Nguyen Le Thanh Hang, Vu Dinh Hoang, Pham Minh Quan, Ngo Quoc Anh, Vo Ngoc Binh
School of Chemistry and Life Sciences, Hanoi University of Science and Technology 1 Dai Co Viet Street Hanoi Vietnam.
Institute of Natural Products Chemistry (INPC), Vietnam Academy of Science and Technology (VAST) Hanoi Vietnam.
RSC Adv. 2025 Jan 28;15(4):2850-2861. doi: 10.1039/d4ra09094b. eCollection 2025 Jan 23.
In this paper, a series of novel quinazoline-4(3)-one-2-carbothioamide derivatives (8a-p) were designed and synthesized the Wilgerodt-Kindler reaction between 2-methylquinazoline-4-one 10 and amines using S/DMSO as the oxidizing system. Their characteristics were confirmed by IR, NMR, HRMS spectra, and their melting point. These novel derivatives (8a-p) were evaluated for their anti-inflammatory activity by inhibiting NO production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophage cells. Compounds 8d (IC = 2.99 μM), 8g (IC = 3.27 μM), and 8k (IC = 1.12 μM) exhibited potent inhibition of NO production compared to the standard drug dexamethasone (IC = 14.20 μM). Compound 8a (IC = 13.44 μM) exhibited NO inhibition comparable to dexamethasone. Structure-activity relationship (SAR) studies indicated that the presence of both the thioamide functional group (NH-C[double bond, length as m-dash]S) directly attached to the phenyl ring containing halogen substituents (4-Cl, 8d), (4-Br, 8g) and (4-CF, 8k), is responsible for the potent anti-inflammatory activity of these novel quinazolinone derivatives. Computational modeling studies revealed that compounds 8d, 8g, and 8k are potent inhibitors of TLR4 signaling through the formation of hydrophobic interactions and are stabilized by hydrogen bonds. Replacing the thioamide (8k) with an amide (8q) resulted in an 83-fold decrease in NO inhibitory potency. This highlights the important role of H-bonding involving the thioamide group. The structural shape difference results in favorable interactions of quinazolinones containing thioamide linkers compared to amide linkers to the target receptor. Furthermore, the ADMET profiles and physicochemical properties of these three lead compounds were predicted to meet the criteria for drug-like properties. Therefore, these compounds may be potential candidates for the treatment of many inflammatory diseases associated with immune disorders.
在本文中，设计并合成了一系列新型喹唑啉-4(3)-酮-2-碳硫酰胺衍生物(8a - p)，该反应通过使用S/DMSO作为氧化体系，使2-甲基喹唑啉-4-酮10与胺类发生威尔格罗德特-金德勒反应。通过红外光谱(IR)、核磁共振(NMR)、高分辨质谱(HRMS)光谱及其熔点对其结构特征进行了确证。通过抑制脂多糖(LPS)激活的RAW 264.7巨噬细胞中一氧化氮(NO)的产生，对这些新型衍生物(8a - p)的抗炎活性进行了评估。与标准药物地塞米松(IC = 14.20 μM)相比，化合物8d(IC = 2.99 μM)、8g(IC = 3.27 μM)和8k(IC = 1.12 μM)对NO的产生表现出强效抑制作用。化合物8a(IC = 13.44 μM)对NO的抑制作用与地塞米松相当。构效关系(SAR)研究表明，直接连接到含有卤素取代基(4-氯，8d)、(4-溴，8g)和(4-三氟甲基，8k)的苯环上的硫代酰胺官能团(NH-C=S)的存在，是这些新型喹唑啉酮衍生物具有强效抗炎活性的原因。计算模型研究表明，化合物8d、8g和8k通过形成疏水相互作用是Toll样受体4(TLR4)信号通路的强效抑制剂，并通过氢键得以稳定。用酰胺(8q)取代硫代酰胺(8k)导致NO抑制效力下降83倍。这突出了涉及硫代酰胺基团的氢键的重要作用。与酰胺连接体相比，结构形状差异导致含硫代酰胺连接体的喹唑啉酮与靶受体具有良好的相互作用。此外，预测这三种先导化合物的药物代谢动力学(ADMET)特征和理化性质符合类药性质标准。因此，这些化合物可能是治疗许多与免疫紊乱相关的炎症性疾病的潜在候选药物。
