响。使用一组六种不同的测定方法对合成化合物的抗氧化能力进行了实验验证：两种自由基清除测定法（ABTS和DPPH）和四种基于电子转移的测定法（RP、TAC、FRAP和CUPRAC）。体外评估表明，与已确立的抗氧化剂标准品抗坏血酸和Trolox相比，化合物[具体化合物编号]和[具体化合物编号]表现出显著增强的抗氧化活性。这些发现表明，噻唑支架2位的策略性修饰代表了未来研究的一个有前景的方向，旨在开发具有增强抗氧化特性的新型治疗剂。本研究仅限于对基于N-甲基取代噻唑支架的化合物进行体外评估，但未来的研究可以包括改变噻唑氮上的取代基、腙连接基等修饰，或者可能在噻唑环5位插入具有各种电子或物理化学性质的取代基。
